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Slide 1 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010
Slide 2 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information
Slide 3 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge
Slide 4 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor
Slide 5 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity
Slide 6 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy
Slide 7 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups
Slide 8 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance
Slide 9 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance HIPAA Health Insurance Portability and Accountability Act, April 2003. Protects information about the physical or mental health of an individual relating to health, health care, or payment for care in the past, present or future.
Slide 10 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance HIPAA Health Insurance Portability and Accountability Act, April 2003. Protects information about the physical or mental health of an individual relating to health, health care, or payment for care in the past, present or future. Institutional Review Boards (IRB) Protects the rights and welfare of research subjects Oversees the conduct of all human research Ensures compliance with all federal, state, local and institutional requirements in human subject research. Includes members of the community
Slide 11 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance HIPAA Health Insurance Portability and Accountability Act, April 2003. Protects information about the physical or mental health of an individual relating to health, health care, or payment for care in the past, present or future. Institutional Review Boards (IRB) Protects the rights and welfare of research subjects Oversees the conduct of all human research Ensures compliance with all federal, state, local and institutional requirements in human subject research. Includes members of the community Principles governing clinical trials Regulatory codes place the responsibility for the ethical conduct of research on the shoulders of researchers Autonomy Informed consent Confidentiality Comprehension Voluntariness Beneficience Risks-to-Benefit Ratio Research Design (minimizing risk) Investigator Qualifications Conflicts of Interest Justice Balance of Burdens/Benefits Population of Inference Eligibility Criteria Representative of Population Equitable Recruitment Methods
Slide 12 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance HIPAA Health Insurance Portability and Accountability Act, April 2003. Protects information about the physical or mental health of an individual relating to health, health care, or payment for care in the past, present or future. Institutional Review Boards (IRB) Protects the rights and welfare of research subjects Oversees the conduct of all human research Ensures compliance with all federal, state, local and institutional requirements in human subject research. Includes members of the community Principles governing clinical trials Regulatory codes place the responsibility for the ethical conduct of research on the shoulders of researchers Autonomy Informed consent Confidentiality Comprehension Voluntariness Beneficience Risks-to-Benefit Ratio Research Design (minimizing risk) Investigator Qualifications Conflicts of Interest Justice Balance of Burdens/Benefits Population of Inference Eligibility Criteria Representative of Population Equitable Recruitment Methods Informed Consent Purpose Methods and procedures in detail Risks and discomforts Risk of disease vs risk of study participation Benefits Alternatives to participation Voluntary and uncoerced
Slide 13 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance HIPAA Health Insurance Portability and Accountability Act, April 2003. Protects information about the physical or mental health of an individual relating to health, health care, or payment for care in the past, present or future. Institutional Review Boards (IRB) Protects the rights and welfare of research subjects Oversees the conduct of all human research Ensures compliance with all federal, state, local and institutional requirements in human subject research. Includes members of the community Principles governing clinical trials Regulatory codes place the responsibility for the ethical conduct of research on the shoulders of researchers Autonomy Informed consent Confidentiality Comprehension Voluntariness Beneficience Risks-to-Benefit Ratio Research Design (minimizing risk) Investigator Qualifications Conflicts of Interest Justice Balance of Burdens/Benefits Population of Inference Eligibility Criteria Representative of Population Equitable Recruitment Methods Informed Consent Purpose Methods and procedures in detail Risks and discomforts Risk of disease vs risk of study participation Benefits Alternatives to participation Voluntary and uncoerced Randomization Provides the best assurance that prognostic factors, both measured and unmeasured, are similar in treatment and control groups Provides the most credible evidence of treatment effects Placebo control is optimal to evaluate new treatments Only appropriate when no known effective treatment is available
Slide 14 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance HIPAA Health Insurance Portability and Accountability Act, April 2003. Protects information about the physical or mental health of an individual relating to health, health care, or payment for care in the past, present or future. Institutional Review Boards (IRB) Protects the rights and welfare of research subjects Oversees the conduct of all human research Ensures compliance with all federal, state, local and institutional requirements in human subject research. Includes members of the community Principles governing clinical trials Regulatory codes place the responsibility for the ethical conduct of research on the shoulders of researchers Autonomy Informed consent Confidentiality Comprehension Voluntariness Beneficience Risks-to-Benefit Ratio Research Design (minimizing risk) Investigator Qualifications Conflicts of Interest Justice Balance of Burdens/Benefits Population of Inference Eligibility Criteria Representative of Population Equitable Recruitment Methods Informed Consent Purpose Methods and procedures in detail Risks and discomforts Risk of disease vs risk of study participation Benefits Alternatives to participation Voluntary and uncoerced Randomization Provides the best assurance that prognostic factors, both measured and unmeasured, are similar in treatment and control groups Provides the most credible evidence of treatment effects Placebo control is optimal to evaluate new treatments Only appropriate when no known effective treatment is available Blinding Limits possible bias Patient response Physician attitude Outcome evaluation Decision-making during study Single-blind: treating physician knows but patient doesn’t Double-blind: neither the treating physician nor the patient knows
Slide 15 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance HIPAA Health Insurance Portability and Accountability Act, April 2003. Protects information about the physical or mental health of an individual relating to health, health care, or payment for care in the past, present or future. Institutional Review Boards (IRB) Protects the rights and welfare of research subjects Oversees the conduct of all human research Ensures compliance with all federal, state, local and institutional requirements in human subject research. Includes members of the community Principles governing clinical trials Regulatory codes place the responsibility for the ethical conduct of research on the shoulders of researchers Autonomy Informed consent Confidentiality Comprehension Voluntariness Beneficience Risks-to-Benefit Ratio Research Design (minimizing risk) Investigator Qualifications Conflicts of Interest Justice Balance of Burdens/Benefits Population of Inference Eligibility Criteria Representative of Population Equitable Recruitment Methods Informed Consent Purpose Methods and procedures in detail Risks and discomforts Risk of disease vs risk of study participation Benefits Alternatives to participation Voluntary and uncoerced Randomization Provides the best assurance that prognostic factors, both measured and unmeasured, are similar in treatment and control groups Provides the most credible evidence of treatment effects Placebo control is optimal to evaluate new treatments Only appropriate when no known effective treatment is available Blinding Limits possible bias Patient response Physician attitude Outcome evaluation Decision-making during study Single-blind: treating physician knows but patient doesn’t Double-blind: neither the treating physician nor the patient knows Phases Phase I Trials: maximally tolerated dose Safety and tolerability Uncontrolled, unblinded Not randomized Phase II Trials: evaluate for evidence of a clinical effect Dose-finding (and continued safety) (dose dependence) Controlled or uncontrolled; may be blinded or unblinded Randomized or not randomized Phase III Trials: test whether a new treatment is superior Therapeutic ratio (and continued safety) (Drug x compared to drug y) Control is placebo or standard of care. Blinded Randomized Phase IV Trials: post-marketing surveillance (safety)
Slide 16 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance HIPAA Health Insurance Portability and Accountability Act, April 2003. Protects information about the physical or mental health of an individual relating to health, health care, or payment for care in the past, present or future. Institutional Review Boards (IRB) Protects the rights and welfare of research subjects Oversees the conduct of all human research Ensures compliance with all federal, state, local and institutional requirements in human subject research. Includes members of the community Principles governing clinical trials Regulatory codes place the responsibility for the ethical conduct of research on the shoulders of researchers Autonomy Informed consent Confidentiality Comprehension Voluntariness Beneficience Risks-to-Benefit Ratio Research Design (minimizing risk) Investigator Qualifications Conflicts of Interest Justice Balance of Burdens/Benefits Population of Inference Eligibility Criteria Representative of Population Equitable Recruitment Methods Informed Consent Purpose Methods and procedures in detail Risks and discomforts Risk of disease vs risk of study participation Benefits Alternatives to participation Voluntary and uncoerced Randomization Provides the best assurance that prognostic factors, both measured and unmeasured, are similar in treatment and control groups Provides the most credible evidence of treatment effects Placebo control is optimal to evaluate new treatments Only appropriate when no known effective treatment is available Blinding Limits possible bias Patient response Physician attitude Outcome evaluation Decision-making during study Single-blind: treating physician knows but patient doesn’t Double-blind: neither the treating physician nor the patient knows Phases Phase I Trials: maximally tolerated dose Safety and tolerability Uncontrolled, unblinded Not randomized Phase II Trials: evaluate for evidence of a clinical effect Dose-finding (and continued safety) (dose dependence) Controlled or uncontrolled; may be blinded or unblinded Randomized or not randomized Phase III Trials: test whether a new treatment is superior Therapeutic ratio (and continued safety) (Drug x compared to drug y) Control is placebo or standard of care. Blinded Randomized Phase IV Trials: post-marketing surveillance (safety) Eligibility Disease type Prior therapy Performance status Evidence of adequate renal and hepatic function Measurable disease Prior malignancies
Slide 17 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance HIPAA Health Insurance Portability and Accountability Act, April 2003. Protects information about the physical or mental health of an individual relating to health, health care, or payment for care in the past, present or future. Institutional Review Boards (IRB) Protects the rights and welfare of research subjects Oversees the conduct of all human research Ensures compliance with all federal, state, local and institutional requirements in human subject research. Includes members of the community Principles governing clinical trials Regulatory codes place the responsibility for the ethical conduct of research on the shoulders of researchers Autonomy Informed consent Confidentiality Comprehension Voluntariness Beneficience Risks-to-Benefit Ratio Research Design (minimizing risk) Investigator Qualifications Conflicts of Interest Justice Balance of Burdens/Benefits Population of Inference Eligibility Criteria Representative of Population Equitable Recruitment Methods Informed Consent Purpose Methods and procedures in detail Risks and discomforts Risk of disease vs risk of study participation Benefits Alternatives to participation Voluntary and uncoerced Randomization Provides the best assurance that prognostic factors, both measured and unmeasured, are similar in treatment and control groups Provides the most credible evidence of treatment effects Placebo control is optimal to evaluate new treatments Only appropriate when no known effective treatment is available Blinding Limits possible bias Patient response Physician attitude Outcome evaluation Decision-making during study Single-blind: treating physician knows but patient doesn’t Double-blind: neither the treating physician nor the patient knows Phases Phase I Trials: maximally tolerated dose Safety and tolerability Uncontrolled, unblinded Not randomized Phase II Trials: evaluate for evidence of a clinical effect Dose-finding (and continued safety) (dose dependence) Controlled or uncontrolled; may be blinded or unblinded Randomized or not randomized Phase III Trials: test whether a new treatment is superior Therapeutic ratio (and continued safety) (Drug x compared to drug y) Control is placebo or standard of care. Blinded Randomized Phase IV Trials: post-marketing surveillance (safety) Eligibility Disease type Prior therapy Performance status Evidence of adequate renal and hepatic function Measurable disease Prior malignancies Study Endpoints Adverse events standard criteria to categorize as: none, mild, moderate, severe, life-threatening Response Progressive disease Stable disease Parital response: decrease in the size of measurable disease by 50% Complete response Progression-free survival Overall survival Quality of life
Slide 18 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance HIPAA Health Insurance Portability and Accountability Act, April 2003. Protects information about the physical or mental health of an individual relating to health, health care, or payment for care in the past, present or future. Institutional Review Boards (IRB) Protects the rights and welfare of research subjects Oversees the conduct of all human research Ensures compliance with all federal, state, local and institutional requirements in human subject research. Includes members of the community Principles governing clinical trials Regulatory codes place the responsibility for the ethical conduct of research on the shoulders of researchers Autonomy Informed consent Confidentiality Comprehension Voluntariness Beneficience Risks-to-Benefit Ratio Research Design (minimizing risk) Investigator Qualifications Conflicts of Interest Justice Balance of Burdens/Benefits Population of Inference Eligibility Criteria Representative of Population Equitable Recruitment Methods Informed Consent Purpose Methods and procedures in detail Risks and discomforts Risk of disease vs risk of study participation Benefits Alternatives to participation Voluntary and uncoerced Randomization Provides the best assurance that prognostic factors, both measured and unmeasured, are similar in treatment and control groups Provides the most credible evidence of treatment effects Placebo control is optimal to evaluate new treatments Only appropriate when no known effective treatment is available Blinding Limits possible bias Patient response Physician attitude Outcome evaluation Decision-making during study Single-blind: treating physician knows but patient doesn’t Double-blind: neither the treating physician nor the patient knows Phases Phase I Trials: maximally tolerated dose Safety and tolerability Uncontrolled, unblinded Not randomized Phase II Trials: evaluate for evidence of a clinical effect Dose-finding (and continued safety) (dose dependence) Controlled or uncontrolled; may be blinded or unblinded Randomized or not randomized Phase III Trials: test whether a new treatment is superior Therapeutic ratio (and continued safety) (Drug x compared to drug y) Control is placebo or standard of care. Blinded Randomized Phase IV Trials: post-marketing surveillance (safety) Eligibility Disease type Prior therapy Performance status Evidence of adequate renal and hepatic function Measurable disease Prior malignancies Study Endpoints Adverse events standard criteria to categorize as: none, mild, moderate, severe, life-threatening Response Progressive disease Stable disease Parital response: decrease in the size of measurable disease by 50% Complete response Progression-free survival Overall survival Quality of life Early stopping rules To avoid subjecting participants to ineffective therapy Interim analysis: No effect, stop the trial Significant effect, stop the trial Intermediate, continue accrual.
Slide 19 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance HIPAA Health Insurance Portability and Accountability Act, April 2003. Protects information about the physical or mental health of an individual relating to health, health care, or payment for care in the past, present or future. Institutional Review Boards (IRB) Protects the rights and welfare of research subjects Oversees the conduct of all human research Ensures compliance with all federal, state, local and institutional requirements in human subject research. Includes members of the community Principles governing clinical trials Regulatory codes place the responsibility for the ethical conduct of research on the shoulders of researchers Autonomy Informed consent Confidentiality Comprehension Voluntariness Beneficience Risks-to-Benefit Ratio Research Design (minimizing risk) Investigator Qualifications Conflicts of Interest Justice Balance of Burdens/Benefits Population of Inference Eligibility Criteria Representative of Population Equitable Recruitment Methods Informed Consent Purpose Methods and procedures in detail Risks and discomforts Risk of disease vs risk of study participation Benefits Alternatives to participation Voluntary and uncoerced Randomization Provides the best assurance that prognostic factors, both measured and unmeasured, are similar in treatment and control groups Provides the most credible evidence of treatment effects Placebo control is optimal to evaluate new treatments Only appropriate when no known effective treatment is available Blinding Limits possible bias Patient response Physician attitude Outcome evaluation Decision-making during study Single-blind: treating physician knows but patient doesn’t Double-blind: neither the treating physician nor the patient knows Phases Phase I Trials: maximally tolerated dose Safety and tolerability Uncontrolled, unblinded Not randomized Phase II Trials: evaluate for evidence of a clinical effect Dose-finding (and continued safety) (dose dependence) Controlled or uncontrolled; may be blinded or unblinded Randomized or not randomized Phase III Trials: test whether a new treatment is superior Therapeutic ratio (and continued safety) (Drug x compared to drug y) Control is placebo or standard of care. Blinded Randomized Phase IV Trials: post-marketing surveillance (safety) Eligibility Disease type Prior therapy Performance status Evidence of adequate renal and hepatic function Measurable disease Prior malignancies Study Endpoints Adverse events standard criteria to categorize as: none, mild, moderate, severe, life-threatening Response Progressive disease Stable disease Parital response: decrease in the size of measurable disease by 50% Complete response Progression-free survival Overall survival Quality of life Early stopping rules To avoid subjecting participants to ineffective therapy Interim analysis: No effect, stop the trial Significant effect, stop the trial Intermediate, continue accrual. Landmark clinical trials in the treatment of ovarian cancer
Slide 20 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance HIPAA Health Insurance Portability and Accountability Act, April 2003. Protects information about the physical or mental health of an individual relating to health, health care, or payment for care in the past, present or future. Institutional Review Boards (IRB) Protects the rights and welfare of research subjects Oversees the conduct of all human research Ensures compliance with all federal, state, local and institutional requirements in human subject research. Includes members of the community Principles governing clinical trials Regulatory codes place the responsibility for the ethical conduct of research on the shoulders of researchers Autonomy Informed consent Confidentiality Comprehension Voluntariness Beneficience Risks-to-Benefit Ratio Research Design (minimizing risk) Investigator Qualifications Conflicts of Interest Justice Balance of Burdens/Benefits Population of Inference Eligibility Criteria Representative of Population Equitable Recruitment Methods Informed Consent Purpose Methods and procedures in detail Risks and discomforts Risk of disease vs risk of study participation Benefits Alternatives to participation Voluntary and uncoerced Randomization Provides the best assurance that prognostic factors, both measured and unmeasured, are similar in treatment and control groups Provides the most credible evidence of treatment effects Placebo control is optimal to evaluate new treatments Only appropriate when no known effective treatment is available Blinding Limits possible bias Patient response Physician attitude Outcome evaluation Decision-making during study Single-blind: treating physician knows but patient doesn’t Double-blind: neither the treating physician nor the patient knows Phases Phase I Trials: maximally tolerated dose Safety and tolerability Uncontrolled, unblinded Not randomized Phase II Trials: evaluate for evidence of a clinical effect Dose-finding (and continued safety) (dose dependence) Controlled or uncontrolled; may be blinded or unblinded Randomized or not randomized Phase III Trials: test whether a new treatment is superior Therapeutic ratio (and continued safety) (Drug x compared to drug y) Control is placebo or standard of care. Blinded Randomized Phase IV Trials: post-marketing surveillance (safety) Eligibility Disease type Prior therapy Performance status Evidence of adequate renal and hepatic function Measurable disease Prior malignancies Study Endpoints Adverse events standard criteria to categorize as: none, mild, moderate, severe, life-threatening Response Progressive disease Stable disease Parital response: decrease in the size of measurable disease by 50% Complete response Progression-free survival Overall survival Quality of life Early stopping rules To avoid subjecting participants to ineffective therapy Interim analysis: No effect, stop the trial Significant effect, stop the trial Intermediate, continue accrual. Landmark clinical trials in the treatment of ovarian cancer Suboptimal Stage III and any stage IV GOG 111 trial established platinum/taxane combination therapy as the standard of care RANDOMIZE Cisplatin (75 mg/m2 q21d x 6) PLUS Cyclophosphamide (750 mg/m2) Cisplatin (75 mg/m2 q21d x 6) PLUS Paclitaxel (135 mg/m2/24h)
Slide 21 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance HIPAA Health Insurance Portability and Accountability Act, April 2003. Protects information about the physical or mental health of an individual relating to health, health care, or payment for care in the past, present or future. Institutional Review Boards (IRB) Protects the rights and welfare of research subjects Oversees the conduct of all human research Ensures compliance with all federal, state, local and institutional requirements in human subject research. Includes members of the community Principles governing clinical trials Regulatory codes place the responsibility for the ethical conduct of research on the shoulders of researchers Autonomy Informed consent Confidentiality Comprehension Voluntariness Beneficience Risks-to-Benefit Ratio Research Design (minimizing risk) Investigator Qualifications Conflicts of Interest Justice Balance of Burdens/Benefits Population of Inference Eligibility Criteria Representative of Population Equitable Recruitment Methods Informed Consent Purpose Methods and procedures in detail Risks and discomforts Risk of disease vs risk of study participation Benefits Alternatives to participation Voluntary and uncoerced Randomization Provides the best assurance that prognostic factors, both measured and unmeasured, are similar in treatment and control groups Provides the most credible evidence of treatment effects Placebo control is optimal to evaluate new treatments Only appropriate when no known effective treatment is available Blinding Limits possible bias Patient response Physician attitude Outcome evaluation Decision-making during study Single-blind: treating physician knows but patient doesn’t Double-blind: neither the treating physician nor the patient knows Phases Phase I Trials: maximally tolerated dose Safety and tolerability Uncontrolled, unblinded Not randomized Phase II Trials: evaluate for evidence of a clinical effect Dose-finding (and continued safety) (dose dependence) Controlled or uncontrolled; may be blinded or unblinded Randomized or not randomized Phase III Trials: test whether a new treatment is superior Therapeutic ratio (and continued safety) (Drug x compared to drug y) Control is placebo or standard of care. Blinded Randomized Phase IV Trials: post-marketing surveillance (safety) Eligibility Disease type Prior therapy Performance status Evidence of adequate renal and hepatic function Measurable disease Prior malignancies Study Endpoints Adverse events standard criteria to categorize as: none, mild, moderate, severe, life-threatening Response Progressive disease Stable disease Parital response: decrease in the size of measurable disease by 50% Complete response Progression-free survival Overall survival Quality of life Early stopping rules To avoid subjecting participants to ineffective therapy Interim analysis: No effect, stop the trial Significant effect, stop the trial Intermediate, continue accrual. Landmark clinical trials in the treatment of ovarian cancer Suboptimal Stage III and any stage IV GOG 111 trial established platinum/taxane combination therapy as the standard of care RANDOMIZE Cisplatin (75 mg/m2 q21d x 6) PLUS Cyclophosphamide (750 mg/m2) Cisplatin (75 mg/m2 q21d x 6) PLUS Paclitaxel (135 mg/m2/24h) GOG 111: progression-free survival Patients (N) Proportion Surviving Progression Free 6 12 18 24 30 36 42 48 Months After Study Entry 54 60 66 72 78 84 0.8 0.9 0 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Cisplatin/Paclitaxel Cisplatin/ Cyclophosphamide Treatment Progression- Free 18 15 166 187 Failure 184 202 Total Median Survival 18.0 13.3 Relative Risk 0.70 – McGuire, NEJM, 1996
Slide 22 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance HIPAA Health Insurance Portability and Accountability Act, April 2003. Protects information about the physical or mental health of an individual relating to health, health care, or payment for care in the past, present or future. Institutional Review Boards (IRB) Protects the rights and welfare of research subjects Oversees the conduct of all human research Ensures compliance with all federal, state, local and institutional requirements in human subject research. Includes members of the community Principles governing clinical trials Regulatory codes place the responsibility for the ethical conduct of research on the shoulders of researchers Autonomy Informed consent Confidentiality Comprehension Voluntariness Beneficience Risks-to-Benefit Ratio Research Design (minimizing risk) Investigator Qualifications Conflicts of Interest Justice Balance of Burdens/Benefits Population of Inference Eligibility Criteria Representative of Population Equitable Recruitment Methods Informed Consent Purpose Methods and procedures in detail Risks and discomforts Risk of disease vs risk of study participation Benefits Alternatives to participation Voluntary and uncoerced Randomization Provides the best assurance that prognostic factors, both measured and unmeasured, are similar in treatment and control groups Provides the most credible evidence of treatment effects Placebo control is optimal to evaluate new treatments Only appropriate when no known effective treatment is available Blinding Limits possible bias Patient response Physician attitude Outcome evaluation Decision-making during study Single-blind: treating physician knows but patient doesn’t Double-blind: neither the treating physician nor the patient knows Phases Phase I Trials: maximally tolerated dose Safety and tolerability Uncontrolled, unblinded Not randomized Phase II Trials: evaluate for evidence of a clinical effect Dose-finding (and continued safety) (dose dependence) Controlled or uncontrolled; may be blinded or unblinded Randomized or not randomized Phase III Trials: test whether a new treatment is superior Therapeutic ratio (and continued safety) (Drug x compared to drug y) Control is placebo or standard of care. Blinded Randomized Phase IV Trials: post-marketing surveillance (safety) Eligibility Disease type Prior therapy Performance status Evidence of adequate renal and hepatic function Measurable disease Prior malignancies Study Endpoints Adverse events standard criteria to categorize as: none, mild, moderate, severe, life-threatening Response Progressive disease Stable disease Parital response: decrease in the size of measurable disease by 50% Complete response Progression-free survival Overall survival Quality of life Early stopping rules To avoid subjecting participants to ineffective therapy Interim analysis: No effect, stop the trial Significant effect, stop the trial Intermediate, continue accrual. Landmark clinical trials in the treatment of ovarian cancer Suboptimal Stage III and any stage IV GOG 111 trial established platinum/taxane combination therapy as the standard of care RANDOMIZE Cisplatin (75 mg/m2 q21d x 6) PLUS Cyclophosphamide (750 mg/m2) Cisplatin (75 mg/m2 q21d x 6) PLUS Paclitaxel (135 mg/m2/24h) GOG 111: progression-free survival Patients (N) Proportion Surviving Progression Free 6 12 18 24 30 36 42 48 Months After Study Entry 54 60 66 72 78 84 0.8 0.9 0 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Cisplatin/Paclitaxel Cisplatin/ Cyclophosphamide Treatment Progression- Free 18 15 166 187 Failure 184 202 Total Median Survival 18.0 13.3 Relative Risk 0.70 – McGuire, NEJM, 1996 GOG 111: overall survival 0.8 0.9 0 6 12 18 24 30 36 42 48 Months from entry into study Proportion surviving Cisplatin/paclitaxel Cisplatin/ cyclophosphamide 54 60 66 72 78 84 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Treatment Alive 35 28 150 174 Died 184 202 Total Median Survival (mos) 36.9 24.8 Relative Risk 0.69 – No. Pts McGuire, NEJM, 1996
Slide 23 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance HIPAA Health Insurance Portability and Accountability Act, April 2003. Protects information about the physical or mental health of an individual relating to health, health care, or payment for care in the past, present or future. Institutional Review Boards (IRB) Protects the rights and welfare of research subjects Oversees the conduct of all human research Ensures compliance with all federal, state, local and institutional requirements in human subject research. Includes members of the community Principles governing clinical trials Regulatory codes place the responsibility for the ethical conduct of research on the shoulders of researchers Autonomy Informed consent Confidentiality Comprehension Voluntariness Beneficience Risks-to-Benefit Ratio Research Design (minimizing risk) Investigator Qualifications Conflicts of Interest Justice Balance of Burdens/Benefits Population of Inference Eligibility Criteria Representative of Population Equitable Recruitment Methods Informed Consent Purpose Methods and procedures in detail Risks and discomforts Risk of disease vs risk of study participation Benefits Alternatives to participation Voluntary and uncoerced Randomization Provides the best assurance that prognostic factors, both measured and unmeasured, are similar in treatment and control groups Provides the most credible evidence of treatment effects Placebo control is optimal to evaluate new treatments Only appropriate when no known effective treatment is available Blinding Limits possible bias Patient response Physician attitude Outcome evaluation Decision-making during study Single-blind: treating physician knows but patient doesn’t Double-blind: neither the treating physician nor the patient knows Phases Phase I Trials: maximally tolerated dose Safety and tolerability Uncontrolled, unblinded Not randomized Phase II Trials: evaluate for evidence of a clinical effect Dose-finding (and continued safety) (dose dependence) Controlled or uncontrolled; may be blinded or unblinded Randomized or not randomized Phase III Trials: test whether a new treatment is superior Therapeutic ratio (and continued safety) (Drug x compared to drug y) Control is placebo or standard of care. Blinded Randomized Phase IV Trials: post-marketing surveillance (safety) Eligibility Disease type Prior therapy Performance status Evidence of adequate renal and hepatic function Measurable disease Prior malignancies Study Endpoints Adverse events standard criteria to categorize as: none, mild, moderate, severe, life-threatening Response Progressive disease Stable disease Parital response: decrease in the size of measurable disease by 50% Complete response Progression-free survival Overall survival Quality of life Early stopping rules To avoid subjecting participants to ineffective therapy Interim analysis: No effect, stop the trial Significant effect, stop the trial Intermediate, continue accrual. Landmark clinical trials in the treatment of ovarian cancer Suboptimal Stage III and any stage IV GOG 111 trial established platinum/taxane combination therapy as the standard of care RANDOMIZE Cisplatin (75 mg/m2 q21d x 6) PLUS Cyclophosphamide (750 mg/m2) Cisplatin (75 mg/m2 q21d x 6) PLUS Paclitaxel (135 mg/m2/24h) GOG 111: progression-free survival Patients (N) Proportion Surviving Progression Free 6 12 18 24 30 36 42 48 Months After Study Entry 54 60 66 72 78 84 0.8 0.9 0 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Cisplatin/Paclitaxel Cisplatin/ Cyclophosphamide Treatment Progression- Free 18 15 166 187 Failure 184 202 Total Median Survival 18.0 13.3 Relative Risk 0.70 – McGuire, NEJM, 1996 GOG 111: overall survival 0.8 0.9 0 6 12 18 24 30 36 42 48 Months from entry into study Proportion surviving Cisplatin/paclitaxel Cisplatin/ cyclophosphamide 54 60 66 72 78 84 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Treatment Alive 35 28 150 174 Died 184 202 Total Median Survival (mos) 36.9 24.8 Relative Risk 0.69 – No. Pts McGuire, NEJM, 1996 Substituting taxol for cytoxan improved survival Piccart, JNCI, 2000 McGuire, NEJM, 1996 *p<0.001
Slide 24 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance HIPAA Health Insurance Portability and Accountability Act, April 2003. Protects information about the physical or mental health of an individual relating to health, health care, or payment for care in the past, present or future. Institutional Review Boards (IRB) Protects the rights and welfare of research subjects Oversees the conduct of all human research Ensures compliance with all federal, state, local and institutional requirements in human subject research. Includes members of the community Principles governing clinical trials Regulatory codes place the responsibility for the ethical conduct of research on the shoulders of researchers Autonomy Informed consent Confidentiality Comprehension Voluntariness Beneficience Risks-to-Benefit Ratio Research Design (minimizing risk) Investigator Qualifications Conflicts of Interest Justice Balance of Burdens/Benefits Population of Inference Eligibility Criteria Representative of Population Equitable Recruitment Methods Informed Consent Purpose Methods and procedures in detail Risks and discomforts Risk of disease vs risk of study participation Benefits Alternatives to participation Voluntary and uncoerced Randomization Provides the best assurance that prognostic factors, both measured and unmeasured, are similar in treatment and control groups Provides the most credible evidence of treatment effects Placebo control is optimal to evaluate new treatments Only appropriate when no known effective treatment is available Blinding Limits possible bias Patient response Physician attitude Outcome evaluation Decision-making during study Single-blind: treating physician knows but patient doesn’t Double-blind: neither the treating physician nor the patient knows Phases Phase I Trials: maximally tolerated dose Safety and tolerability Uncontrolled, unblinded Not randomized Phase II Trials: evaluate for evidence of a clinical effect Dose-finding (and continued safety) (dose dependence) Controlled or uncontrolled; may be blinded or unblinded Randomized or not randomized Phase III Trials: test whether a new treatment is superior Therapeutic ratio (and continued safety) (Drug x compared to drug y) Control is placebo or standard of care. Blinded Randomized Phase IV Trials: post-marketing surveillance (safety) Eligibility Disease type Prior therapy Performance status Evidence of adequate renal and hepatic function Measurable disease Prior malignancies Study Endpoints Adverse events standard criteria to categorize as: none, mild, moderate, severe, life-threatening Response Progressive disease Stable disease Parital response: decrease in the size of measurable disease by 50% Complete response Progression-free survival Overall survival Quality of life Early stopping rules To avoid subjecting participants to ineffective therapy Interim analysis: No effect, stop the trial Significant effect, stop the trial Intermediate, continue accrual. Landmark clinical trials in the treatment of ovarian cancer Suboptimal Stage III and any stage IV GOG 111 trial established platinum/taxane combination therapy as the standard of care RANDOMIZE Cisplatin (75 mg/m2 q21d x 6) PLUS Cyclophosphamide (750 mg/m2) Cisplatin (75 mg/m2 q21d x 6) PLUS Paclitaxel (135 mg/m2/24h) GOG 111: progression-free survival Patients (N) Proportion Surviving Progression Free 6 12 18 24 30 36 42 48 Months After Study Entry 54 60 66 72 78 84 0.8 0.9 0 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Cisplatin/Paclitaxel Cisplatin/ Cyclophosphamide Treatment Progression- Free 18 15 166 187 Failure 184 202 Total Median Survival 18.0 13.3 Relative Risk 0.70 – McGuire, NEJM, 1996 GOG 111: overall survival 0.8 0.9 0 6 12 18 24 30 36 42 48 Months from entry into study Proportion surviving Cisplatin/paclitaxel Cisplatin/ cyclophosphamide 54 60 66 72 78 84 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Treatment Alive 35 28 150 174 Died 184 202 Total Median Survival (mos) 36.9 24.8 Relative Risk 0.69 – No. Pts McGuire, NEJM, 1996 Substituting taxol for cytoxan improved survival Piccart, JNCI, 2000 McGuire, NEJM, 1996 *p<0.001 GOG 158: Is carboplatin as effective as cisplatin? Ozols, JCO, 2003
Slide 25 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance HIPAA Health Insurance Portability and Accountability Act, April 2003. Protects information about the physical or mental health of an individual relating to health, health care, or payment for care in the past, present or future. Institutional Review Boards (IRB) Protects the rights and welfare of research subjects Oversees the conduct of all human research Ensures compliance with all federal, state, local and institutional requirements in human subject research. Includes members of the community Principles governing clinical trials Regulatory codes place the responsibility for the ethical conduct of research on the shoulders of researchers Autonomy Informed consent Confidentiality Comprehension Voluntariness Beneficience Risks-to-Benefit Ratio Research Design (minimizing risk) Investigator Qualifications Conflicts of Interest Justice Balance of Burdens/Benefits Population of Inference Eligibility Criteria Representative of Population Equitable Recruitment Methods Informed Consent Purpose Methods and procedures in detail Risks and discomforts Risk of disease vs risk of study participation Benefits Alternatives to participation Voluntary and uncoerced Randomization Provides the best assurance that prognostic factors, both measured and unmeasured, are similar in treatment and control groups Provides the most credible evidence of treatment effects Placebo control is optimal to evaluate new treatments Only appropriate when no known effective treatment is available Blinding Limits possible bias Patient response Physician attitude Outcome evaluation Decision-making during study Single-blind: treating physician knows but patient doesn’t Double-blind: neither the treating physician nor the patient knows Phases Phase I Trials: maximally tolerated dose Safety and tolerability Uncontrolled, unblinded Not randomized Phase II Trials: evaluate for evidence of a clinical effect Dose-finding (and continued safety) (dose dependence) Controlled or uncontrolled; may be blinded or unblinded Randomized or not randomized Phase III Trials: test whether a new treatment is superior Therapeutic ratio (and continued safety) (Drug x compared to drug y) Control is placebo or standard of care. Blinded Randomized Phase IV Trials: post-marketing surveillance (safety) Eligibility Disease type Prior therapy Performance status Evidence of adequate renal and hepatic function Measurable disease Prior malignancies Study Endpoints Adverse events standard criteria to categorize as: none, mild, moderate, severe, life-threatening Response Progressive disease Stable disease Parital response: decrease in the size of measurable disease by 50% Complete response Progression-free survival Overall survival Quality of life Early stopping rules To avoid subjecting participants to ineffective therapy Interim analysis: No effect, stop the trial Significant effect, stop the trial Intermediate, continue accrual. Landmark clinical trials in the treatment of ovarian cancer Suboptimal Stage III and any stage IV GOG 111 trial established platinum/taxane combination therapy as the standard of care RANDOMIZE Cisplatin (75 mg/m2 q21d x 6) PLUS Cyclophosphamide (750 mg/m2) Cisplatin (75 mg/m2 q21d x 6) PLUS Paclitaxel (135 mg/m2/24h) GOG 111: progression-free survival Patients (N) Proportion Surviving Progression Free 6 12 18 24 30 36 42 48 Months After Study Entry 54 60 66 72 78 84 0.8 0.9 0 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Cisplatin/Paclitaxel Cisplatin/ Cyclophosphamide Treatment Progression- Free 18 15 166 187 Failure 184 202 Total Median Survival 18.0 13.3 Relative Risk 0.70 – McGuire, NEJM, 1996 GOG 111: overall survival 0.8 0.9 0 6 12 18 24 30 36 42 48 Months from entry into study Proportion surviving Cisplatin/paclitaxel Cisplatin/ cyclophosphamide 54 60 66 72 78 84 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Treatment Alive 35 28 150 174 Died 184 202 Total Median Survival (mos) 36.9 24.8 Relative Risk 0.69 – No. Pts McGuire, NEJM, 1996 Substituting taxol for cytoxan improved survival Piccart, JNCI, 2000 McGuire, NEJM, 1996 *p<0.001 GOG 158: Is carboplatin as effective as cisplatin? Ozols, JCO, 2003 Outcome is the same, toxicity is different Ozols, JCO, 2003
Slide 26 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance HIPAA Health Insurance Portability and Accountability Act, April 2003. Protects information about the physical or mental health of an individual relating to health, health care, or payment for care in the past, present or future. Institutional Review Boards (IRB) Protects the rights and welfare of research subjects Oversees the conduct of all human research Ensures compliance with all federal, state, local and institutional requirements in human subject research. Includes members of the community Principles governing clinical trials Regulatory codes place the responsibility for the ethical conduct of research on the shoulders of researchers Autonomy Informed consent Confidentiality Comprehension Voluntariness Beneficience Risks-to-Benefit Ratio Research Design (minimizing risk) Investigator Qualifications Conflicts of Interest Justice Balance of Burdens/Benefits Population of Inference Eligibility Criteria Representative of Population Equitable Recruitment Methods Informed Consent Purpose Methods and procedures in detail Risks and discomforts Risk of disease vs risk of study participation Benefits Alternatives to participation Voluntary and uncoerced Randomization Provides the best assurance that prognostic factors, both measured and unmeasured, are similar in treatment and control groups Provides the most credible evidence of treatment effects Placebo control is optimal to evaluate new treatments Only appropriate when no known effective treatment is available Blinding Limits possible bias Patient response Physician attitude Outcome evaluation Decision-making during study Single-blind: treating physician knows but patient doesn’t Double-blind: neither the treating physician nor the patient knows Phases Phase I Trials: maximally tolerated dose Safety and tolerability Uncontrolled, unblinded Not randomized Phase II Trials: evaluate for evidence of a clinical effect Dose-finding (and continued safety) (dose dependence) Controlled or uncontrolled; may be blinded or unblinded Randomized or not randomized Phase III Trials: test whether a new treatment is superior Therapeutic ratio (and continued safety) (Drug x compared to drug y) Control is placebo or standard of care. Blinded Randomized Phase IV Trials: post-marketing surveillance (safety) Eligibility Disease type Prior therapy Performance status Evidence of adequate renal and hepatic function Measurable disease Prior malignancies Study Endpoints Adverse events standard criteria to categorize as: none, mild, moderate, severe, life-threatening Response Progressive disease Stable disease Parital response: decrease in the size of measurable disease by 50% Complete response Progression-free survival Overall survival Quality of life Early stopping rules To avoid subjecting participants to ineffective therapy Interim analysis: No effect, stop the trial Significant effect, stop the trial Intermediate, continue accrual. Landmark clinical trials in the treatment of ovarian cancer Suboptimal Stage III and any stage IV GOG 111 trial established platinum/taxane combination therapy as the standard of care RANDOMIZE Cisplatin (75 mg/m2 q21d x 6) PLUS Cyclophosphamide (750 mg/m2) Cisplatin (75 mg/m2 q21d x 6) PLUS Paclitaxel (135 mg/m2/24h) GOG 111: progression-free survival Patients (N) Proportion Surviving Progression Free 6 12 18 24 30 36 42 48 Months After Study Entry 54 60 66 72 78 84 0.8 0.9 0 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Cisplatin/Paclitaxel Cisplatin/ Cyclophosphamide Treatment Progression- Free 18 15 166 187 Failure 184 202 Total Median Survival 18.0 13.3 Relative Risk 0.70 – McGuire, NEJM, 1996 GOG 111: overall survival 0.8 0.9 0 6 12 18 24 30 36 42 48 Months from entry into study Proportion surviving Cisplatin/paclitaxel Cisplatin/ cyclophosphamide 54 60 66 72 78 84 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Treatment Alive 35 28 150 174 Died 184 202 Total Median Survival (mos) 36.9 24.8 Relative Risk 0.69 – No. Pts McGuire, NEJM, 1996 Substituting taxol for cytoxan improved survival Piccart, JNCI, 2000 McGuire, NEJM, 1996 *p<0.001 GOG 158: Is carboplatin as effective as cisplatin? Ozols, JCO, 2003 Outcome is the same, toxicity is different Ozols, JCO, 2003 Carboplatin and Taxol currently are standard chemotherapy for ovarian cancer.
Slide 27 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance HIPAA Health Insurance Portability and Accountability Act, April 2003. Protects information about the physical or mental health of an individual relating to health, health care, or payment for care in the past, present or future. Institutional Review Boards (IRB) Protects the rights and welfare of research subjects Oversees the conduct of all human research Ensures compliance with all federal, state, local and institutional requirements in human subject research. Includes members of the community Principles governing clinical trials Regulatory codes place the responsibility for the ethical conduct of research on the shoulders of researchers Autonomy Informed consent Confidentiality Comprehension Voluntariness Beneficience Risks-to-Benefit Ratio Research Design (minimizing risk) Investigator Qualifications Conflicts of Interest Justice Balance of Burdens/Benefits Population of Inference Eligibility Criteria Representative of Population Equitable Recruitment Methods Informed Consent Purpose Methods and procedures in detail Risks and discomforts Risk of disease vs risk of study participation Benefits Alternatives to participation Voluntary and uncoerced Randomization Provides the best assurance that prognostic factors, both measured and unmeasured, are similar in treatment and control groups Provides the most credible evidence of treatment effects Placebo control is optimal to evaluate new treatments Only appropriate when no known effective treatment is available Blinding Limits possible bias Patient response Physician attitude Outcome evaluation Decision-making during study Single-blind: treating physician knows but patient doesn’t Double-blind: neither the treating physician nor the patient knows Phases Phase I Trials: maximally tolerated dose Safety and tolerability Uncontrolled, unblinded Not randomized Phase II Trials: evaluate for evidence of a clinical effect Dose-finding (and continued safety) (dose dependence) Controlled or uncontrolled; may be blinded or unblinded Randomized or not randomized Phase III Trials: test whether a new treatment is superior Therapeutic ratio (and continued safety) (Drug x compared to drug y) Control is placebo or standard of care. Blinded Randomized Phase IV Trials: post-marketing surveillance (safety) Eligibility Disease type Prior therapy Performance status Evidence of adequate renal and hepatic function Measurable disease Prior malignancies Study Endpoints Adverse events standard criteria to categorize as: none, mild, moderate, severe, life-threatening Response Progressive disease Stable disease Parital response: decrease in the size of measurable disease by 50% Complete response Progression-free survival Overall survival Quality of life Early stopping rules To avoid subjecting participants to ineffective therapy Interim analysis: No effect, stop the trial Significant effect, stop the trial Intermediate, continue accrual. Landmark clinical trials in the treatment of ovarian cancer Suboptimal Stage III and any stage IV GOG 111 trial established platinum/taxane combination therapy as the standard of care RANDOMIZE Cisplatin (75 mg/m2 q21d x 6) PLUS Cyclophosphamide (750 mg/m2) Cisplatin (75 mg/m2 q21d x 6) PLUS Paclitaxel (135 mg/m2/24h) GOG 111: progression-free survival Patients (N) Proportion Surviving Progression Free 6 12 18 24 30 36 42 48 Months After Study Entry 54 60 66 72 78 84 0.8 0.9 0 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Cisplatin/Paclitaxel Cisplatin/ Cyclophosphamide Treatment Progression- Free 18 15 166 187 Failure 184 202 Total Median Survival 18.0 13.3 Relative Risk 0.70 – McGuire, NEJM, 1996 GOG 111: overall survival 0.8 0.9 0 6 12 18 24 30 36 42 48 Months from entry into study Proportion surviving Cisplatin/paclitaxel Cisplatin/ cyclophosphamide 54 60 66 72 78 84 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Treatment Alive 35 28 150 174 Died 184 202 Total Median Survival (mos) 36.9 24.8 Relative Risk 0.69 – No. Pts McGuire, NEJM, 1996 Substituting taxol for cytoxan improved survival Piccart, JNCI, 2000 McGuire, NEJM, 1996 *p<0.001 GOG 158: Is carboplatin as effective as cisplatin? Ozols, JCO, 2003 Outcome is the same, toxicity is different Ozols, JCO, 2003 Carboplatin and Taxol currently are standard chemotherapy for ovarian cancer. GOG 182: Is there anything to add to Carbo and taxol to improve outcomes?
Slide 28 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance HIPAA Health Insurance Portability and Accountability Act, April 2003. Protects information about the physical or mental health of an individual relating to health, health care, or payment for care in the past, present or future. Institutional Review Boards (IRB) Protects the rights and welfare of research subjects Oversees the conduct of all human research Ensures compliance with all federal, state, local and institutional requirements in human subject research. Includes members of the community Principles governing clinical trials Regulatory codes place the responsibility for the ethical conduct of research on the shoulders of researchers Autonomy Informed consent Confidentiality Comprehension Voluntariness Beneficience Risks-to-Benefit Ratio Research Design (minimizing risk) Investigator Qualifications Conflicts of Interest Justice Balance of Burdens/Benefits Population of Inference Eligibility Criteria Representative of Population Equitable Recruitment Methods Informed Consent Purpose Methods and procedures in detail Risks and discomforts Risk of disease vs risk of study participation Benefits Alternatives to participation Voluntary and uncoerced Randomization Provides the best assurance that prognostic factors, both measured and unmeasured, are similar in treatment and control groups Provides the most credible evidence of treatment effects Placebo control is optimal to evaluate new treatments Only appropriate when no known effective treatment is available Blinding Limits possible bias Patient response Physician attitude Outcome evaluation Decision-making during study Single-blind: treating physician knows but patient doesn’t Double-blind: neither the treating physician nor the patient knows Phases Phase I Trials: maximally tolerated dose Safety and tolerability Uncontrolled, unblinded Not randomized Phase II Trials: evaluate for evidence of a clinical effect Dose-finding (and continued safety) (dose dependence) Controlled or uncontrolled; may be blinded or unblinded Randomized or not randomized Phase III Trials: test whether a new treatment is superior Therapeutic ratio (and continued safety) (Drug x compared to drug y) Control is placebo or standard of care. Blinded Randomized Phase IV Trials: post-marketing surveillance (safety) Eligibility Disease type Prior therapy Performance status Evidence of adequate renal and hepatic function Measurable disease Prior malignancies Study Endpoints Adverse events standard criteria to categorize as: none, mild, moderate, severe, life-threatening Response Progressive disease Stable disease Parital response: decrease in the size of measurable disease by 50% Complete response Progression-free survival Overall survival Quality of life Early stopping rules To avoid subjecting participants to ineffective therapy Interim analysis: No effect, stop the trial Significant effect, stop the trial Intermediate, continue accrual. Landmark clinical trials in the treatment of ovarian cancer Suboptimal Stage III and any stage IV GOG 111 trial established platinum/taxane combination therapy as the standard of care RANDOMIZE Cisplatin (75 mg/m2 q21d x 6) PLUS Cyclophosphamide (750 mg/m2) Cisplatin (75 mg/m2 q21d x 6) PLUS Paclitaxel (135 mg/m2/24h) GOG 111: progression-free survival Patients (N) Proportion Surviving Progression Free 6 12 18 24 30 36 42 48 Months After Study Entry 54 60 66 72 78 84 0.8 0.9 0 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Cisplatin/Paclitaxel Cisplatin/ Cyclophosphamide Treatment Progression- Free 18 15 166 187 Failure 184 202 Total Median Survival 18.0 13.3 Relative Risk 0.70 – McGuire, NEJM, 1996 GOG 111: overall survival 0.8 0.9 0 6 12 18 24 30 36 42 48 Months from entry into study Proportion surviving Cisplatin/paclitaxel Cisplatin/ cyclophosphamide 54 60 66 72 78 84 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Treatment Alive 35 28 150 174 Died 184 202 Total Median Survival (mos) 36.9 24.8 Relative Risk 0.69 – No. Pts McGuire, NEJM, 1996 Substituting taxol for cytoxan improved survival Piccart, JNCI, 2000 McGuire, NEJM, 1996 *p<0.001 GOG 158: Is carboplatin as effective as cisplatin? Ozols, JCO, 2003 Outcome is the same, toxicity is different Ozols, JCO, 2003 Carboplatin and Taxol currently are standard chemotherapy for ovarian cancer. GOG 182: Is there anything to add to Carbo and taxol to improve outcomes? Does the route of administration make a difference? GOG 104: patients with optimally debulked stage III disease were randomized to IV cyclophosphamide and IV cisplatin or IV cyclophosphamide and IP cisplatin IP regimen was superior 25 vs 20% reponse rate 49 vs 41 month median survival Not widely adopted because standard of care shifted to carboplatin/taxol
Slide 29 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance HIPAA Health Insurance Portability and Accountability Act, April 2003. Protects information about the physical or mental health of an individual relating to health, health care, or payment for care in the past, present or future. Institutional Review Boards (IRB) Protects the rights and welfare of research subjects Oversees the conduct of all human research Ensures compliance with all federal, state, local and institutional requirements in human subject research. Includes members of the community Principles governing clinical trials Regulatory codes place the responsibility for the ethical conduct of research on the shoulders of researchers Autonomy Informed consent Confidentiality Comprehension Voluntariness Beneficience Risks-to-Benefit Ratio Research Design (minimizing risk) Investigator Qualifications Conflicts of Interest Justice Balance of Burdens/Benefits Population of Inference Eligibility Criteria Representative of Population Equitable Recruitment Methods Informed Consent Purpose Methods and procedures in detail Risks and discomforts Risk of disease vs risk of study participation Benefits Alternatives to participation Voluntary and uncoerced Randomization Provides the best assurance that prognostic factors, both measured and unmeasured, are similar in treatment and control groups Provides the most credible evidence of treatment effects Placebo control is optimal to evaluate new treatments Only appropriate when no known effective treatment is available Blinding Limits possible bias Patient response Physician attitude Outcome evaluation Decision-making during study Single-blind: treating physician knows but patient doesn’t Double-blind: neither the treating physician nor the patient knows Phases Phase I Trials: maximally tolerated dose Safety and tolerability Uncontrolled, unblinded Not randomized Phase II Trials: evaluate for evidence of a clinical effect Dose-finding (and continued safety) (dose dependence) Controlled or uncontrolled; may be blinded or unblinded Randomized or not randomized Phase III Trials: test whether a new treatment is superior Therapeutic ratio (and continued safety) (Drug x compared to drug y) Control is placebo or standard of care. Blinded Randomized Phase IV Trials: post-marketing surveillance (safety) Eligibility Disease type Prior therapy Performance status Evidence of adequate renal and hepatic function Measurable disease Prior malignancies Study Endpoints Adverse events standard criteria to categorize as: none, mild, moderate, severe, life-threatening Response Progressive disease Stable disease Parital response: decrease in the size of measurable disease by 50% Complete response Progression-free survival Overall survival Quality of life Early stopping rules To avoid subjecting participants to ineffective therapy Interim analysis: No effect, stop the trial Significant effect, stop the trial Intermediate, continue accrual. Landmark clinical trials in the treatment of ovarian cancer Suboptimal Stage III and any stage IV GOG 111 trial established platinum/taxane combination therapy as the standard of care RANDOMIZE Cisplatin (75 mg/m2 q21d x 6) PLUS Cyclophosphamide (750 mg/m2) Cisplatin (75 mg/m2 q21d x 6) PLUS Paclitaxel (135 mg/m2/24h) GOG 111: progression-free survival Patients (N) Proportion Surviving Progression Free 6 12 18 24 30 36 42 48 Months After Study Entry 54 60 66 72 78 84 0.8 0.9 0 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Cisplatin/Paclitaxel Cisplatin/ Cyclophosphamide Treatment Progression- Free 18 15 166 187 Failure 184 202 Total Median Survival 18.0 13.3 Relative Risk 0.70 – McGuire, NEJM, 1996 GOG 111: overall survival 0.8 0.9 0 6 12 18 24 30 36 42 48 Months from entry into study Proportion surviving Cisplatin/paclitaxel Cisplatin/ cyclophosphamide 54 60 66 72 78 84 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Treatment Alive 35 28 150 174 Died 184 202 Total Median Survival (mos) 36.9 24.8 Relative Risk 0.69 – No. Pts McGuire, NEJM, 1996 Substituting taxol for cytoxan improved survival Piccart, JNCI, 2000 McGuire, NEJM, 1996 *p<0.001 GOG 158: Is carboplatin as effective as cisplatin? Ozols, JCO, 2003 Outcome is the same, toxicity is different Ozols, JCO, 2003 Carboplatin and Taxol currently are standard chemotherapy for ovarian cancer. GOG 182: Is there anything to add to Carbo and taxol to improve outcomes? Does the route of administration make a difference? GOG 104: patients with optimally debulked stage III disease were randomized to IV cyclophosphamide and IV cisplatin or IV cyclophosphamide and IP cisplatin IP regimen was superior 25 vs 20% reponse rate 49 vs 41 month median survival Not widely adopted because standard of care shifted to carboplatin/taxol Cisplatin IV (75 mg/m2) PLUS Paclitaxel IV (135 mg/m2) Stage III, all < 1.0 cm RANDOMIZE Paclitaxel (135 mg/m2) IV Day 1 THEN Cisplatin (100 mg/m2) IP Day 2 THEN Paclitaxel (60 mg/m2) IP Day 8 GOG 172: Does IP administration improve results with platinum/taxane therapy?
Slide 30 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance HIPAA Health Insurance Portability and Accountability Act, April 2003. Protects information about the physical or mental health of an individual relating to health, health care, or payment for care in the past, present or future. Institutional Review Boards (IRB) Protects the rights and welfare of research subjects Oversees the conduct of all human research Ensures compliance with all federal, state, local and institutional requirements in human subject research. Includes members of the community Principles governing clinical trials Regulatory codes place the responsibility for the ethical conduct of research on the shoulders of researchers Autonomy Informed consent Confidentiality Comprehension Voluntariness Beneficience Risks-to-Benefit Ratio Research Design (minimizing risk) Investigator Qualifications Conflicts of Interest Justice Balance of Burdens/Benefits Population of Inference Eligibility Criteria Representative of Population Equitable Recruitment Methods Informed Consent Purpose Methods and procedures in detail Risks and discomforts Risk of disease vs risk of study participation Benefits Alternatives to participation Voluntary and uncoerced Randomization Provides the best assurance that prognostic factors, both measured and unmeasured, are similar in treatment and control groups Provides the most credible evidence of treatment effects Placebo control is optimal to evaluate new treatments Only appropriate when no known effective treatment is available Blinding Limits possible bias Patient response Physician attitude Outcome evaluation Decision-making during study Single-blind: treating physician knows but patient doesn’t Double-blind: neither the treating physician nor the patient knows Phases Phase I Trials: maximally tolerated dose Safety and tolerability Uncontrolled, unblinded Not randomized Phase II Trials: evaluate for evidence of a clinical effect Dose-finding (and continued safety) (dose dependence) Controlled or uncontrolled; may be blinded or unblinded Randomized or not randomized Phase III Trials: test whether a new treatment is superior Therapeutic ratio (and continued safety) (Drug x compared to drug y) Control is placebo or standard of care. Blinded Randomized Phase IV Trials: post-marketing surveillance (safety) Eligibility Disease type Prior therapy Performance status Evidence of adequate renal and hepatic function Measurable disease Prior malignancies Study Endpoints Adverse events standard criteria to categorize as: none, mild, moderate, severe, life-threatening Response Progressive disease Stable disease Parital response: decrease in the size of measurable disease by 50% Complete response Progression-free survival Overall survival Quality of life Early stopping rules To avoid subjecting participants to ineffective therapy Interim analysis: No effect, stop the trial Significant effect, stop the trial Intermediate, continue accrual. Landmark clinical trials in the treatment of ovarian cancer Suboptimal Stage III and any stage IV GOG 111 trial established platinum/taxane combination therapy as the standard of care RANDOMIZE Cisplatin (75 mg/m2 q21d x 6) PLUS Cyclophosphamide (750 mg/m2) Cisplatin (75 mg/m2 q21d x 6) PLUS Paclitaxel (135 mg/m2/24h) GOG 111: progression-free survival Patients (N) Proportion Surviving Progression Free 6 12 18 24 30 36 42 48 Months After Study Entry 54 60 66 72 78 84 0.8 0.9 0 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Cisplatin/Paclitaxel Cisplatin/ Cyclophosphamide Treatment Progression- Free 18 15 166 187 Failure 184 202 Total Median Survival 18.0 13.3 Relative Risk 0.70 – McGuire, NEJM, 1996 GOG 111: overall survival 0.8 0.9 0 6 12 18 24 30 36 42 48 Months from entry into study Proportion surviving Cisplatin/paclitaxel Cisplatin/ cyclophosphamide 54 60 66 72 78 84 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Treatment Alive 35 28 150 174 Died 184 202 Total Median Survival (mos) 36.9 24.8 Relative Risk 0.69 – No. Pts McGuire, NEJM, 1996 Substituting taxol for cytoxan improved survival Piccart, JNCI, 2000 McGuire, NEJM, 1996 *p<0.001 GOG 158: Is carboplatin as effective as cisplatin? Ozols, JCO, 2003 Outcome is the same, toxicity is different Ozols, JCO, 2003 Carboplatin and Taxol currently are standard chemotherapy for ovarian cancer. GOG 182: Is there anything to add to Carbo and taxol to improve outcomes? Does the route of administration make a difference? GOG 104: patients with optimally debulked stage III disease were randomized to IV cyclophosphamide and IV cisplatin or IV cyclophosphamide and IP cisplatin IP regimen was superior 25 vs 20% reponse rate 49 vs 41 month median survival Not widely adopted because standard of care shifted to carboplatin/taxol Cisplatin IV (75 mg/m2) PLUS Paclitaxel IV (135 mg/m2) Stage III, all < 1.0 cm RANDOMIZE Paclitaxel (135 mg/m2) IV Day 1 THEN Cisplatin (100 mg/m2) IP Day 2 THEN Paclitaxel (60 mg/m2) IP Day 8 GOG 172: Does IP administration improve results with platinum/taxane therapy? Prolonged remission seen with IP administration Armstrong, NEJM, 2006
Slide 31 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance HIPAA Health Insurance Portability and Accountability Act, April 2003. Protects information about the physical or mental health of an individual relating to health, health care, or payment for care in the past, present or future. Institutional Review Boards (IRB) Protects the rights and welfare of research subjects Oversees the conduct of all human research Ensures compliance with all federal, state, local and institutional requirements in human subject research. Includes members of the community Principles governing clinical trials Regulatory codes place the responsibility for the ethical conduct of research on the shoulders of researchers Autonomy Informed consent Confidentiality Comprehension Voluntariness Beneficience Risks-to-Benefit Ratio Research Design (minimizing risk) Investigator Qualifications Conflicts of Interest Justice Balance of Burdens/Benefits Population of Inference Eligibility Criteria Representative of Population Equitable Recruitment Methods Informed Consent Purpose Methods and procedures in detail Risks and discomforts Risk of disease vs risk of study participation Benefits Alternatives to participation Voluntary and uncoerced Randomization Provides the best assurance that prognostic factors, both measured and unmeasured, are similar in treatment and control groups Provides the most credible evidence of treatment effects Placebo control is optimal to evaluate new treatments Only appropriate when no known effective treatment is available Blinding Limits possible bias Patient response Physician attitude Outcome evaluation Decision-making during study Single-blind: treating physician knows but patient doesn’t Double-blind: neither the treating physician nor the patient knows Phases Phase I Trials: maximally tolerated dose Safety and tolerability Uncontrolled, unblinded Not randomized Phase II Trials: evaluate for evidence of a clinical effect Dose-finding (and continued safety) (dose dependence) Controlled or uncontrolled; may be blinded or unblinded Randomized or not randomized Phase III Trials: test whether a new treatment is superior Therapeutic ratio (and continued safety) (Drug x compared to drug y) Control is placebo or standard of care. Blinded Randomized Phase IV Trials: post-marketing surveillance (safety) Eligibility Disease type Prior therapy Performance status Evidence of adequate renal and hepatic function Measurable disease Prior malignancies Study Endpoints Adverse events standard criteria to categorize as: none, mild, moderate, severe, life-threatening Response Progressive disease Stable disease Parital response: decrease in the size of measurable disease by 50% Complete response Progression-free survival Overall survival Quality of life Early stopping rules To avoid subjecting participants to ineffective therapy Interim analysis: No effect, stop the trial Significant effect, stop the trial Intermediate, continue accrual. Landmark clinical trials in the treatment of ovarian cancer Suboptimal Stage III and any stage IV GOG 111 trial established platinum/taxane combination therapy as the standard of care RANDOMIZE Cisplatin (75 mg/m2 q21d x 6) PLUS Cyclophosphamide (750 mg/m2) Cisplatin (75 mg/m2 q21d x 6) PLUS Paclitaxel (135 mg/m2/24h) GOG 111: progression-free survival Patients (N) Proportion Surviving Progression Free 6 12 18 24 30 36 42 48 Months After Study Entry 54 60 66 72 78 84 0.8 0.9 0 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Cisplatin/Paclitaxel Cisplatin/ Cyclophosphamide Treatment Progression- Free 18 15 166 187 Failure 184 202 Total Median Survival 18.0 13.3 Relative Risk 0.70 – McGuire, NEJM, 1996 GOG 111: overall survival 0.8 0.9 0 6 12 18 24 30 36 42 48 Months from entry into study Proportion surviving Cisplatin/paclitaxel Cisplatin/ cyclophosphamide 54 60 66 72 78 84 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Treatment Alive 35 28 150 174 Died 184 202 Total Median Survival (mos) 36.9 24.8 Relative Risk 0.69 – No. Pts McGuire, NEJM, 1996 Substituting taxol for cytoxan improved survival Piccart, JNCI, 2000 McGuire, NEJM, 1996 *p<0.001 GOG 158: Is carboplatin as effective as cisplatin? Ozols, JCO, 2003 Outcome is the same, toxicity is different Ozols, JCO, 2003 Carboplatin and Taxol currently are standard chemotherapy for ovarian cancer. GOG 182: Is there anything to add to Carbo and taxol to improve outcomes? Does the route of administration make a difference? GOG 104: patients with optimally debulked stage III disease were randomized to IV cyclophosphamide and IV cisplatin or IV cyclophosphamide and IP cisplatin IP regimen was superior 25 vs 20% reponse rate 49 vs 41 month median survival Not widely adopted because standard of care shifted to carboplatin/taxol Cisplatin IV (75 mg/m2) PLUS Paclitaxel IV (135 mg/m2) Stage III, all < 1.0 cm RANDOMIZE Paclitaxel (135 mg/m2) IV Day 1 THEN Cisplatin (100 mg/m2) IP Day 2 THEN Paclitaxel (60 mg/m2) IP Day 8 GOG 172: Does IP administration improve results with platinum/taxane therapy? Prolonged remission seen with IP administration Armstrong, NEJM, 2006 Overall survival improved with IP administration Armstrong, NEJM, 2006
Slide 32 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance HIPAA Health Insurance Portability and Accountability Act, April 2003. Protects information about the physical or mental health of an individual relating to health, health care, or payment for care in the past, present or future. Institutional Review Boards (IRB) Protects the rights and welfare of research subjects Oversees the conduct of all human research Ensures compliance with all federal, state, local and institutional requirements in human subject research. Includes members of the community Principles governing clinical trials Regulatory codes place the responsibility for the ethical conduct of research on the shoulders of researchers Autonomy Informed consent Confidentiality Comprehension Voluntariness Beneficience Risks-to-Benefit Ratio Research Design (minimizing risk) Investigator Qualifications Conflicts of Interest Justice Balance of Burdens/Benefits Population of Inference Eligibility Criteria Representative of Population Equitable Recruitment Methods Informed Consent Purpose Methods and procedures in detail Risks and discomforts Risk of disease vs risk of study participation Benefits Alternatives to participation Voluntary and uncoerced Randomization Provides the best assurance that prognostic factors, both measured and unmeasured, are similar in treatment and control groups Provides the most credible evidence of treatment effects Placebo control is optimal to evaluate new treatments Only appropriate when no known effective treatment is available Blinding Limits possible bias Patient response Physician attitude Outcome evaluation Decision-making during study Single-blind: treating physician knows but patient doesn’t Double-blind: neither the treating physician nor the patient knows Phases Phase I Trials: maximally tolerated dose Safety and tolerability Uncontrolled, unblinded Not randomized Phase II Trials: evaluate for evidence of a clinical effect Dose-finding (and continued safety) (dose dependence) Controlled or uncontrolled; may be blinded or unblinded Randomized or not randomized Phase III Trials: test whether a new treatment is superior Therapeutic ratio (and continued safety) (Drug x compared to drug y) Control is placebo or standard of care. Blinded Randomized Phase IV Trials: post-marketing surveillance (safety) Eligibility Disease type Prior therapy Performance status Evidence of adequate renal and hepatic function Measurable disease Prior malignancies Study Endpoints Adverse events standard criteria to categorize as: none, mild, moderate, severe, life-threatening Response Progressive disease Stable disease Parital response: decrease in the size of measurable disease by 50% Complete response Progression-free survival Overall survival Quality of life Early stopping rules To avoid subjecting participants to ineffective therapy Interim analysis: No effect, stop the trial Significant effect, stop the trial Intermediate, continue accrual. Landmark clinical trials in the treatment of ovarian cancer Suboptimal Stage III and any stage IV GOG 111 trial established platinum/taxane combination therapy as the standard of care RANDOMIZE Cisplatin (75 mg/m2 q21d x 6) PLUS Cyclophosphamide (750 mg/m2) Cisplatin (75 mg/m2 q21d x 6) PLUS Paclitaxel (135 mg/m2/24h) GOG 111: progression-free survival Patients (N) Proportion Surviving Progression Free 6 12 18 24 30 36 42 48 Months After Study Entry 54 60 66 72 78 84 0.8 0.9 0 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Cisplatin/Paclitaxel Cisplatin/ Cyclophosphamide Treatment Progression- Free 18 15 166 187 Failure 184 202 Total Median Survival 18.0 13.3 Relative Risk 0.70 – McGuire, NEJM, 1996 GOG 111: overall survival 0.8 0.9 0 6 12 18 24 30 36 42 48 Months from entry into study Proportion surviving Cisplatin/paclitaxel Cisplatin/ cyclophosphamide 54 60 66 72 78 84 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Treatment Alive 35 28 150 174 Died 184 202 Total Median Survival (mos) 36.9 24.8 Relative Risk 0.69 – No. Pts McGuire, NEJM, 1996 Substituting taxol for cytoxan improved survival Piccart, JNCI, 2000 McGuire, NEJM, 1996 *p<0.001 GOG 158: Is carboplatin as effective as cisplatin? Ozols, JCO, 2003 Outcome is the same, toxicity is different Ozols, JCO, 2003 Carboplatin and Taxol currently are standard chemotherapy for ovarian cancer. GOG 182: Is there anything to add to Carbo and taxol to improve outcomes? Does the route of administration make a difference? GOG 104: patients with optimally debulked stage III disease were randomized to IV cyclophosphamide and IV cisplatin or IV cyclophosphamide and IP cisplatin IP regimen was superior 25 vs 20% reponse rate 49 vs 41 month median survival Not widely adopted because standard of care shifted to carboplatin/taxol Cisplatin IV (75 mg/m2) PLUS Paclitaxel IV (135 mg/m2) Stage III, all < 1.0 cm RANDOMIZE Paclitaxel (135 mg/m2) IV Day 1 THEN Cisplatin (100 mg/m2) IP Day 2 THEN Paclitaxel (60 mg/m2) IP Day 8 GOG 172: Does IP administration improve results with platinum/taxane therapy? Prolonged remission seen with IP administration Armstrong, NEJM, 2006 Overall survival improved with IP administration Armstrong, NEJM, 2006 GOG 172 participation 86/205 = 41.9% 84/205 = 41.0% Armstrong, NEJM, 2006
Slide 33 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance HIPAA Health Insurance Portability and Accountability Act, April 2003. Protects information about the physical or mental health of an individual relating to health, health care, or payment for care in the past, present or future. Institutional Review Boards (IRB) Protects the rights and welfare of research subjects Oversees the conduct of all human research Ensures compliance with all federal, state, local and institutional requirements in human subject research. Includes members of the community Principles governing clinical trials Regulatory codes place the responsibility for the ethical conduct of research on the shoulders of researchers Autonomy Informed consent Confidentiality Comprehension Voluntariness Beneficience Risks-to-Benefit Ratio Research Design (minimizing risk) Investigator Qualifications Conflicts of Interest Justice Balance of Burdens/Benefits Population of Inference Eligibility Criteria Representative of Population Equitable Recruitment Methods Informed Consent Purpose Methods and procedures in detail Risks and discomforts Risk of disease vs risk of study participation Benefits Alternatives to participation Voluntary and uncoerced Randomization Provides the best assurance that prognostic factors, both measured and unmeasured, are similar in treatment and control groups Provides the most credible evidence of treatment effects Placebo control is optimal to evaluate new treatments Only appropriate when no known effective treatment is available Blinding Limits possible bias Patient response Physician attitude Outcome evaluation Decision-making during study Single-blind: treating physician knows but patient doesn’t Double-blind: neither the treating physician nor the patient knows Phases Phase I Trials: maximally tolerated dose Safety and tolerability Uncontrolled, unblinded Not randomized Phase II Trials: evaluate for evidence of a clinical effect Dose-finding (and continued safety) (dose dependence) Controlled or uncontrolled; may be blinded or unblinded Randomized or not randomized Phase III Trials: test whether a new treatment is superior Therapeutic ratio (and continued safety) (Drug x compared to drug y) Control is placebo or standard of care. Blinded Randomized Phase IV Trials: post-marketing surveillance (safety) Eligibility Disease type Prior therapy Performance status Evidence of adequate renal and hepatic function Measurable disease Prior malignancies Study Endpoints Adverse events standard criteria to categorize as: none, mild, moderate, severe, life-threatening Response Progressive disease Stable disease Parital response: decrease in the size of measurable disease by 50% Complete response Progression-free survival Overall survival Quality of life Early stopping rules To avoid subjecting participants to ineffective therapy Interim analysis: No effect, stop the trial Significant effect, stop the trial Intermediate, continue accrual. Landmark clinical trials in the treatment of ovarian cancer Suboptimal Stage III and any stage IV GOG 111 trial established platinum/taxane combination therapy as the standard of care RANDOMIZE Cisplatin (75 mg/m2 q21d x 6) PLUS Cyclophosphamide (750 mg/m2) Cisplatin (75 mg/m2 q21d x 6) PLUS Paclitaxel (135 mg/m2/24h) GOG 111: progression-free survival Patients (N) Proportion Surviving Progression Free 6 12 18 24 30 36 42 48 Months After Study Entry 54 60 66 72 78 84 0.8 0.9 0 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Cisplatin/Paclitaxel Cisplatin/ Cyclophosphamide Treatment Progression- Free 18 15 166 187 Failure 184 202 Total Median Survival 18.0 13.3 Relative Risk 0.70 – McGuire, NEJM, 1996 GOG 111: overall survival 0.8 0.9 0 6 12 18 24 30 36 42 48 Months from entry into study Proportion surviving Cisplatin/paclitaxel Cisplatin/ cyclophosphamide 54 60 66 72 78 84 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Treatment Alive 35 28 150 174 Died 184 202 Total Median Survival (mos) 36.9 24.8 Relative Risk 0.69 – No. Pts McGuire, NEJM, 1996 Substituting taxol for cytoxan improved survival Piccart, JNCI, 2000 McGuire, NEJM, 1996 *p<0.001 GOG 158: Is carboplatin as effective as cisplatin? Ozols, JCO, 2003 Outcome is the same, toxicity is different Ozols, JCO, 2003 Carboplatin and Taxol currently are standard chemotherapy for ovarian cancer. GOG 182: Is there anything to add to Carbo and taxol to improve outcomes? Does the route of administration make a difference? GOG 104: patients with optimally debulked stage III disease were randomized to IV cyclophosphamide and IV cisplatin or IV cyclophosphamide and IP cisplatin IP regimen was superior 25 vs 20% reponse rate 49 vs 41 month median survival Not widely adopted because standard of care shifted to carboplatin/taxol Cisplatin IV (75 mg/m2) PLUS Paclitaxel IV (135 mg/m2) Stage III, all < 1.0 cm RANDOMIZE Paclitaxel (135 mg/m2) IV Day 1 THEN Cisplatin (100 mg/m2) IP Day 2 THEN Paclitaxel (60 mg/m2) IP Day 8 GOG 172: Does IP administration improve results with platinum/taxane therapy? Prolonged remission seen with IP administration Armstrong, NEJM, 2006 Overall survival improved with IP administration Armstrong, NEJM, 2006 GOG 172 participation 86/205 = 41.9% 84/205 = 41.0% Armstrong, NEJM, 2006 IP chemotherapy summary
Slide 34 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance HIPAA Health Insurance Portability and Accountability Act, April 2003. Protects information about the physical or mental health of an individual relating to health, health care, or payment for care in the past, present or future. Institutional Review Boards (IRB) Protects the rights and welfare of research subjects Oversees the conduct of all human research Ensures compliance with all federal, state, local and institutional requirements in human subject research. Includes members of the community Principles governing clinical trials Regulatory codes place the responsibility for the ethical conduct of research on the shoulders of researchers Autonomy Informed consent Confidentiality Comprehension Voluntariness Beneficience Risks-to-Benefit Ratio Research Design (minimizing risk) Investigator Qualifications Conflicts of Interest Justice Balance of Burdens/Benefits Population of Inference Eligibility Criteria Representative of Population Equitable Recruitment Methods Informed Consent Purpose Methods and procedures in detail Risks and discomforts Risk of disease vs risk of study participation Benefits Alternatives to participation Voluntary and uncoerced Randomization Provides the best assurance that prognostic factors, both measured and unmeasured, are similar in treatment and control groups Provides the most credible evidence of treatment effects Placebo control is optimal to evaluate new treatments Only appropriate when no known effective treatment is available Blinding Limits possible bias Patient response Physician attitude Outcome evaluation Decision-making during study Single-blind: treating physician knows but patient doesn’t Double-blind: neither the treating physician nor the patient knows Phases Phase I Trials: maximally tolerated dose Safety and tolerability Uncontrolled, unblinded Not randomized Phase II Trials: evaluate for evidence of a clinical effect Dose-finding (and continued safety) (dose dependence) Controlled or uncontrolled; may be blinded or unblinded Randomized or not randomized Phase III Trials: test whether a new treatment is superior Therapeutic ratio (and continued safety) (Drug x compared to drug y) Control is placebo or standard of care. Blinded Randomized Phase IV Trials: post-marketing surveillance (safety) Eligibility Disease type Prior therapy Performance status Evidence of adequate renal and hepatic function Measurable disease Prior malignancies Study Endpoints Adverse events standard criteria to categorize as: none, mild, moderate, severe, life-threatening Response Progressive disease Stable disease Parital response: decrease in the size of measurable disease by 50% Complete response Progression-free survival Overall survival Quality of life Early stopping rules To avoid subjecting participants to ineffective therapy Interim analysis: No effect, stop the trial Significant effect, stop the trial Intermediate, continue accrual. Landmark clinical trials in the treatment of ovarian cancer Suboptimal Stage III and any stage IV GOG 111 trial established platinum/taxane combination therapy as the standard of care RANDOMIZE Cisplatin (75 mg/m2 q21d x 6) PLUS Cyclophosphamide (750 mg/m2) Cisplatin (75 mg/m2 q21d x 6) PLUS Paclitaxel (135 mg/m2/24h) GOG 111: progression-free survival Patients (N) Proportion Surviving Progression Free 6 12 18 24 30 36 42 48 Months After Study Entry 54 60 66 72 78 84 0.8 0.9 0 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Cisplatin/Paclitaxel Cisplatin/ Cyclophosphamide Treatment Progression- Free 18 15 166 187 Failure 184 202 Total Median Survival 18.0 13.3 Relative Risk 0.70 – McGuire, NEJM, 1996 GOG 111: overall survival 0.8 0.9 0 6 12 18 24 30 36 42 48 Months from entry into study Proportion surviving Cisplatin/paclitaxel Cisplatin/ cyclophosphamide 54 60 66 72 78 84 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Treatment Alive 35 28 150 174 Died 184 202 Total Median Survival (mos) 36.9 24.8 Relative Risk 0.69 – No. Pts McGuire, NEJM, 1996 Substituting taxol for cytoxan improved survival Piccart, JNCI, 2000 McGuire, NEJM, 1996 *p<0.001 GOG 158: Is carboplatin as effective as cisplatin? Ozols, JCO, 2003 Outcome is the same, toxicity is different Ozols, JCO, 2003 Carboplatin and Taxol currently are standard chemotherapy for ovarian cancer. GOG 182: Is there anything to add to Carbo and taxol to improve outcomes? Does the route of administration make a difference? GOG 104: patients with optimally debulked stage III disease were randomized to IV cyclophosphamide and IV cisplatin or IV cyclophosphamide and IP cisplatin IP regimen was superior 25 vs 20% reponse rate 49 vs 41 month median survival Not widely adopted because standard of care shifted to carboplatin/taxol Cisplatin IV (75 mg/m2) PLUS Paclitaxel IV (135 mg/m2) Stage III, all < 1.0 cm RANDOMIZE Paclitaxel (135 mg/m2) IV Day 1 THEN Cisplatin (100 mg/m2) IP Day 2 THEN Paclitaxel (60 mg/m2) IP Day 8 GOG 172: Does IP administration improve results with platinum/taxane therapy? Prolonged remission seen with IP administration Armstrong, NEJM, 2006 Overall survival improved with IP administration Armstrong, NEJM, 2006 GOG 172 participation 86/205 = 41.9% 84/205 = 41.0% Armstrong, NEJM, 2006 IP chemotherapy summary Will targeted therapeutics improve response? Bevacizumab (Avastin) is an antibody to the vascular endothelial growth factor (VEGF) which blocks the formation of new blood vessels In phase II trials, Avastin demonstrated significant activity in patients with recurrent ovarian cancer GOG 218 tested Carboplatin/Taxol/Placebo vs Carboplatin/Taxol/Avastin vs Carboplatin/Taxol/Avastin + maintenance Avastin Improved progression free survival was seen in the group that got maintenance Avastin Most patients experience only mild toxicity with Avastin treatment
Slide 35 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance HIPAA Health Insurance Portability and Accountability Act, April 2003. Protects information about the physical or mental health of an individual relating to health, health care, or payment for care in the past, present or future. Institutional Review Boards (IRB) Protects the rights and welfare of research subjects Oversees the conduct of all human research Ensures compliance with all federal, state, local and institutional requirements in human subject research. Includes members of the community Principles governing clinical trials Regulatory codes place the responsibility for the ethical conduct of research on the shoulders of researchers Autonomy Informed consent Confidentiality Comprehension Voluntariness Beneficience Risks-to-Benefit Ratio Research Design (minimizing risk) Investigator Qualifications Conflicts of Interest Justice Balance of Burdens/Benefits Population of Inference Eligibility Criteria Representative of Population Equitable Recruitment Methods Informed Consent Purpose Methods and procedures in detail Risks and discomforts Risk of disease vs risk of study participation Benefits Alternatives to participation Voluntary and uncoerced Randomization Provides the best assurance that prognostic factors, both measured and unmeasured, are similar in treatment and control groups Provides the most credible evidence of treatment effects Placebo control is optimal to evaluate new treatments Only appropriate when no known effective treatment is available Blinding Limits possible bias Patient response Physician attitude Outcome evaluation Decision-making during study Single-blind: treating physician knows but patient doesn’t Double-blind: neither the treating physician nor the patient knows Phases Phase I Trials: maximally tolerated dose Safety and tolerability Uncontrolled, unblinded Not randomized Phase II Trials: evaluate for evidence of a clinical effect Dose-finding (and continued safety) (dose dependence) Controlled or uncontrolled; may be blinded or unblinded Randomized or not randomized Phase III Trials: test whether a new treatment is superior Therapeutic ratio (and continued safety) (Drug x compared to drug y) Control is placebo or standard of care. Blinded Randomized Phase IV Trials: post-marketing surveillance (safety) Eligibility Disease type Prior therapy Performance status Evidence of adequate renal and hepatic function Measurable disease Prior malignancies Study Endpoints Adverse events standard criteria to categorize as: none, mild, moderate, severe, life-threatening Response Progressive disease Stable disease Parital response: decrease in the size of measurable disease by 50% Complete response Progression-free survival Overall survival Quality of life Early stopping rules To avoid subjecting participants to ineffective therapy Interim analysis: No effect, stop the trial Significant effect, stop the trial Intermediate, continue accrual. Landmark clinical trials in the treatment of ovarian cancer Suboptimal Stage III and any stage IV GOG 111 trial established platinum/taxane combination therapy as the standard of care RANDOMIZE Cisplatin (75 mg/m2 q21d x 6) PLUS Cyclophosphamide (750 mg/m2) Cisplatin (75 mg/m2 q21d x 6) PLUS Paclitaxel (135 mg/m2/24h) GOG 111: progression-free survival Patients (N) Proportion Surviving Progression Free 6 12 18 24 30 36 42 48 Months After Study Entry 54 60 66 72 78 84 0.8 0.9 0 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Cisplatin/Paclitaxel Cisplatin/ Cyclophosphamide Treatment Progression- Free 18 15 166 187 Failure 184 202 Total Median Survival 18.0 13.3 Relative Risk 0.70 – McGuire, NEJM, 1996 GOG 111: overall survival 0.8 0.9 0 6 12 18 24 30 36 42 48 Months from entry into study Proportion surviving Cisplatin/paclitaxel Cisplatin/ cyclophosphamide 54 60 66 72 78 84 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Treatment Alive 35 28 150 174 Died 184 202 Total Median Survival (mos) 36.9 24.8 Relative Risk 0.69 – No. Pts McGuire, NEJM, 1996 Substituting taxol for cytoxan improved survival Piccart, JNCI, 2000 McGuire, NEJM, 1996 *p<0.001 GOG 158: Is carboplatin as effective as cisplatin? Ozols, JCO, 2003 Outcome is the same, toxicity is different Ozols, JCO, 2003 Carboplatin and Taxol currently are standard chemotherapy for ovarian cancer. GOG 182: Is there anything to add to Carbo and taxol to improve outcomes? Does the route of administration make a difference? GOG 104: patients with optimally debulked stage III disease were randomized to IV cyclophosphamide and IV cisplatin or IV cyclophosphamide and IP cisplatin IP regimen was superior 25 vs 20% reponse rate 49 vs 41 month median survival Not widely adopted because standard of care shifted to carboplatin/taxol Cisplatin IV (75 mg/m2) PLUS Paclitaxel IV (135 mg/m2) Stage III, all < 1.0 cm RANDOMIZE Paclitaxel (135 mg/m2) IV Day 1 THEN Cisplatin (100 mg/m2) IP Day 2 THEN Paclitaxel (60 mg/m2) IP Day 8 GOG 172: Does IP administration improve results with platinum/taxane therapy? Prolonged remission seen with IP administration Armstrong, NEJM, 2006 Overall survival improved with IP administration Armstrong, NEJM, 2006 GOG 172 participation 86/205 = 41.9% 84/205 = 41.0% Armstrong, NEJM, 2006 IP chemotherapy summary Will targeted therapeutics improve response? Bevacizumab (Avastin) is an antibody to the vascular endothelial growth factor (VEGF) which blocks the formation of new blood vessels In phase II trials, Avastin demonstrated significant activity in patients with recurrent ovarian cancer GOG 218 tested Carboplatin/Taxol/Placebo vs Carboplatin/Taxol/Avastin vs Carboplatin/Taxol/Avastin + maintenance Avastin Improved progression free survival was seen in the group that got maintenance Avastin Most patients experience only mild toxicity with Avastin treatment Active GOG trials GOG 262: Does administering dose-dense Taxol improve the response? Weekly Taxol vs every three weeks with carboplatin, with or without Avastin GOG 213: Does Avastin improve the response to chemotherapy for recurrent disease? Does secondary surgical debulking benefit patients? Randomized to secondary debulking or no surgery Randomized to Carboplatin/Taxol/Placebo vs Carboplatin/Taxol/Avastin (concurrent and maintenance) GOG 252: Does Avastin improve response to IP chemotherapy? IV Carboplatin, IV weekly Taxol, Avastin IP Carboplatin, IV weekly Taxol, Avastin IV Taxol (day 1), IP Cisplatin (day 2), IP Taxol (day 8), Avastin GOG 212: Does monthly Taxol improve survival after primary adjuvant chemotherapy? Maintenance therapy with Taxol or CT2103 or no treatment for 12 months after primary adjuvant chemotherapy
Slide 36 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance HIPAA Health Insurance Portability and Accountability Act, April 2003. Protects information about the physical or mental health of an individual relating to health, health care, or payment for care in the past, present or future. Institutional Review Boards (IRB) Protects the rights and welfare of research subjects Oversees the conduct of all human research Ensures compliance with all federal, state, local and institutional requirements in human subject research. Includes members of the community Principles governing clinical trials Regulatory codes place the responsibility for the ethical conduct of research on the shoulders of researchers Autonomy Informed consent Confidentiality Comprehension Voluntariness Beneficience Risks-to-Benefit Ratio Research Design (minimizing risk) Investigator Qualifications Conflicts of Interest Justice Balance of Burdens/Benefits Population of Inference Eligibility Criteria Representative of Population Equitable Recruitment Methods Informed Consent Purpose Methods and procedures in detail Risks and discomforts Risk of disease vs risk of study participation Benefits Alternatives to participation Voluntary and uncoerced Randomization Provides the best assurance that prognostic factors, both measured and unmeasured, are similar in treatment and control groups Provides the most credible evidence of treatment effects Placebo control is optimal to evaluate new treatments Only appropriate when no known effective treatment is available Blinding Limits possible bias Patient response Physician attitude Outcome evaluation Decision-making during study Single-blind: treating physician knows but patient doesn’t Double-blind: neither the treating physician nor the patient knows Phases Phase I Trials: maximally tolerated dose Safety and tolerability Uncontrolled, unblinded Not randomized Phase II Trials: evaluate for evidence of a clinical effect Dose-finding (and continued safety) (dose dependence) Controlled or uncontrolled; may be blinded or unblinded Randomized or not randomized Phase III Trials: test whether a new treatment is superior Therapeutic ratio (and continued safety) (Drug x compared to drug y) Control is placebo or standard of care. Blinded Randomized Phase IV Trials: post-marketing surveillance (safety) Eligibility Disease type Prior therapy Performance status Evidence of adequate renal and hepatic function Measurable disease Prior malignancies Study Endpoints Adverse events standard criteria to categorize as: none, mild, moderate, severe, life-threatening Response Progressive disease Stable disease Parital response: decrease in the size of measurable disease by 50% Complete response Progression-free survival Overall survival Quality of life Early stopping rules To avoid subjecting participants to ineffective therapy Interim analysis: No effect, stop the trial Significant effect, stop the trial Intermediate, continue accrual. Landmark clinical trials in the treatment of ovarian cancer Suboptimal Stage III and any stage IV GOG 111 trial established platinum/taxane combination therapy as the standard of care RANDOMIZE Cisplatin (75 mg/m2 q21d x 6) PLUS Cyclophosphamide (750 mg/m2) Cisplatin (75 mg/m2 q21d x 6) PLUS Paclitaxel (135 mg/m2/24h) GOG 111: progression-free survival Patients (N) Proportion Surviving Progression Free 6 12 18 24 30 36 42 48 Months After Study Entry 54 60 66 72 78 84 0.8 0.9 0 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Cisplatin/Paclitaxel Cisplatin/ Cyclophosphamide Treatment Progression- Free 18 15 166 187 Failure 184 202 Total Median Survival 18.0 13.3 Relative Risk 0.70 – McGuire, NEJM, 1996 GOG 111: overall survival 0.8 0.9 0 6 12 18 24 30 36 42 48 Months from entry into study Proportion surviving Cisplatin/paclitaxel Cisplatin/ cyclophosphamide 54 60 66 72 78 84 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Treatment Alive 35 28 150 174 Died 184 202 Total Median Survival (mos) 36.9 24.8 Relative Risk 0.69 – No. Pts McGuire, NEJM, 1996 Substituting taxol for cytoxan improved survival Piccart, JNCI, 2000 McGuire, NEJM, 1996 *p<0.001 GOG 158: Is carboplatin as effective as cisplatin? Ozols, JCO, 2003 Outcome is the same, toxicity is different Ozols, JCO, 2003 Carboplatin and Taxol currently are standard chemotherapy for ovarian cancer. GOG 182: Is there anything to add to Carbo and taxol to improve outcomes? Does the route of administration make a difference? GOG 104: patients with optimally debulked stage III disease were randomized to IV cyclophosphamide and IV cisplatin or IV cyclophosphamide and IP cisplatin IP regimen was superior 25 vs 20% reponse rate 49 vs 41 month median survival Not widely adopted because standard of care shifted to carboplatin/taxol Cisplatin IV (75 mg/m2) PLUS Paclitaxel IV (135 mg/m2) Stage III, all < 1.0 cm RANDOMIZE Paclitaxel (135 mg/m2) IV Day 1 THEN Cisplatin (100 mg/m2) IP Day 2 THEN Paclitaxel (60 mg/m2) IP Day 8 GOG 172: Does IP administration improve results with platinum/taxane therapy? Prolonged remission seen with IP administration Armstrong, NEJM, 2006 Overall survival improved with IP administration Armstrong, NEJM, 2006 GOG 172 participation 86/205 = 41.9% 84/205 = 41.0% Armstrong, NEJM, 2006 IP chemotherapy summary Will targeted therapeutics improve response? Bevacizumab (Avastin) is an antibody to the vascular endothelial growth factor (VEGF) which blocks the formation of new blood vessels In phase II trials, Avastin demonstrated significant activity in patients with recurrent ovarian cancer GOG 218 tested Carboplatin/Taxol/Placebo vs Carboplatin/Taxol/Avastin vs Carboplatin/Taxol/Avastin + maintenance Avastin Improved progression free survival was seen in the group that got maintenance Avastin Most patients experience only mild toxicity with Avastin treatment Active GOG trials GOG 262: Does administering dose-dense Taxol improve the response? Weekly Taxol vs every three weeks with carboplatin, with or without Avastin GOG 213: Does Avastin improve the response to chemotherapy for recurrent disease? Does secondary surgical debulking benefit patients? Randomized to secondary debulking or no surgery Randomized to Carboplatin/Taxol/Placebo vs Carboplatin/Taxol/Avastin (concurrent and maintenance) GOG 252: Does Avastin improve response to IP chemotherapy? IV Carboplatin, IV weekly Taxol, Avastin IP Carboplatin, IV weekly Taxol, Avastin IV Taxol (day 1), IP Cisplatin (day 2), IP Taxol (day 8), Avastin GOG 212: Does monthly Taxol improve survival after primary adjuvant chemotherapy? Maintenance therapy with Taxol or CT2103 or no treatment for 12 months after primary adjuvant chemotherapy Evolution of a clinical trial: Penn 2003: T cells in the tumor correlates with improved survival Survival of patients with ovarian cancer: Tumor Infiltrating Lymphocytes (TIL) TIL+ TIL-
Slide 37 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance HIPAA Health Insurance Portability and Accountability Act, April 2003. Protects information about the physical or mental health of an individual relating to health, health care, or payment for care in the past, present or future. Institutional Review Boards (IRB) Protects the rights and welfare of research subjects Oversees the conduct of all human research Ensures compliance with all federal, state, local and institutional requirements in human subject research. Includes members of the community Principles governing clinical trials Regulatory codes place the responsibility for the ethical conduct of research on the shoulders of researchers Autonomy Informed consent Confidentiality Comprehension Voluntariness Beneficience Risks-to-Benefit Ratio Research Design (minimizing risk) Investigator Qualifications Conflicts of Interest Justice Balance of Burdens/Benefits Population of Inference Eligibility Criteria Representative of Population Equitable Recruitment Methods Informed Consent Purpose Methods and procedures in detail Risks and discomforts Risk of disease vs risk of study participation Benefits Alternatives to participation Voluntary and uncoerced Randomization Provides the best assurance that prognostic factors, both measured and unmeasured, are similar in treatment and control groups Provides the most credible evidence of treatment effects Placebo control is optimal to evaluate new treatments Only appropriate when no known effective treatment is available Blinding Limits possible bias Patient response Physician attitude Outcome evaluation Decision-making during study Single-blind: treating physician knows but patient doesn’t Double-blind: neither the treating physician nor the patient knows Phases Phase I Trials: maximally tolerated dose Safety and tolerability Uncontrolled, unblinded Not randomized Phase II Trials: evaluate for evidence of a clinical effect Dose-finding (and continued safety) (dose dependence) Controlled or uncontrolled; may be blinded or unblinded Randomized or not randomized Phase III Trials: test whether a new treatment is superior Therapeutic ratio (and continued safety) (Drug x compared to drug y) Control is placebo or standard of care. Blinded Randomized Phase IV Trials: post-marketing surveillance (safety) Eligibility Disease type Prior therapy Performance status Evidence of adequate renal and hepatic function Measurable disease Prior malignancies Study Endpoints Adverse events standard criteria to categorize as: none, mild, moderate, severe, life-threatening Response Progressive disease Stable disease Parital response: decrease in the size of measurable disease by 50% Complete response Progression-free survival Overall survival Quality of life Early stopping rules To avoid subjecting participants to ineffective therapy Interim analysis: No effect, stop the trial Significant effect, stop the trial Intermediate, continue accrual. Landmark clinical trials in the treatment of ovarian cancer Suboptimal Stage III and any stage IV GOG 111 trial established platinum/taxane combination therapy as the standard of care RANDOMIZE Cisplatin (75 mg/m2 q21d x 6) PLUS Cyclophosphamide (750 mg/m2) Cisplatin (75 mg/m2 q21d x 6) PLUS Paclitaxel (135 mg/m2/24h) GOG 111: progression-free survival Patients (N) Proportion Surviving Progression Free 6 12 18 24 30 36 42 48 Months After Study Entry 54 60 66 72 78 84 0.8 0.9 0 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Cisplatin/Paclitaxel Cisplatin/ Cyclophosphamide Treatment Progression- Free 18 15 166 187 Failure 184 202 Total Median Survival 18.0 13.3 Relative Risk 0.70 – McGuire, NEJM, 1996 GOG 111: overall survival 0.8 0.9 0 6 12 18 24 30 36 42 48 Months from entry into study Proportion surviving Cisplatin/paclitaxel Cisplatin/ cyclophosphamide 54 60 66 72 78 84 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Treatment Alive 35 28 150 174 Died 184 202 Total Median Survival (mos) 36.9 24.8 Relative Risk 0.69 – No. Pts McGuire, NEJM, 1996 Substituting taxol for cytoxan improved survival Piccart, JNCI, 2000 McGuire, NEJM, 1996 *p<0.001 GOG 158: Is carboplatin as effective as cisplatin? Ozols, JCO, 2003 Outcome is the same, toxicity is different Ozols, JCO, 2003 Carboplatin and Taxol currently are standard chemotherapy for ovarian cancer. GOG 182: Is there anything to add to Carbo and taxol to improve outcomes? Does the route of administration make a difference? GOG 104: patients with optimally debulked stage III disease were randomized to IV cyclophosphamide and IV cisplatin or IV cyclophosphamide and IP cisplatin IP regimen was superior 25 vs 20% reponse rate 49 vs 41 month median survival Not widely adopted because standard of care shifted to carboplatin/taxol Cisplatin IV (75 mg/m2) PLUS Paclitaxel IV (135 mg/m2) Stage III, all < 1.0 cm RANDOMIZE Paclitaxel (135 mg/m2) IV Day 1 THEN Cisplatin (100 mg/m2) IP Day 2 THEN Paclitaxel (60 mg/m2) IP Day 8 GOG 172: Does IP administration improve results with platinum/taxane therapy? Prolonged remission seen with IP administration Armstrong, NEJM, 2006 Overall survival improved with IP administration Armstrong, NEJM, 2006 GOG 172 participation 86/205 = 41.9% 84/205 = 41.0% Armstrong, NEJM, 2006 IP chemotherapy summary Will targeted therapeutics improve response? Bevacizumab (Avastin) is an antibody to the vascular endothelial growth factor (VEGF) which blocks the formation of new blood vessels In phase II trials, Avastin demonstrated significant activity in patients with recurrent ovarian cancer GOG 218 tested Carboplatin/Taxol/Placebo vs Carboplatin/Taxol/Avastin vs Carboplatin/Taxol/Avastin + maintenance Avastin Improved progression free survival was seen in the group that got maintenance Avastin Most patients experience only mild toxicity with Avastin treatment Active GOG trials GOG 262: Does administering dose-dense Taxol improve the response? Weekly Taxol vs every three weeks with carboplatin, with or without Avastin GOG 213: Does Avastin improve the response to chemotherapy for recurrent disease? Does secondary surgical debulking benefit patients? Randomized to secondary debulking or no surgery Randomized to Carboplatin/Taxol/Placebo vs Carboplatin/Taxol/Avastin (concurrent and maintenance) GOG 252: Does Avastin improve response to IP chemotherapy? IV Carboplatin, IV weekly Taxol, Avastin IP Carboplatin, IV weekly Taxol, Avastin IV Taxol (day 1), IP Cisplatin (day 2), IP Taxol (day 8), Avastin GOG 212: Does monthly Taxol improve survival after primary adjuvant chemotherapy? Maintenance therapy with Taxol or CT2103 or no treatment for 12 months after primary adjuvant chemotherapy Evolution of a clinical trial: Penn 2003: T cells in the tumor correlates with improved survival Survival of patients with ovarian cancer: Tumor Infiltrating Lymphocytes (TIL) TIL+ TIL- First Phase I Vaccine Trial 2006: Dendritic cell vaccine Goal: to enhance the anti-tumor T cell response A cellular vaccine comprised of a subject’s own cells primed against ovarian cancer was developed Confirmed the safety of this approach
Slide 38 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance HIPAA Health Insurance Portability and Accountability Act, April 2003. Protects information about the physical or mental health of an individual relating to health, health care, or payment for care in the past, present or future. Institutional Review Boards (IRB) Protects the rights and welfare of research subjects Oversees the conduct of all human research Ensures compliance with all federal, state, local and institutional requirements in human subject research. Includes members of the community Principles governing clinical trials Regulatory codes place the responsibility for the ethical conduct of research on the shoulders of researchers Autonomy Informed consent Confidentiality Comprehension Voluntariness Beneficience Risks-to-Benefit Ratio Research Design (minimizing risk) Investigator Qualifications Conflicts of Interest Justice Balance of Burdens/Benefits Population of Inference Eligibility Criteria Representative of Population Equitable Recruitment Methods Informed Consent Purpose Methods and procedures in detail Risks and discomforts Risk of disease vs risk of study participation Benefits Alternatives to participation Voluntary and uncoerced Randomization Provides the best assurance that prognostic factors, both measured and unmeasured, are similar in treatment and control groups Provides the most credible evidence of treatment effects Placebo control is optimal to evaluate new treatments Only appropriate when no known effective treatment is available Blinding Limits possible bias Patient response Physician attitude Outcome evaluation Decision-making during study Single-blind: treating physician knows but patient doesn’t Double-blind: neither the treating physician nor the patient knows Phases Phase I Trials: maximally tolerated dose Safety and tolerability Uncontrolled, unblinded Not randomized Phase II Trials: evaluate for evidence of a clinical effect Dose-finding (and continued safety) (dose dependence) Controlled or uncontrolled; may be blinded or unblinded Randomized or not randomized Phase III Trials: test whether a new treatment is superior Therapeutic ratio (and continued safety) (Drug x compared to drug y) Control is placebo or standard of care. Blinded Randomized Phase IV Trials: post-marketing surveillance (safety) Eligibility Disease type Prior therapy Performance status Evidence of adequate renal and hepatic function Measurable disease Prior malignancies Study Endpoints Adverse events standard criteria to categorize as: none, mild, moderate, severe, life-threatening Response Progressive disease Stable disease Parital response: decrease in the size of measurable disease by 50% Complete response Progression-free survival Overall survival Quality of life Early stopping rules To avoid subjecting participants to ineffective therapy Interim analysis: No effect, stop the trial Significant effect, stop the trial Intermediate, continue accrual. Landmark clinical trials in the treatment of ovarian cancer Suboptimal Stage III and any stage IV GOG 111 trial established platinum/taxane combination therapy as the standard of care RANDOMIZE Cisplatin (75 mg/m2 q21d x 6) PLUS Cyclophosphamide (750 mg/m2) Cisplatin (75 mg/m2 q21d x 6) PLUS Paclitaxel (135 mg/m2/24h) GOG 111: progression-free survival Patients (N) Proportion Surviving Progression Free 6 12 18 24 30 36 42 48 Months After Study Entry 54 60 66 72 78 84 0.8 0.9 0 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Cisplatin/Paclitaxel Cisplatin/ Cyclophosphamide Treatment Progression- Free 18 15 166 187 Failure 184 202 Total Median Survival 18.0 13.3 Relative Risk 0.70 – McGuire, NEJM, 1996 GOG 111: overall survival 0.8 0.9 0 6 12 18 24 30 36 42 48 Months from entry into study Proportion surviving Cisplatin/paclitaxel Cisplatin/ cyclophosphamide 54 60 66 72 78 84 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Treatment Alive 35 28 150 174 Died 184 202 Total Median Survival (mos) 36.9 24.8 Relative Risk 0.69 – No. Pts McGuire, NEJM, 1996 Substituting taxol for cytoxan improved survival Piccart, JNCI, 2000 McGuire, NEJM, 1996 *p<0.001 GOG 158: Is carboplatin as effective as cisplatin? Ozols, JCO, 2003 Outcome is the same, toxicity is different Ozols, JCO, 2003 Carboplatin and Taxol currently are standard chemotherapy for ovarian cancer. GOG 182: Is there anything to add to Carbo and taxol to improve outcomes? Does the route of administration make a difference? GOG 104: patients with optimally debulked stage III disease were randomized to IV cyclophosphamide and IV cisplatin or IV cyclophosphamide and IP cisplatin IP regimen was superior 25 vs 20% reponse rate 49 vs 41 month median survival Not widely adopted because standard of care shifted to carboplatin/taxol Cisplatin IV (75 mg/m2) PLUS Paclitaxel IV (135 mg/m2) Stage III, all < 1.0 cm RANDOMIZE Paclitaxel (135 mg/m2) IV Day 1 THEN Cisplatin (100 mg/m2) IP Day 2 THEN Paclitaxel (60 mg/m2) IP Day 8 GOG 172: Does IP administration improve results with platinum/taxane therapy? Prolonged remission seen with IP administration Armstrong, NEJM, 2006 Overall survival improved with IP administration Armstrong, NEJM, 2006 GOG 172 participation 86/205 = 41.9% 84/205 = 41.0% Armstrong, NEJM, 2006 IP chemotherapy summary Will targeted therapeutics improve response? Bevacizumab (Avastin) is an antibody to the vascular endothelial growth factor (VEGF) which blocks the formation of new blood vessels In phase II trials, Avastin demonstrated significant activity in patients with recurrent ovarian cancer GOG 218 tested Carboplatin/Taxol/Placebo vs Carboplatin/Taxol/Avastin vs Carboplatin/Taxol/Avastin + maintenance Avastin Improved progression free survival was seen in the group that got maintenance Avastin Most patients experience only mild toxicity with Avastin treatment Active GOG trials GOG 262: Does administering dose-dense Taxol improve the response? Weekly Taxol vs every three weeks with carboplatin, with or without Avastin GOG 213: Does Avastin improve the response to chemotherapy for recurrent disease? Does secondary surgical debulking benefit patients? Randomized to secondary debulking or no surgery Randomized to Carboplatin/Taxol/Placebo vs Carboplatin/Taxol/Avastin (concurrent and maintenance) GOG 252: Does Avastin improve response to IP chemotherapy? IV Carboplatin, IV weekly Taxol, Avastin IP Carboplatin, IV weekly Taxol, Avastin IV Taxol (day 1), IP Cisplatin (day 2), IP Taxol (day 8), Avastin GOG 212: Does monthly Taxol improve survival after primary adjuvant chemotherapy? Maintenance therapy with Taxol or CT2103 or no treatment for 12 months after primary adjuvant chemotherapy Evolution of a clinical trial: Penn 2003: T cells in the tumor correlates with improved survival Survival of patients with ovarian cancer: Tumor Infiltrating Lymphocytes (TIL) TIL+ TIL- First Phase I Vaccine Trial 2006: Dendritic cell vaccine Goal: to enhance the anti-tumor T cell response A cellular vaccine comprised of a subject’s own cells primed against ovarian cancer was developed Confirmed the safety of this approach Second Phase I trial: Whole tumor antigen vaccine Evidence in other solid tumors of a survival benefit following vaccination with dendritic cells pulsed with tumor lysate Demonstration of immunomodulatory effects of Avastin and Cytoxan chemotherapy UPCC 11807
Slide 39 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance HIPAA Health Insurance Portability and Accountability Act, April 2003. Protects information about the physical or mental health of an individual relating to health, health care, or payment for care in the past, present or future. Institutional Review Boards (IRB) Protects the rights and welfare of research subjects Oversees the conduct of all human research Ensures compliance with all federal, state, local and institutional requirements in human subject research. Includes members of the community Principles governing clinical trials Regulatory codes place the responsibility for the ethical conduct of research on the shoulders of researchers Autonomy Informed consent Confidentiality Comprehension Voluntariness Beneficience Risks-to-Benefit Ratio Research Design (minimizing risk) Investigator Qualifications Conflicts of Interest Justice Balance of Burdens/Benefits Population of Inference Eligibility Criteria Representative of Population Equitable Recruitment Methods Informed Consent Purpose Methods and procedures in detail Risks and discomforts Risk of disease vs risk of study participation Benefits Alternatives to participation Voluntary and uncoerced Randomization Provides the best assurance that prognostic factors, both measured and unmeasured, are similar in treatment and control groups Provides the most credible evidence of treatment effects Placebo control is optimal to evaluate new treatments Only appropriate when no known effective treatment is available Blinding Limits possible bias Patient response Physician attitude Outcome evaluation Decision-making during study Single-blind: treating physician knows but patient doesn’t Double-blind: neither the treating physician nor the patient knows Phases Phase I Trials: maximally tolerated dose Safety and tolerability Uncontrolled, unblinded Not randomized Phase II Trials: evaluate for evidence of a clinical effect Dose-finding (and continued safety) (dose dependence) Controlled or uncontrolled; may be blinded or unblinded Randomized or not randomized Phase III Trials: test whether a new treatment is superior Therapeutic ratio (and continued safety) (Drug x compared to drug y) Control is placebo or standard of care. Blinded Randomized Phase IV Trials: post-marketing surveillance (safety) Eligibility Disease type Prior therapy Performance status Evidence of adequate renal and hepatic function Measurable disease Prior malignancies Study Endpoints Adverse events standard criteria to categorize as: none, mild, moderate, severe, life-threatening Response Progressive disease Stable disease Parital response: decrease in the size of measurable disease by 50% Complete response Progression-free survival Overall survival Quality of life Early stopping rules To avoid subjecting participants to ineffective therapy Interim analysis: No effect, stop the trial Significant effect, stop the trial Intermediate, continue accrual. Landmark clinical trials in the treatment of ovarian cancer Suboptimal Stage III and any stage IV GOG 111 trial established platinum/taxane combination therapy as the standard of care RANDOMIZE Cisplatin (75 mg/m2 q21d x 6) PLUS Cyclophosphamide (750 mg/m2) Cisplatin (75 mg/m2 q21d x 6) PLUS Paclitaxel (135 mg/m2/24h) GOG 111: progression-free survival Patients (N) Proportion Surviving Progression Free 6 12 18 24 30 36 42 48 Months After Study Entry 54 60 66 72 78 84 0.8 0.9 0 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Cisplatin/Paclitaxel Cisplatin/ Cyclophosphamide Treatment Progression- Free 18 15 166 187 Failure 184 202 Total Median Survival 18.0 13.3 Relative Risk 0.70 – McGuire, NEJM, 1996 GOG 111: overall survival 0.8 0.9 0 6 12 18 24 30 36 42 48 Months from entry into study Proportion surviving Cisplatin/paclitaxel Cisplatin/ cyclophosphamide 54 60 66 72 78 84 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Treatment Alive 35 28 150 174 Died 184 202 Total Median Survival (mos) 36.9 24.8 Relative Risk 0.69 – No. Pts McGuire, NEJM, 1996 Substituting taxol for cytoxan improved survival Piccart, JNCI, 2000 McGuire, NEJM, 1996 *p<0.001 GOG 158: Is carboplatin as effective as cisplatin? Ozols, JCO, 2003 Outcome is the same, toxicity is different Ozols, JCO, 2003 Carboplatin and Taxol currently are standard chemotherapy for ovarian cancer. GOG 182: Is there anything to add to Carbo and taxol to improve outcomes? Does the route of administration make a difference? GOG 104: patients with optimally debulked stage III disease were randomized to IV cyclophosphamide and IV cisplatin or IV cyclophosphamide and IP cisplatin IP regimen was superior 25 vs 20% reponse rate 49 vs 41 month median survival Not widely adopted because standard of care shifted to carboplatin/taxol Cisplatin IV (75 mg/m2) PLUS Paclitaxel IV (135 mg/m2) Stage III, all < 1.0 cm RANDOMIZE Paclitaxel (135 mg/m2) IV Day 1 THEN Cisplatin (100 mg/m2) IP Day 2 THEN Paclitaxel (60 mg/m2) IP Day 8 GOG 172: Does IP administration improve results with platinum/taxane therapy? Prolonged remission seen with IP administration Armstrong, NEJM, 2006 Overall survival improved with IP administration Armstrong, NEJM, 2006 GOG 172 participation 86/205 = 41.9% 84/205 = 41.0% Armstrong, NEJM, 2006 IP chemotherapy summary Will targeted therapeutics improve response? Bevacizumab (Avastin) is an antibody to the vascular endothelial growth factor (VEGF) which blocks the formation of new blood vessels In phase II trials, Avastin demonstrated significant activity in patients with recurrent ovarian cancer GOG 218 tested Carboplatin/Taxol/Placebo vs Carboplatin/Taxol/Avastin vs Carboplatin/Taxol/Avastin + maintenance Avastin Improved progression free survival was seen in the group that got maintenance Avastin Most patients experience only mild toxicity with Avastin treatment Active GOG trials GOG 262: Does administering dose-dense Taxol improve the response? Weekly Taxol vs every three weeks with carboplatin, with or without Avastin GOG 213: Does Avastin improve the response to chemotherapy for recurrent disease? Does secondary surgical debulking benefit patients? Randomized to secondary debulking or no surgery Randomized to Carboplatin/Taxol/Placebo vs Carboplatin/Taxol/Avastin (concurrent and maintenance) GOG 252: Does Avastin improve response to IP chemotherapy? IV Carboplatin, IV weekly Taxol, Avastin IP Carboplatin, IV weekly Taxol, Avastin IV Taxol (day 1), IP Cisplatin (day 2), IP Taxol (day 8), Avastin GOG 212: Does monthly Taxol improve survival after primary adjuvant chemotherapy? Maintenance therapy with Taxol or CT2103 or no treatment for 12 months after primary adjuvant chemotherapy Evolution of a clinical trial: Penn 2003: T cells in the tumor correlates with improved survival Survival of patients with ovarian cancer: Tumor Infiltrating Lymphocytes (TIL) TIL+ TIL- First Phase I Vaccine Trial 2006: Dendritic cell vaccine Goal: to enhance the anti-tumor T cell response A cellular vaccine comprised of a subject’s own cells primed against ovarian cancer was developed Confirmed the safety of this approach Second Phase I trial: Whole tumor antigen vaccine Evidence in other solid tumors of a survival benefit following vaccination with dendritic cells pulsed with tumor lysate Demonstration of immunomodulatory effects of Avastin and Cytoxan chemotherapy UPCC 11807 Monocytes GMCSF+IL4 - Whole tumor antigen vaccine Pulsing with Tumor antigen Mature DC Immature DC
Slide 40 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance HIPAA Health Insurance Portability and Accountability Act, April 2003. Protects information about the physical or mental health of an individual relating to health, health care, or payment for care in the past, present or future. Institutional Review Boards (IRB) Protects the rights and welfare of research subjects Oversees the conduct of all human research Ensures compliance with all federal, state, local and institutional requirements in human subject research. Includes members of the community Principles governing clinical trials Regulatory codes place the responsibility for the ethical conduct of research on the shoulders of researchers Autonomy Informed consent Confidentiality Comprehension Voluntariness Beneficience Risks-to-Benefit Ratio Research Design (minimizing risk) Investigator Qualifications Conflicts of Interest Justice Balance of Burdens/Benefits Population of Inference Eligibility Criteria Representative of Population Equitable Recruitment Methods Informed Consent Purpose Methods and procedures in detail Risks and discomforts Risk of disease vs risk of study participation Benefits Alternatives to participation Voluntary and uncoerced Randomization Provides the best assurance that prognostic factors, both measured and unmeasured, are similar in treatment and control groups Provides the most credible evidence of treatment effects Placebo control is optimal to evaluate new treatments Only appropriate when no known effective treatment is available Blinding Limits possible bias Patient response Physician attitude Outcome evaluation Decision-making during study Single-blind: treating physician knows but patient doesn’t Double-blind: neither the treating physician nor the patient knows Phases Phase I Trials: maximally tolerated dose Safety and tolerability Uncontrolled, unblinded Not randomized Phase II Trials: evaluate for evidence of a clinical effect Dose-finding (and continued safety) (dose dependence) Controlled or uncontrolled; may be blinded or unblinded Randomized or not randomized Phase III Trials: test whether a new treatment is superior Therapeutic ratio (and continued safety) (Drug x compared to drug y) Control is placebo or standard of care. Blinded Randomized Phase IV Trials: post-marketing surveillance (safety) Eligibility Disease type Prior therapy Performance status Evidence of adequate renal and hepatic function Measurable disease Prior malignancies Study Endpoints Adverse events standard criteria to categorize as: none, mild, moderate, severe, life-threatening Response Progressive disease Stable disease Parital response: decrease in the size of measurable disease by 50% Complete response Progression-free survival Overall survival Quality of life Early stopping rules To avoid subjecting participants to ineffective therapy Interim analysis: No effect, stop the trial Significant effect, stop the trial Intermediate, continue accrual. Landmark clinical trials in the treatment of ovarian cancer Suboptimal Stage III and any stage IV GOG 111 trial established platinum/taxane combination therapy as the standard of care RANDOMIZE Cisplatin (75 mg/m2 q21d x 6) PLUS Cyclophosphamide (750 mg/m2) Cisplatin (75 mg/m2 q21d x 6) PLUS Paclitaxel (135 mg/m2/24h) GOG 111: progression-free survival Patients (N) Proportion Surviving Progression Free 6 12 18 24 30 36 42 48 Months After Study Entry 54 60 66 72 78 84 0.8 0.9 0 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Cisplatin/Paclitaxel Cisplatin/ Cyclophosphamide Treatment Progression- Free 18 15 166 187 Failure 184 202 Total Median Survival 18.0 13.3 Relative Risk 0.70 – McGuire, NEJM, 1996 GOG 111: overall survival 0.8 0.9 0 6 12 18 24 30 36 42 48 Months from entry into study Proportion surviving Cisplatin/paclitaxel Cisplatin/ cyclophosphamide 54 60 66 72 78 84 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Treatment Alive 35 28 150 174 Died 184 202 Total Median Survival (mos) 36.9 24.8 Relative Risk 0.69 – No. Pts McGuire, NEJM, 1996 Substituting taxol for cytoxan improved survival Piccart, JNCI, 2000 McGuire, NEJM, 1996 *p<0.001 GOG 158: Is carboplatin as effective as cisplatin? Ozols, JCO, 2003 Outcome is the same, toxicity is different Ozols, JCO, 2003 Carboplatin and Taxol currently are standard chemotherapy for ovarian cancer. GOG 182: Is there anything to add to Carbo and taxol to improve outcomes? Does the route of administration make a difference? GOG 104: patients with optimally debulked stage III disease were randomized to IV cyclophosphamide and IV cisplatin or IV cyclophosphamide and IP cisplatin IP regimen was superior 25 vs 20% reponse rate 49 vs 41 month median survival Not widely adopted because standard of care shifted to carboplatin/taxol Cisplatin IV (75 mg/m2) PLUS Paclitaxel IV (135 mg/m2) Stage III, all < 1.0 cm RANDOMIZE Paclitaxel (135 mg/m2) IV Day 1 THEN Cisplatin (100 mg/m2) IP Day 2 THEN Paclitaxel (60 mg/m2) IP Day 8 GOG 172: Does IP administration improve results with platinum/taxane therapy? Prolonged remission seen with IP administration Armstrong, NEJM, 2006 Overall survival improved with IP administration Armstrong, NEJM, 2006 GOG 172 participation 86/205 = 41.9% 84/205 = 41.0% Armstrong, NEJM, 2006 IP chemotherapy summary Will targeted therapeutics improve response? Bevacizumab (Avastin) is an antibody to the vascular endothelial growth factor (VEGF) which blocks the formation of new blood vessels In phase II trials, Avastin demonstrated significant activity in patients with recurrent ovarian cancer GOG 218 tested Carboplatin/Taxol/Placebo vs Carboplatin/Taxol/Avastin vs Carboplatin/Taxol/Avastin + maintenance Avastin Improved progression free survival was seen in the group that got maintenance Avastin Most patients experience only mild toxicity with Avastin treatment Active GOG trials GOG 262: Does administering dose-dense Taxol improve the response? Weekly Taxol vs every three weeks with carboplatin, with or without Avastin GOG 213: Does Avastin improve the response to chemotherapy for recurrent disease? Does secondary surgical debulking benefit patients? Randomized to secondary debulking or no surgery Randomized to Carboplatin/Taxol/Placebo vs Carboplatin/Taxol/Avastin (concurrent and maintenance) GOG 252: Does Avastin improve response to IP chemotherapy? IV Carboplatin, IV weekly Taxol, Avastin IP Carboplatin, IV weekly Taxol, Avastin IV Taxol (day 1), IP Cisplatin (day 2), IP Taxol (day 8), Avastin GOG 212: Does monthly Taxol improve survival after primary adjuvant chemotherapy? Maintenance therapy with Taxol or CT2103 or no treatment for 12 months after primary adjuvant chemotherapy Evolution of a clinical trial: Penn 2003: T cells in the tumor correlates with improved survival Survival of patients with ovarian cancer: Tumor Infiltrating Lymphocytes (TIL) TIL+ TIL- First Phase I Vaccine Trial 2006: Dendritic cell vaccine Goal: to enhance the anti-tumor T cell response A cellular vaccine comprised of a subject’s own cells primed against ovarian cancer was developed Confirmed the safety of this approach Second Phase I trial: Whole tumor antigen vaccine Evidence in other solid tumors of a survival benefit following vaccination with dendritic cells pulsed with tumor lysate Demonstration of immunomodulatory effects of Avastin and Cytoxan chemotherapy UPCC 11807 Monocytes GMCSF+IL4 - Whole tumor antigen vaccine Pulsing with Tumor antigen Mature DC Immature DC Pre-treatment Post-vaccine An example of disease regression in a patient treated with Avastin and vaccine Pre-treatment PET scan 11807-01 Nov 2007 L PAoLN - 1.1x1.5 cm Feb 2008 L PAoLN - 0.6 x 1.1 cm
Slide 41 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance HIPAA Health Insurance Portability and Accountability Act, April 2003. Protects information about the physical or mental health of an individual relating to health, health care, or payment for care in the past, present or future. Institutional Review Boards (IRB) Protects the rights and welfare of research subjects Oversees the conduct of all human research Ensures compliance with all federal, state, local and institutional requirements in human subject research. Includes members of the community Principles governing clinical trials Regulatory codes place the responsibility for the ethical conduct of research on the shoulders of researchers Autonomy Informed consent Confidentiality Comprehension Voluntariness Beneficience Risks-to-Benefit Ratio Research Design (minimizing risk) Investigator Qualifications Conflicts of Interest Justice Balance of Burdens/Benefits Population of Inference Eligibility Criteria Representative of Population Equitable Recruitment Methods Informed Consent Purpose Methods and procedures in detail Risks and discomforts Risk of disease vs risk of study participation Benefits Alternatives to participation Voluntary and uncoerced Randomization Provides the best assurance that prognostic factors, both measured and unmeasured, are similar in treatment and control groups Provides the most credible evidence of treatment effects Placebo control is optimal to evaluate new treatments Only appropriate when no known effective treatment is available Blinding Limits possible bias Patient response Physician attitude Outcome evaluation Decision-making during study Single-blind: treating physician knows but patient doesn’t Double-blind: neither the treating physician nor the patient knows Phases Phase I Trials: maximally tolerated dose Safety and tolerability Uncontrolled, unblinded Not randomized Phase II Trials: evaluate for evidence of a clinical effect Dose-finding (and continued safety) (dose dependence) Controlled or uncontrolled; may be blinded or unblinded Randomized or not randomized Phase III Trials: test whether a new treatment is superior Therapeutic ratio (and continued safety) (Drug x compared to drug y) Control is placebo or standard of care. Blinded Randomized Phase IV Trials: post-marketing surveillance (safety) Eligibility Disease type Prior therapy Performance status Evidence of adequate renal and hepatic function Measurable disease Prior malignancies Study Endpoints Adverse events standard criteria to categorize as: none, mild, moderate, severe, life-threatening Response Progressive disease Stable disease Parital response: decrease in the size of measurable disease by 50% Complete response Progression-free survival Overall survival Quality of life Early stopping rules To avoid subjecting participants to ineffective therapy Interim analysis: No effect, stop the trial Significant effect, stop the trial Intermediate, continue accrual. Landmark clinical trials in the treatment of ovarian cancer Suboptimal Stage III and any stage IV GOG 111 trial established platinum/taxane combination therapy as the standard of care RANDOMIZE Cisplatin (75 mg/m2 q21d x 6) PLUS Cyclophosphamide (750 mg/m2) Cisplatin (75 mg/m2 q21d x 6) PLUS Paclitaxel (135 mg/m2/24h) GOG 111: progression-free survival Patients (N) Proportion Surviving Progression Free 6 12 18 24 30 36 42 48 Months After Study Entry 54 60 66 72 78 84 0.8 0.9 0 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Cisplatin/Paclitaxel Cisplatin/ Cyclophosphamide Treatment Progression- Free 18 15 166 187 Failure 184 202 Total Median Survival 18.0 13.3 Relative Risk 0.70 – McGuire, NEJM, 1996 GOG 111: overall survival 0.8 0.9 0 6 12 18 24 30 36 42 48 Months from entry into study Proportion surviving Cisplatin/paclitaxel Cisplatin/ cyclophosphamide 54 60 66 72 78 84 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Treatment Alive 35 28 150 174 Died 184 202 Total Median Survival (mos) 36.9 24.8 Relative Risk 0.69 – No. Pts McGuire, NEJM, 1996 Substituting taxol for cytoxan improved survival Piccart, JNCI, 2000 McGuire, NEJM, 1996 *p<0.001 GOG 158: Is carboplatin as effective as cisplatin? Ozols, JCO, 2003 Outcome is the same, toxicity is different Ozols, JCO, 2003 Carboplatin and Taxol currently are standard chemotherapy for ovarian cancer. GOG 182: Is there anything to add to Carbo and taxol to improve outcomes? Does the route of administration make a difference? GOG 104: patients with optimally debulked stage III disease were randomized to IV cyclophosphamide and IV cisplatin or IV cyclophosphamide and IP cisplatin IP regimen was superior 25 vs 20% reponse rate 49 vs 41 month median survival Not widely adopted because standard of care shifted to carboplatin/taxol Cisplatin IV (75 mg/m2) PLUS Paclitaxel IV (135 mg/m2) Stage III, all < 1.0 cm RANDOMIZE Paclitaxel (135 mg/m2) IV Day 1 THEN Cisplatin (100 mg/m2) IP Day 2 THEN Paclitaxel (60 mg/m2) IP Day 8 GOG 172: Does IP administration improve results with platinum/taxane therapy? Prolonged remission seen with IP administration Armstrong, NEJM, 2006 Overall survival improved with IP administration Armstrong, NEJM, 2006 GOG 172 participation 86/205 = 41.9% 84/205 = 41.0% Armstrong, NEJM, 2006 IP chemotherapy summary Will targeted therapeutics improve response? Bevacizumab (Avastin) is an antibody to the vascular endothelial growth factor (VEGF) which blocks the formation of new blood vessels In phase II trials, Avastin demonstrated significant activity in patients with recurrent ovarian cancer GOG 218 tested Carboplatin/Taxol/Placebo vs Carboplatin/Taxol/Avastin vs Carboplatin/Taxol/Avastin + maintenance Avastin Improved progression free survival was seen in the group that got maintenance Avastin Most patients experience only mild toxicity with Avastin treatment Active GOG trials GOG 262: Does administering dose-dense Taxol improve the response? Weekly Taxol vs every three weeks with carboplatin, with or without Avastin GOG 213: Does Avastin improve the response to chemotherapy for recurrent disease? Does secondary surgical debulking benefit patients? Randomized to secondary debulking or no surgery Randomized to Carboplatin/Taxol/Placebo vs Carboplatin/Taxol/Avastin (concurrent and maintenance) GOG 252: Does Avastin improve response to IP chemotherapy? IV Carboplatin, IV weekly Taxol, Avastin IP Carboplatin, IV weekly Taxol, Avastin IV Taxol (day 1), IP Cisplatin (day 2), IP Taxol (day 8), Avastin GOG 212: Does monthly Taxol improve survival after primary adjuvant chemotherapy? Maintenance therapy with Taxol or CT2103 or no treatment for 12 months after primary adjuvant chemotherapy Evolution of a clinical trial: Penn 2003: T cells in the tumor correlates with improved survival Survival of patients with ovarian cancer: Tumor Infiltrating Lymphocytes (TIL) TIL+ TIL- First Phase I Vaccine Trial 2006: Dendritic cell vaccine Goal: to enhance the anti-tumor T cell response A cellular vaccine comprised of a subject’s own cells primed against ovarian cancer was developed Confirmed the safety of this approach Second Phase I trial: Whole tumor antigen vaccine Evidence in other solid tumors of a survival benefit following vaccination with dendritic cells pulsed with tumor lysate Demonstration of immunomodulatory effects of Avastin and Cytoxan chemotherapy UPCC 11807 Monocytes GMCSF+IL4 - Whole tumor antigen vaccine Pulsing with Tumor antigen Mature DC Immature DC Pre-treatment Post-vaccine An example of disease regression in a patient treated with Avastin and vaccine Pre-treatment PET scan 11807-01 Nov 2007 L PAoLN - 1.1x1.5 cm Feb 2008 L PAoLN - 0.6 x 1.1 cm Combination therapy was feasible and well tolerated Of the six patients enrolled, two had a partial response (PR), 2 had stable disease (SD), and two had progressive disease (PD) Responses paralleled decreases in serum CA-125 levels. Evidence of vaccine-specific immune responses were demonstrated UPCC-11807: Vaccination was safe and well-tolerated with evidence of a clinical response
Slide 42 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance HIPAA Health Insurance Portability and Accountability Act, April 2003. Protects information about the physical or mental health of an individual relating to health, health care, or payment for care in the past, present or future. Institutional Review Boards (IRB) Protects the rights and welfare of research subjects Oversees the conduct of all human research Ensures compliance with all federal, state, local and institutional requirements in human subject research. Includes members of the community Principles governing clinical trials Regulatory codes place the responsibility for the ethical conduct of research on the shoulders of researchers Autonomy Informed consent Confidentiality Comprehension Voluntariness Beneficience Risks-to-Benefit Ratio Research Design (minimizing risk) Investigator Qualifications Conflicts of Interest Justice Balance of Burdens/Benefits Population of Inference Eligibility Criteria Representative of Population Equitable Recruitment Methods Informed Consent Purpose Methods and procedures in detail Risks and discomforts Risk of disease vs risk of study participation Benefits Alternatives to participation Voluntary and uncoerced Randomization Provides the best assurance that prognostic factors, both measured and unmeasured, are similar in treatment and control groups Provides the most credible evidence of treatment effects Placebo control is optimal to evaluate new treatments Only appropriate when no known effective treatment is available Blinding Limits possible bias Patient response Physician attitude Outcome evaluation Decision-making during study Single-blind: treating physician knows but patient doesn’t Double-blind: neither the treating physician nor the patient knows Phases Phase I Trials: maximally tolerated dose Safety and tolerability Uncontrolled, unblinded Not randomized Phase II Trials: evaluate for evidence of a clinical effect Dose-finding (and continued safety) (dose dependence) Controlled or uncontrolled; may be blinded or unblinded Randomized or not randomized Phase III Trials: test whether a new treatment is superior Therapeutic ratio (and continued safety) (Drug x compared to drug y) Control is placebo or standard of care. Blinded Randomized Phase IV Trials: post-marketing surveillance (safety) Eligibility Disease type Prior therapy Performance status Evidence of adequate renal and hepatic function Measurable disease Prior malignancies Study Endpoints Adverse events standard criteria to categorize as: none, mild, moderate, severe, life-threatening Response Progressive disease Stable disease Parital response: decrease in the size of measurable disease by 50% Complete response Progression-free survival Overall survival Quality of life Early stopping rules To avoid subjecting participants to ineffective therapy Interim analysis: No effect, stop the trial Significant effect, stop the trial Intermediate, continue accrual. Landmark clinical trials in the treatment of ovarian cancer Suboptimal Stage III and any stage IV GOG 111 trial established platinum/taxane combination therapy as the standard of care RANDOMIZE Cisplatin (75 mg/m2 q21d x 6) PLUS Cyclophosphamide (750 mg/m2) Cisplatin (75 mg/m2 q21d x 6) PLUS Paclitaxel (135 mg/m2/24h) GOG 111: progression-free survival Patients (N) Proportion Surviving Progression Free 6 12 18 24 30 36 42 48 Months After Study Entry 54 60 66 72 78 84 0.8 0.9 0 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Cisplatin/Paclitaxel Cisplatin/ Cyclophosphamide Treatment Progression- Free 18 15 166 187 Failure 184 202 Total Median Survival 18.0 13.3 Relative Risk 0.70 – McGuire, NEJM, 1996 GOG 111: overall survival 0.8 0.9 0 6 12 18 24 30 36 42 48 Months from entry into study Proportion surviving Cisplatin/paclitaxel Cisplatin/ cyclophosphamide 54 60 66 72 78 84 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Treatment Alive 35 28 150 174 Died 184 202 Total Median Survival (mos) 36.9 24.8 Relative Risk 0.69 – No. Pts McGuire, NEJM, 1996 Substituting taxol for cytoxan improved survival Piccart, JNCI, 2000 McGuire, NEJM, 1996 *p<0.001 GOG 158: Is carboplatin as effective as cisplatin? Ozols, JCO, 2003 Outcome is the same, toxicity is different Ozols, JCO, 2003 Carboplatin and Taxol currently are standard chemotherapy for ovarian cancer. GOG 182: Is there anything to add to Carbo and taxol to improve outcomes? Does the route of administration make a difference? GOG 104: patients with optimally debulked stage III disease were randomized to IV cyclophosphamide and IV cisplatin or IV cyclophosphamide and IP cisplatin IP regimen was superior 25 vs 20% reponse rate 49 vs 41 month median survival Not widely adopted because standard of care shifted to carboplatin/taxol Cisplatin IV (75 mg/m2) PLUS Paclitaxel IV (135 mg/m2) Stage III, all < 1.0 cm RANDOMIZE Paclitaxel (135 mg/m2) IV Day 1 THEN Cisplatin (100 mg/m2) IP Day 2 THEN Paclitaxel (60 mg/m2) IP Day 8 GOG 172: Does IP administration improve results with platinum/taxane therapy? Prolonged remission seen with IP administration Armstrong, NEJM, 2006 Overall survival improved with IP administration Armstrong, NEJM, 2006 GOG 172 participation 86/205 = 41.9% 84/205 = 41.0% Armstrong, NEJM, 2006 IP chemotherapy summary Will targeted therapeutics improve response? Bevacizumab (Avastin) is an antibody to the vascular endothelial growth factor (VEGF) which blocks the formation of new blood vessels In phase II trials, Avastin demonstrated significant activity in patients with recurrent ovarian cancer GOG 218 tested Carboplatin/Taxol/Placebo vs Carboplatin/Taxol/Avastin vs Carboplatin/Taxol/Avastin + maintenance Avastin Improved progression free survival was seen in the group that got maintenance Avastin Most patients experience only mild toxicity with Avastin treatment Active GOG trials GOG 262: Does administering dose-dense Taxol improve the response? Weekly Taxol vs every three weeks with carboplatin, with or without Avastin GOG 213: Does Avastin improve the response to chemotherapy for recurrent disease? Does secondary surgical debulking benefit patients? Randomized to secondary debulking or no surgery Randomized to Carboplatin/Taxol/Placebo vs Carboplatin/Taxol/Avastin (concurrent and maintenance) GOG 252: Does Avastin improve response to IP chemotherapy? IV Carboplatin, IV weekly Taxol, Avastin IP Carboplatin, IV weekly Taxol, Avastin IV Taxol (day 1), IP Cisplatin (day 2), IP Taxol (day 8), Avastin GOG 212: Does monthly Taxol improve survival after primary adjuvant chemotherapy? Maintenance therapy with Taxol or CT2103 or no treatment for 12 months after primary adjuvant chemotherapy Evolution of a clinical trial: Penn 2003: T cells in the tumor correlates with improved survival Survival of patients with ovarian cancer: Tumor Infiltrating Lymphocytes (TIL) TIL+ TIL- First Phase I Vaccine Trial 2006: Dendritic cell vaccine Goal: to enhance the anti-tumor T cell response A cellular vaccine comprised of a subject’s own cells primed against ovarian cancer was developed Confirmed the safety of this approach Second Phase I trial: Whole tumor antigen vaccine Evidence in other solid tumors of a survival benefit following vaccination with dendritic cells pulsed with tumor lysate Demonstration of immunomodulatory effects of Avastin and Cytoxan chemotherapy UPCC 11807 Monocytes GMCSF+IL4 - Whole tumor antigen vaccine Pulsing with Tumor antigen Mature DC Immature DC Pre-treatment Post-vaccine An example of disease regression in a patient treated with Avastin and vaccine Pre-treatment PET scan 11807-01 Nov 2007 L PAoLN - 1.1x1.5 cm Feb 2008 L PAoLN - 0.6 x 1.1 cm Combination therapy was feasible and well tolerated Of the six patients enrolled, two had a partial response (PR), 2 had stable disease (SD), and two had progressive disease (PD) Responses paralleled decreases in serum CA-125 levels. Evidence of vaccine-specific immune responses were demonstrated UPCC-11807: Vaccination was safe and well-tolerated with evidence of a clinical response Pilot study of T cell transfer following anti-tumor vaccination Goal is to amplify anti-tumor T cells in the lab and then administer large numbers of tumor-specific T cells to the subject along with additional vaccinations and metronomic cytoxan chemotherapy.
Slide 43 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance HIPAA Health Insurance Portability and Accountability Act, April 2003. Protects information about the physical or mental health of an individual relating to health, health care, or payment for care in the past, present or future. Institutional Review Boards (IRB) Protects the rights and welfare of research subjects Oversees the conduct of all human research Ensures compliance with all federal, state, local and institutional requirements in human subject research. Includes members of the community Principles governing clinical trials Regulatory codes place the responsibility for the ethical conduct of research on the shoulders of researchers Autonomy Informed consent Confidentiality Comprehension Voluntariness Beneficience Risks-to-Benefit Ratio Research Design (minimizing risk) Investigator Qualifications Conflicts of Interest Justice Balance of Burdens/Benefits Population of Inference Eligibility Criteria Representative of Population Equitable Recruitment Methods Informed Consent Purpose Methods and procedures in detail Risks and discomforts Risk of disease vs risk of study participation Benefits Alternatives to participation Voluntary and uncoerced Randomization Provides the best assurance that prognostic factors, both measured and unmeasured, are similar in treatment and control groups Provides the most credible evidence of treatment effects Placebo control is optimal to evaluate new treatments Only appropriate when no known effective treatment is available Blinding Limits possible bias Patient response Physician attitude Outcome evaluation Decision-making during study Single-blind: treating physician knows but patient doesn’t Double-blind: neither the treating physician nor the patient knows Phases Phase I Trials: maximally tolerated dose Safety and tolerability Uncontrolled, unblinded Not randomized Phase II Trials: evaluate for evidence of a clinical effect Dose-finding (and continued safety) (dose dependence) Controlled or uncontrolled; may be blinded or unblinded Randomized or not randomized Phase III Trials: test whether a new treatment is superior Therapeutic ratio (and continued safety) (Drug x compared to drug y) Control is placebo or standard of care. Blinded Randomized Phase IV Trials: post-marketing surveillance (safety) Eligibility Disease type Prior therapy Performance status Evidence of adequate renal and hepatic function Measurable disease Prior malignancies Study Endpoints Adverse events standard criteria to categorize as: none, mild, moderate, severe, life-threatening Response Progressive disease Stable disease Parital response: decrease in the size of measurable disease by 50% Complete response Progression-free survival Overall survival Quality of life Early stopping rules To avoid subjecting participants to ineffective therapy Interim analysis: No effect, stop the trial Significant effect, stop the trial Intermediate, continue accrual. Landmark clinical trials in the treatment of ovarian cancer Suboptimal Stage III and any stage IV GOG 111 trial established platinum/taxane combination therapy as the standard of care RANDOMIZE Cisplatin (75 mg/m2 q21d x 6) PLUS Cyclophosphamide (750 mg/m2) Cisplatin (75 mg/m2 q21d x 6) PLUS Paclitaxel (135 mg/m2/24h) GOG 111: progression-free survival Patients (N) Proportion Surviving Progression Free 6 12 18 24 30 36 42 48 Months After Study Entry 54 60 66 72 78 84 0.8 0.9 0 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Cisplatin/Paclitaxel Cisplatin/ Cyclophosphamide Treatment Progression- Free 18 15 166 187 Failure 184 202 Total Median Survival 18.0 13.3 Relative Risk 0.70 – McGuire, NEJM, 1996 GOG 111: overall survival 0.8 0.9 0 6 12 18 24 30 36 42 48 Months from entry into study Proportion surviving Cisplatin/paclitaxel Cisplatin/ cyclophosphamide 54 60 66 72 78 84 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Treatment Alive 35 28 150 174 Died 184 202 Total Median Survival (mos) 36.9 24.8 Relative Risk 0.69 – No. Pts McGuire, NEJM, 1996 Substituting taxol for cytoxan improved survival Piccart, JNCI, 2000 McGuire, NEJM, 1996 *p<0.001 GOG 158: Is carboplatin as effective as cisplatin? Ozols, JCO, 2003 Outcome is the same, toxicity is different Ozols, JCO, 2003 Carboplatin and Taxol currently are standard chemotherapy for ovarian cancer. GOG 182: Is there anything to add to Carbo and taxol to improve outcomes? Does the route of administration make a difference? GOG 104: patients with optimally debulked stage III disease were randomized to IV cyclophosphamide and IV cisplatin or IV cyclophosphamide and IP cisplatin IP regimen was superior 25 vs 20% reponse rate 49 vs 41 month median survival Not widely adopted because standard of care shifted to carboplatin/taxol Cisplatin IV (75 mg/m2) PLUS Paclitaxel IV (135 mg/m2) Stage III, all < 1.0 cm RANDOMIZE Paclitaxel (135 mg/m2) IV Day 1 THEN Cisplatin (100 mg/m2) IP Day 2 THEN Paclitaxel (60 mg/m2) IP Day 8 GOG 172: Does IP administration improve results with platinum/taxane therapy? Prolonged remission seen with IP administration Armstrong, NEJM, 2006 Overall survival improved with IP administration Armstrong, NEJM, 2006 GOG 172 participation 86/205 = 41.9% 84/205 = 41.0% Armstrong, NEJM, 2006 IP chemotherapy summary Will targeted therapeutics improve response? Bevacizumab (Avastin) is an antibody to the vascular endothelial growth factor (VEGF) which blocks the formation of new blood vessels In phase II trials, Avastin demonstrated significant activity in patients with recurrent ovarian cancer GOG 218 tested Carboplatin/Taxol/Placebo vs Carboplatin/Taxol/Avastin vs Carboplatin/Taxol/Avastin + maintenance Avastin Improved progression free survival was seen in the group that got maintenance Avastin Most patients experience only mild toxicity with Avastin treatment Active GOG trials GOG 262: Does administering dose-dense Taxol improve the response? Weekly Taxol vs every three weeks with carboplatin, with or without Avastin GOG 213: Does Avastin improve the response to chemotherapy for recurrent disease? Does secondary surgical debulking benefit patients? Randomized to secondary debulking or no surgery Randomized to Carboplatin/Taxol/Placebo vs Carboplatin/Taxol/Avastin (concurrent and maintenance) GOG 252: Does Avastin improve response to IP chemotherapy? IV Carboplatin, IV weekly Taxol, Avastin IP Carboplatin, IV weekly Taxol, Avastin IV Taxol (day 1), IP Cisplatin (day 2), IP Taxol (day 8), Avastin GOG 212: Does monthly Taxol improve survival after primary adjuvant chemotherapy? Maintenance therapy with Taxol or CT2103 or no treatment for 12 months after primary adjuvant chemotherapy Evolution of a clinical trial: Penn 2003: T cells in the tumor correlates with improved survival Survival of patients with ovarian cancer: Tumor Infiltrating Lymphocytes (TIL) TIL+ TIL- First Phase I Vaccine Trial 2006: Dendritic cell vaccine Goal: to enhance the anti-tumor T cell response A cellular vaccine comprised of a subject’s own cells primed against ovarian cancer was developed Confirmed the safety of this approach Second Phase I trial: Whole tumor antigen vaccine Evidence in other solid tumors of a survival benefit following vaccination with dendritic cells pulsed with tumor lysate Demonstration of immunomodulatory effects of Avastin and Cytoxan chemotherapy UPCC 11807 Monocytes GMCSF+IL4 - Whole tumor antigen vaccine Pulsing with Tumor antigen Mature DC Immature DC Pre-treatment Post-vaccine An example of disease regression in a patient treated with Avastin and vaccine Pre-treatment PET scan 11807-01 Nov 2007 L PAoLN - 1.1x1.5 cm Feb 2008 L PAoLN - 0.6 x 1.1 cm Combination therapy was feasible and well tolerated Of the six patients enrolled, two had a partial response (PR), 2 had stable disease (SD), and two had progressive disease (PD) Responses paralleled decreases in serum CA-125 levels. Evidence of vaccine-specific immune responses were demonstrated UPCC-11807: Vaccination was safe and well-tolerated with evidence of a clinical response Pilot study of T cell transfer following anti-tumor vaccination Goal is to amplify anti-tumor T cells in the lab and then administer large numbers of tumor-specific T cells to the subject along with additional vaccinations and metronomic cytoxan chemotherapy. A second-generation whole tumor vaccine Growing evidence of the impact of the immunosuppressive tumor environment Research in the lab demonstrates enhanced immune function with changes in cell preparation UPCC 11809 Vaccine Tumor harvest Apheresis
Slide 44 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance HIPAA Health Insurance Portability and Accountability Act, April 2003. Protects information about the physical or mental health of an individual relating to health, health care, or payment for care in the past, present or future. Institutional Review Boards (IRB) Protects the rights and welfare of research subjects Oversees the conduct of all human research Ensures compliance with all federal, state, local and institutional requirements in human subject research. Includes members of the community Principles governing clinical trials Regulatory codes place the responsibility for the ethical conduct of research on the shoulders of researchers Autonomy Informed consent Confidentiality Comprehension Voluntariness Beneficience Risks-to-Benefit Ratio Research Design (minimizing risk) Investigator Qualifications Conflicts of Interest Justice Balance of Burdens/Benefits Population of Inference Eligibility Criteria Representative of Population Equitable Recruitment Methods Informed Consent Purpose Methods and procedures in detail Risks and discomforts Risk of disease vs risk of study participation Benefits Alternatives to participation Voluntary and uncoerced Randomization Provides the best assurance that prognostic factors, both measured and unmeasured, are similar in treatment and control groups Provides the most credible evidence of treatment effects Placebo control is optimal to evaluate new treatments Only appropriate when no known effective treatment is available Blinding Limits possible bias Patient response Physician attitude Outcome evaluation Decision-making during study Single-blind: treating physician knows but patient doesn’t Double-blind: neither the treating physician nor the patient knows Phases Phase I Trials: maximally tolerated dose Safety and tolerability Uncontrolled, unblinded Not randomized Phase II Trials: evaluate for evidence of a clinical effect Dose-finding (and continued safety) (dose dependence) Controlled or uncontrolled; may be blinded or unblinded Randomized or not randomized Phase III Trials: test whether a new treatment is superior Therapeutic ratio (and continued safety) (Drug x compared to drug y) Control is placebo or standard of care. Blinded Randomized Phase IV Trials: post-marketing surveillance (safety) Eligibility Disease type Prior therapy Performance status Evidence of adequate renal and hepatic function Measurable disease Prior malignancies Study Endpoints Adverse events standard criteria to categorize as: none, mild, moderate, severe, life-threatening Response Progressive disease Stable disease Parital response: decrease in the size of measurable disease by 50% Complete response Progression-free survival Overall survival Quality of life Early stopping rules To avoid subjecting participants to ineffective therapy Interim analysis: No effect, stop the trial Significant effect, stop the trial Intermediate, continue accrual. Landmark clinical trials in the treatment of ovarian cancer Suboptimal Stage III and any stage IV GOG 111 trial established platinum/taxane combination therapy as the standard of care RANDOMIZE Cisplatin (75 mg/m2 q21d x 6) PLUS Cyclophosphamide (750 mg/m2) Cisplatin (75 mg/m2 q21d x 6) PLUS Paclitaxel (135 mg/m2/24h) GOG 111: progression-free survival Patients (N) Proportion Surviving Progression Free 6 12 18 24 30 36 42 48 Months After Study Entry 54 60 66 72 78 84 0.8 0.9 0 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Cisplatin/Paclitaxel Cisplatin/ Cyclophosphamide Treatment Progression- Free 18 15 166 187 Failure 184 202 Total Median Survival 18.0 13.3 Relative Risk 0.70 – McGuire, NEJM, 1996 GOG 111: overall survival 0.8 0.9 0 6 12 18 24 30 36 42 48 Months from entry into study Proportion surviving Cisplatin/paclitaxel Cisplatin/ cyclophosphamide 54 60 66 72 78 84 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Treatment Alive 35 28 150 174 Died 184 202 Total Median Survival (mos) 36.9 24.8 Relative Risk 0.69 – No. Pts McGuire, NEJM, 1996 Substituting taxol for cytoxan improved survival Piccart, JNCI, 2000 McGuire, NEJM, 1996 *p<0.001 GOG 158: Is carboplatin as effective as cisplatin? Ozols, JCO, 2003 Outcome is the same, toxicity is different Ozols, JCO, 2003 Carboplatin and Taxol currently are standard chemotherapy for ovarian cancer. GOG 182: Is there anything to add to Carbo and taxol to improve outcomes? Does the route of administration make a difference? GOG 104: patients with optimally debulked stage III disease were randomized to IV cyclophosphamide and IV cisplatin or IV cyclophosphamide and IP cisplatin IP regimen was superior 25 vs 20% reponse rate 49 vs 41 month median survival Not widely adopted because standard of care shifted to carboplatin/taxol Cisplatin IV (75 mg/m2) PLUS Paclitaxel IV (135 mg/m2) Stage III, all < 1.0 cm RANDOMIZE Paclitaxel (135 mg/m2) IV Day 1 THEN Cisplatin (100 mg/m2) IP Day 2 THEN Paclitaxel (60 mg/m2) IP Day 8 GOG 172: Does IP administration improve results with platinum/taxane therapy? Prolonged remission seen with IP administration Armstrong, NEJM, 2006 Overall survival improved with IP administration Armstrong, NEJM, 2006 GOG 172 participation 86/205 = 41.9% 84/205 = 41.0% Armstrong, NEJM, 2006 IP chemotherapy summary Will targeted therapeutics improve response? Bevacizumab (Avastin) is an antibody to the vascular endothelial growth factor (VEGF) which blocks the formation of new blood vessels In phase II trials, Avastin demonstrated significant activity in patients with recurrent ovarian cancer GOG 218 tested Carboplatin/Taxol/Placebo vs Carboplatin/Taxol/Avastin vs Carboplatin/Taxol/Avastin + maintenance Avastin Improved progression free survival was seen in the group that got maintenance Avastin Most patients experience only mild toxicity with Avastin treatment Active GOG trials GOG 262: Does administering dose-dense Taxol improve the response? Weekly Taxol vs every three weeks with carboplatin, with or without Avastin GOG 213: Does Avastin improve the response to chemotherapy for recurrent disease? Does secondary surgical debulking benefit patients? Randomized to secondary debulking or no surgery Randomized to Carboplatin/Taxol/Placebo vs Carboplatin/Taxol/Avastin (concurrent and maintenance) GOG 252: Does Avastin improve response to IP chemotherapy? IV Carboplatin, IV weekly Taxol, Avastin IP Carboplatin, IV weekly Taxol, Avastin IV Taxol (day 1), IP Cisplatin (day 2), IP Taxol (day 8), Avastin GOG 212: Does monthly Taxol improve survival after primary adjuvant chemotherapy? Maintenance therapy with Taxol or CT2103 or no treatment for 12 months after primary adjuvant chemotherapy Evolution of a clinical trial: Penn 2003: T cells in the tumor correlates with improved survival Survival of patients with ovarian cancer: Tumor Infiltrating Lymphocytes (TIL) TIL+ TIL- First Phase I Vaccine Trial 2006: Dendritic cell vaccine Goal: to enhance the anti-tumor T cell response A cellular vaccine comprised of a subject’s own cells primed against ovarian cancer was developed Confirmed the safety of this approach Second Phase I trial: Whole tumor antigen vaccine Evidence in other solid tumors of a survival benefit following vaccination with dendritic cells pulsed with tumor lysate Demonstration of immunomodulatory effects of Avastin and Cytoxan chemotherapy UPCC 11807 Monocytes GMCSF+IL4 - Whole tumor antigen vaccine Pulsing with Tumor antigen Mature DC Immature DC Pre-treatment Post-vaccine An example of disease regression in a patient treated with Avastin and vaccine Pre-treatment PET scan 11807-01 Nov 2007 L PAoLN - 1.1x1.5 cm Feb 2008 L PAoLN - 0.6 x 1.1 cm Combination therapy was feasible and well tolerated Of the six patients enrolled, two had a partial response (PR), 2 had stable disease (SD), and two had progressive disease (PD) Responses paralleled decreases in serum CA-125 levels. Evidence of vaccine-specific immune responses were demonstrated UPCC-11807: Vaccination was safe and well-tolerated with evidence of a clinical response Pilot study of T cell transfer following anti-tumor vaccination Goal is to amplify anti-tumor T cells in the lab and then administer large numbers of tumor-specific T cells to the subject along with additional vaccinations and metronomic cytoxan chemotherapy. A second-generation whole tumor vaccine Growing evidence of the impact of the immunosuppressive tumor environment Research in the lab demonstrates enhanced immune function with changes in cell preparation UPCC 11809 Vaccine Tumor harvest Apheresis UPCC-11809 Eligibility Women with recurrent ovarian, fallopian tube or primary peritoneal cancer Prior cytoreductive surgery yielding tumor for lysate No residual tumor nodules >4.5 cm Good performance status May have received chemotherapy or other therapy after harvest of tumor and prior to enrollment – subjects without evidence of disease after therapy are still eligible Must recover from any toxicities resulting from chemotherapy prior to receiving the vaccine
Slide 45 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance HIPAA Health Insurance Portability and Accountability Act, April 2003. Protects information about the physical or mental health of an individual relating to health, health care, or payment for care in the past, present or future. Institutional Review Boards (IRB) Protects the rights and welfare of research subjects Oversees the conduct of all human research Ensures compliance with all federal, state, local and institutional requirements in human subject research. Includes members of the community Principles governing clinical trials Regulatory codes place the responsibility for the ethical conduct of research on the shoulders of researchers Autonomy Informed consent Confidentiality Comprehension Voluntariness Beneficience Risks-to-Benefit Ratio Research Design (minimizing risk) Investigator Qualifications Conflicts of Interest Justice Balance of Burdens/Benefits Population of Inference Eligibility Criteria Representative of Population Equitable Recruitment Methods Informed Consent Purpose Methods and procedures in detail Risks and discomforts Risk of disease vs risk of study participation Benefits Alternatives to participation Voluntary and uncoerced Randomization Provides the best assurance that prognostic factors, both measured and unmeasured, are similar in treatment and control groups Provides the most credible evidence of treatment effects Placebo control is optimal to evaluate new treatments Only appropriate when no known effective treatment is available Blinding Limits possible bias Patient response Physician attitude Outcome evaluation Decision-making during study Single-blind: treating physician knows but patient doesn’t Double-blind: neither the treating physician nor the patient knows Phases Phase I Trials: maximally tolerated dose Safety and tolerability Uncontrolled, unblinded Not randomized Phase II Trials: evaluate for evidence of a clinical effect Dose-finding (and continued safety) (dose dependence) Controlled or uncontrolled; may be blinded or unblinded Randomized or not randomized Phase III Trials: test whether a new treatment is superior Therapeutic ratio (and continued safety) (Drug x compared to drug y) Control is placebo or standard of care. Blinded Randomized Phase IV Trials: post-marketing surveillance (safety) Eligibility Disease type Prior therapy Performance status Evidence of adequate renal and hepatic function Measurable disease Prior malignancies Study Endpoints Adverse events standard criteria to categorize as: none, mild, moderate, severe, life-threatening Response Progressive disease Stable disease Parital response: decrease in the size of measurable disease by 50% Complete response Progression-free survival Overall survival Quality of life Early stopping rules To avoid subjecting participants to ineffective therapy Interim analysis: No effect, stop the trial Significant effect, stop the trial Intermediate, continue accrual. Landmark clinical trials in the treatment of ovarian cancer Suboptimal Stage III and any stage IV GOG 111 trial established platinum/taxane combination therapy as the standard of care RANDOMIZE Cisplatin (75 mg/m2 q21d x 6) PLUS Cyclophosphamide (750 mg/m2) Cisplatin (75 mg/m2 q21d x 6) PLUS Paclitaxel (135 mg/m2/24h) GOG 111: progression-free survival Patients (N) Proportion Surviving Progression Free 6 12 18 24 30 36 42 48 Months After Study Entry 54 60 66 72 78 84 0.8 0.9 0 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Cisplatin/Paclitaxel Cisplatin/ Cyclophosphamide Treatment Progression- Free 18 15 166 187 Failure 184 202 Total Median Survival 18.0 13.3 Relative Risk 0.70 – McGuire, NEJM, 1996 GOG 111: overall survival 0.8 0.9 0 6 12 18 24 30 36 42 48 Months from entry into study Proportion surviving Cisplatin/paclitaxel Cisplatin/ cyclophosphamide 54 60 66 72 78 84 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Treatment Alive 35 28 150 174 Died 184 202 Total Median Survival (mos) 36.9 24.8 Relative Risk 0.69 – No. Pts McGuire, NEJM, 1996 Substituting taxol for cytoxan improved survival Piccart, JNCI, 2000 McGuire, NEJM, 1996 *p<0.001 GOG 158: Is carboplatin as effective as cisplatin? Ozols, JCO, 2003 Outcome is the same, toxicity is different Ozols, JCO, 2003 Carboplatin and Taxol currently are standard chemotherapy for ovarian cancer. GOG 182: Is there anything to add to Carbo and taxol to improve outcomes? Does the route of administration make a difference? GOG 104: patients with optimally debulked stage III disease were randomized to IV cyclophosphamide and IV cisplatin or IV cyclophosphamide and IP cisplatin IP regimen was superior 25 vs 20% reponse rate 49 vs 41 month median survival Not widely adopted because standard of care shifted to carboplatin/taxol Cisplatin IV (75 mg/m2) PLUS Paclitaxel IV (135 mg/m2) Stage III, all < 1.0 cm RANDOMIZE Paclitaxel (135 mg/m2) IV Day 1 THEN Cisplatin (100 mg/m2) IP Day 2 THEN Paclitaxel (60 mg/m2) IP Day 8 GOG 172: Does IP administration improve results with platinum/taxane therapy? Prolonged remission seen with IP administration Armstrong, NEJM, 2006 Overall survival improved with IP administration Armstrong, NEJM, 2006 GOG 172 participation 86/205 = 41.9% 84/205 = 41.0% Armstrong, NEJM, 2006 IP chemotherapy summary Will targeted therapeutics improve response? Bevacizumab (Avastin) is an antibody to the vascular endothelial growth factor (VEGF) which blocks the formation of new blood vessels In phase II trials, Avastin demonstrated significant activity in patients with recurrent ovarian cancer GOG 218 tested Carboplatin/Taxol/Placebo vs Carboplatin/Taxol/Avastin vs Carboplatin/Taxol/Avastin + maintenance Avastin Improved progression free survival was seen in the group that got maintenance Avastin Most patients experience only mild toxicity with Avastin treatment Active GOG trials GOG 262: Does administering dose-dense Taxol improve the response? Weekly Taxol vs every three weeks with carboplatin, with or without Avastin GOG 213: Does Avastin improve the response to chemotherapy for recurrent disease? Does secondary surgical debulking benefit patients? Randomized to secondary debulking or no surgery Randomized to Carboplatin/Taxol/Placebo vs Carboplatin/Taxol/Avastin (concurrent and maintenance) GOG 252: Does Avastin improve response to IP chemotherapy? IV Carboplatin, IV weekly Taxol, Avastin IP Carboplatin, IV weekly Taxol, Avastin IV Taxol (day 1), IP Cisplatin (day 2), IP Taxol (day 8), Avastin GOG 212: Does monthly Taxol improve survival after primary adjuvant chemotherapy? Maintenance therapy with Taxol or CT2103 or no treatment for 12 months after primary adjuvant chemotherapy Evolution of a clinical trial: Penn 2003: T cells in the tumor correlates with improved survival Survival of patients with ovarian cancer: Tumor Infiltrating Lymphocytes (TIL) TIL+ TIL- First Phase I Vaccine Trial 2006: Dendritic cell vaccine Goal: to enhance the anti-tumor T cell response A cellular vaccine comprised of a subject’s own cells primed against ovarian cancer was developed Confirmed the safety of this approach Second Phase I trial: Whole tumor antigen vaccine Evidence in other solid tumors of a survival benefit following vaccination with dendritic cells pulsed with tumor lysate Demonstration of immunomodulatory effects of Avastin and Cytoxan chemotherapy UPCC 11807 Monocytes GMCSF+IL4 - Whole tumor antigen vaccine Pulsing with Tumor antigen Mature DC Immature DC Pre-treatment Post-vaccine An example of disease regression in a patient treated with Avastin and vaccine Pre-treatment PET scan 11807-01 Nov 2007 L PAoLN - 1.1x1.5 cm Feb 2008 L PAoLN - 0.6 x 1.1 cm Combination therapy was feasible and well tolerated Of the six patients enrolled, two had a partial response (PR), 2 had stable disease (SD), and two had progressive disease (PD) Responses paralleled decreases in serum CA-125 levels. Evidence of vaccine-specific immune responses were demonstrated UPCC-11807: Vaccination was safe and well-tolerated with evidence of a clinical response Pilot study of T cell transfer following anti-tumor vaccination Goal is to amplify anti-tumor T cells in the lab and then administer large numbers of tumor-specific T cells to the subject along with additional vaccinations and metronomic cytoxan chemotherapy. A second-generation whole tumor vaccine Growing evidence of the impact of the immunosuppressive tumor environment Research in the lab demonstrates enhanced immune function with changes in cell preparation UPCC 11809 Vaccine Tumor harvest Apheresis UPCC-11809 Eligibility Women with recurrent ovarian, fallopian tube or primary peritoneal cancer Prior cytoreductive surgery yielding tumor for lysate No residual tumor nodules >4.5 cm Good performance status May have received chemotherapy or other therapy after harvest of tumor and prior to enrollment – subjects without evidence of disease after therapy are still eligible Must recover from any toxicities resulting from chemotherapy prior to receiving the vaccine Future Directions New approaches to vaccine development: Planned clinical trial of intradermal vaccination with killed tumor lysate Transfer of T cells genetically engineered to recognize tumor Preclinical data in a mouse model suggests that an anti-tumor vaccine could be developed using ascites cells This could have the potential to reduce the cost and increase the availability of immune therapy for women with advanced disease
Slide 46 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance HIPAA Health Insurance Portability and Accountability Act, April 2003. Protects information about the physical or mental health of an individual relating to health, health care, or payment for care in the past, present or future. Institutional Review Boards (IRB) Protects the rights and welfare of research subjects Oversees the conduct of all human research Ensures compliance with all federal, state, local and institutional requirements in human subject research. Includes members of the community Principles governing clinical trials Regulatory codes place the responsibility for the ethical conduct of research on the shoulders of researchers Autonomy Informed consent Confidentiality Comprehension Voluntariness Beneficience Risks-to-Benefit Ratio Research Design (minimizing risk) Investigator Qualifications Conflicts of Interest Justice Balance of Burdens/Benefits Population of Inference Eligibility Criteria Representative of Population Equitable Recruitment Methods Informed Consent Purpose Methods and procedures in detail Risks and discomforts Risk of disease vs risk of study participation Benefits Alternatives to participation Voluntary and uncoerced Randomization Provides the best assurance that prognostic factors, both measured and unmeasured, are similar in treatment and control groups Provides the most credible evidence of treatment effects Placebo control is optimal to evaluate new treatments Only appropriate when no known effective treatment is available Blinding Limits possible bias Patient response Physician attitude Outcome evaluation Decision-making during study Single-blind: treating physician knows but patient doesn’t Double-blind: neither the treating physician nor the patient knows Phases Phase I Trials: maximally tolerated dose Safety and tolerability Uncontrolled, unblinded Not randomized Phase II Trials: evaluate for evidence of a clinical effect Dose-finding (and continued safety) (dose dependence) Controlled or uncontrolled; may be blinded or unblinded Randomized or not randomized Phase III Trials: test whether a new treatment is superior Therapeutic ratio (and continued safety) (Drug x compared to drug y) Control is placebo or standard of care. Blinded Randomized Phase IV Trials: post-marketing surveillance (safety) Eligibility Disease type Prior therapy Performance status Evidence of adequate renal and hepatic function Measurable disease Prior malignancies Study Endpoints Adverse events standard criteria to categorize as: none, mild, moderate, severe, life-threatening Response Progressive disease Stable disease Parital response: decrease in the size of measurable disease by 50% Complete response Progression-free survival Overall survival Quality of life Early stopping rules To avoid subjecting participants to ineffective therapy Interim analysis: No effect, stop the trial Significant effect, stop the trial Intermediate, continue accrual. Landmark clinical trials in the treatment of ovarian cancer Suboptimal Stage III and any stage IV GOG 111 trial established platinum/taxane combination therapy as the standard of care RANDOMIZE Cisplatin (75 mg/m2 q21d x 6) PLUS Cyclophosphamide (750 mg/m2) Cisplatin (75 mg/m2 q21d x 6) PLUS Paclitaxel (135 mg/m2/24h) GOG 111: progression-free survival Patients (N) Proportion Surviving Progression Free 6 12 18 24 30 36 42 48 Months After Study Entry 54 60 66 72 78 84 0.8 0.9 0 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Cisplatin/Paclitaxel Cisplatin/ Cyclophosphamide Treatment Progression- Free 18 15 166 187 Failure 184 202 Total Median Survival 18.0 13.3 Relative Risk 0.70 – McGuire, NEJM, 1996 GOG 111: overall survival 0.8 0.9 0 6 12 18 24 30 36 42 48 Months from entry into study Proportion surviving Cisplatin/paclitaxel Cisplatin/ cyclophosphamide 54 60 66 72 78 84 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Treatment Alive 35 28 150 174 Died 184 202 Total Median Survival (mos) 36.9 24.8 Relative Risk 0.69 – No. Pts McGuire, NEJM, 1996 Substituting taxol for cytoxan improved survival Piccart, JNCI, 2000 McGuire, NEJM, 1996 *p<0.001 GOG 158: Is carboplatin as effective as cisplatin? Ozols, JCO, 2003 Outcome is the same, toxicity is different Ozols, JCO, 2003 Carboplatin and Taxol currently are standard chemotherapy for ovarian cancer. GOG 182: Is there anything to add to Carbo and taxol to improve outcomes? Does the route of administration make a difference? GOG 104: patients with optimally debulked stage III disease were randomized to IV cyclophosphamide and IV cisplatin or IV cyclophosphamide and IP cisplatin IP regimen was superior 25 vs 20% reponse rate 49 vs 41 month median survival Not widely adopted because standard of care shifted to carboplatin/taxol Cisplatin IV (75 mg/m2) PLUS Paclitaxel IV (135 mg/m2) Stage III, all < 1.0 cm RANDOMIZE Paclitaxel (135 mg/m2) IV Day 1 THEN Cisplatin (100 mg/m2) IP Day 2 THEN Paclitaxel (60 mg/m2) IP Day 8 GOG 172: Does IP administration improve results with platinum/taxane therapy? Prolonged remission seen with IP administration Armstrong, NEJM, 2006 Overall survival improved with IP administration Armstrong, NEJM, 2006 GOG 172 participation 86/205 = 41.9% 84/205 = 41.0% Armstrong, NEJM, 2006 IP chemotherapy summary Will targeted therapeutics improve response? Bevacizumab (Avastin) is an antibody to the vascular endothelial growth factor (VEGF) which blocks the formation of new blood vessels In phase II trials, Avastin demonstrated significant activity in patients with recurrent ovarian cancer GOG 218 tested Carboplatin/Taxol/Placebo vs Carboplatin/Taxol/Avastin vs Carboplatin/Taxol/Avastin + maintenance Avastin Improved progression free survival was seen in the group that got maintenance Avastin Most patients experience only mild toxicity with Avastin treatment Active GOG trials GOG 262: Does administering dose-dense Taxol improve the response? Weekly Taxol vs every three weeks with carboplatin, with or without Avastin GOG 213: Does Avastin improve the response to chemotherapy for recurrent disease? Does secondary surgical debulking benefit patients? Randomized to secondary debulking or no surgery Randomized to Carboplatin/Taxol/Placebo vs Carboplatin/Taxol/Avastin (concurrent and maintenance) GOG 252: Does Avastin improve response to IP chemotherapy? IV Carboplatin, IV weekly Taxol, Avastin IP Carboplatin, IV weekly Taxol, Avastin IV Taxol (day 1), IP Cisplatin (day 2), IP Taxol (day 8), Avastin GOG 212: Does monthly Taxol improve survival after primary adjuvant chemotherapy? Maintenance therapy with Taxol or CT2103 or no treatment for 12 months after primary adjuvant chemotherapy Evolution of a clinical trial: Penn 2003: T cells in the tumor correlates with improved survival Survival of patients with ovarian cancer: Tumor Infiltrating Lymphocytes (TIL) TIL+ TIL- First Phase I Vaccine Trial 2006: Dendritic cell vaccine Goal: to enhance the anti-tumor T cell response A cellular vaccine comprised of a subject’s own cells primed against ovarian cancer was developed Confirmed the safety of this approach Second Phase I trial: Whole tumor antigen vaccine Evidence in other solid tumors of a survival benefit following vaccination with dendritic cells pulsed with tumor lysate Demonstration of immunomodulatory effects of Avastin and Cytoxan chemotherapy UPCC 11807 Monocytes GMCSF+IL4 - Whole tumor antigen vaccine Pulsing with Tumor antigen Mature DC Immature DC Pre-treatment Post-vaccine An example of disease regression in a patient treated with Avastin and vaccine Pre-treatment PET scan 11807-01 Nov 2007 L PAoLN - 1.1x1.5 cm Feb 2008 L PAoLN - 0.6 x 1.1 cm Combination therapy was feasible and well tolerated Of the six patients enrolled, two had a partial response (PR), 2 had stable disease (SD), and two had progressive disease (PD) Responses paralleled decreases in serum CA-125 levels. Evidence of vaccine-specific immune responses were demonstrated UPCC-11807: Vaccination was safe and well-tolerated with evidence of a clinical response Pilot study of T cell transfer following anti-tumor vaccination Goal is to amplify anti-tumor T cells in the lab and then administer large numbers of tumor-specific T cells to the subject along with additional vaccinations and metronomic cytoxan chemotherapy. A second-generation whole tumor vaccine Growing evidence of the impact of the immunosuppressive tumor environment Research in the lab demonstrates enhanced immune function with changes in cell preparation UPCC 11809 Vaccine Tumor harvest Apheresis UPCC-11809 Eligibility Women with recurrent ovarian, fallopian tube or primary peritoneal cancer Prior cytoreductive surgery yielding tumor for lysate No residual tumor nodules >4.5 cm Good performance status May have received chemotherapy or other therapy after harvest of tumor and prior to enrollment – subjects without evidence of disease after therapy are still eligible Must recover from any toxicities resulting from chemotherapy prior to receiving the vaccine Future Directions New approaches to vaccine development: Planned clinical trial of intradermal vaccination with killed tumor lysate Transfer of T cells genetically engineered to recognize tumor Preclinical data in a mouse model suggests that an anti-tumor vaccine could be developed using ascites cells This could have the potential to reduce the cost and increase the availability of immune therapy for women with advanced disease Hurdles Differences in the characteristics of clinical trial subjects and the general population Persistent bias Competition for patients Research Funding
Slide 47 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance HIPAA Health Insurance Portability and Accountability Act, April 2003. Protects information about the physical or mental health of an individual relating to health, health care, or payment for care in the past, present or future. Institutional Review Boards (IRB) Protects the rights and welfare of research subjects Oversees the conduct of all human research Ensures compliance with all federal, state, local and institutional requirements in human subject research. Includes members of the community Principles governing clinical trials Regulatory codes place the responsibility for the ethical conduct of research on the shoulders of researchers Autonomy Informed consent Confidentiality Comprehension Voluntariness Beneficience Risks-to-Benefit Ratio Research Design (minimizing risk) Investigator Qualifications Conflicts of Interest Justice Balance of Burdens/Benefits Population of Inference Eligibility Criteria Representative of Population Equitable Recruitment Methods Informed Consent Purpose Methods and procedures in detail Risks and discomforts Risk of disease vs risk of study participation Benefits Alternatives to participation Voluntary and uncoerced Randomization Provides the best assurance that prognostic factors, both measured and unmeasured, are similar in treatment and control groups Provides the most credible evidence of treatment effects Placebo control is optimal to evaluate new treatments Only appropriate when no known effective treatment is available Blinding Limits possible bias Patient response Physician attitude Outcome evaluation Decision-making during study Single-blind: treating physician knows but patient doesn’t Double-blind: neither the treating physician nor the patient knows Phases Phase I Trials: maximally tolerated dose Safety and tolerability Uncontrolled, unblinded Not randomized Phase II Trials: evaluate for evidence of a clinical effect Dose-finding (and continued safety) (dose dependence) Controlled or uncontrolled; may be blinded or unblinded Randomized or not randomized Phase III Trials: test whether a new treatment is superior Therapeutic ratio (and continued safety) (Drug x compared to drug y) Control is placebo or standard of care. Blinded Randomized Phase IV Trials: post-marketing surveillance (safety) Eligibility Disease type Prior therapy Performance status Evidence of adequate renal and hepatic function Measurable disease Prior malignancies Study Endpoints Adverse events standard criteria to categorize as: none, mild, moderate, severe, life-threatening Response Progressive disease Stable disease Parital response: decrease in the size of measurable disease by 50% Complete response Progression-free survival Overall survival Quality of life Early stopping rules To avoid subjecting participants to ineffective therapy Interim analysis: No effect, stop the trial Significant effect, stop the trial Intermediate, continue accrual. Landmark clinical trials in the treatment of ovarian cancer Suboptimal Stage III and any stage IV GOG 111 trial established platinum/taxane combination therapy as the standard of care RANDOMIZE Cisplatin (75 mg/m2 q21d x 6) PLUS Cyclophosphamide (750 mg/m2) Cisplatin (75 mg/m2 q21d x 6) PLUS Paclitaxel (135 mg/m2/24h) GOG 111: progression-free survival Patients (N) Proportion Surviving Progression Free 6 12 18 24 30 36 42 48 Months After Study Entry 54 60 66 72 78 84 0.8 0.9 0 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Cisplatin/Paclitaxel Cisplatin/ Cyclophosphamide Treatment Progression- Free 18 15 166 187 Failure 184 202 Total Median Survival 18.0 13.3 Relative Risk 0.70 – McGuire, NEJM, 1996 GOG 111: overall survival 0.8 0.9 0 6 12 18 24 30 36 42 48 Months from entry into study Proportion surviving Cisplatin/paclitaxel Cisplatin/ cyclophosphamide 54 60 66 72 78 84 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Treatment Alive 35 28 150 174 Died 184 202 Total Median Survival (mos) 36.9 24.8 Relative Risk 0.69 – No. Pts McGuire, NEJM, 1996 Substituting taxol for cytoxan improved survival Piccart, JNCI, 2000 McGuire, NEJM, 1996 *p<0.001 GOG 158: Is carboplatin as effective as cisplatin? Ozols, JCO, 2003 Outcome is the same, toxicity is different Ozols, JCO, 2003 Carboplatin and Taxol currently are standard chemotherapy for ovarian cancer. GOG 182: Is there anything to add to Carbo and taxol to improve outcomes? Does the route of administration make a difference? GOG 104: patients with optimally debulked stage III disease were randomized to IV cyclophosphamide and IV cisplatin or IV cyclophosphamide and IP cisplatin IP regimen was superior 25 vs 20% reponse rate 49 vs 41 month median survival Not widely adopted because standard of care shifted to carboplatin/taxol Cisplatin IV (75 mg/m2) PLUS Paclitaxel IV (135 mg/m2) Stage III, all < 1.0 cm RANDOMIZE Paclitaxel (135 mg/m2) IV Day 1 THEN Cisplatin (100 mg/m2) IP Day 2 THEN Paclitaxel (60 mg/m2) IP Day 8 GOG 172: Does IP administration improve results with platinum/taxane therapy? Prolonged remission seen with IP administration Armstrong, NEJM, 2006 Overall survival improved with IP administration Armstrong, NEJM, 2006 GOG 172 participation 86/205 = 41.9% 84/205 = 41.0% Armstrong, NEJM, 2006 IP chemotherapy summary Will targeted therapeutics improve response? Bevacizumab (Avastin) is an antibody to the vascular endothelial growth factor (VEGF) which blocks the formation of new blood vessels In phase II trials, Avastin demonstrated significant activity in patients with recurrent ovarian cancer GOG 218 tested Carboplatin/Taxol/Placebo vs Carboplatin/Taxol/Avastin vs Carboplatin/Taxol/Avastin + maintenance Avastin Improved progression free survival was seen in the group that got maintenance Avastin Most patients experience only mild toxicity with Avastin treatment Active GOG trials GOG 262: Does administering dose-dense Taxol improve the response? Weekly Taxol vs every three weeks with carboplatin, with or without Avastin GOG 213: Does Avastin improve the response to chemotherapy for recurrent disease? Does secondary surgical debulking benefit patients? Randomized to secondary debulking or no surgery Randomized to Carboplatin/Taxol/Placebo vs Carboplatin/Taxol/Avastin (concurrent and maintenance) GOG 252: Does Avastin improve response to IP chemotherapy? IV Carboplatin, IV weekly Taxol, Avastin IP Carboplatin, IV weekly Taxol, Avastin IV Taxol (day 1), IP Cisplatin (day 2), IP Taxol (day 8), Avastin GOG 212: Does monthly Taxol improve survival after primary adjuvant chemotherapy? Maintenance therapy with Taxol or CT2103 or no treatment for 12 months after primary adjuvant chemotherapy Evolution of a clinical trial: Penn 2003: T cells in the tumor correlates with improved survival Survival of patients with ovarian cancer: Tumor Infiltrating Lymphocytes (TIL) TIL+ TIL- First Phase I Vaccine Trial 2006: Dendritic cell vaccine Goal: to enhance the anti-tumor T cell response A cellular vaccine comprised of a subject’s own cells primed against ovarian cancer was developed Confirmed the safety of this approach Second Phase I trial: Whole tumor antigen vaccine Evidence in other solid tumors of a survival benefit following vaccination with dendritic cells pulsed with tumor lysate Demonstration of immunomodulatory effects of Avastin and Cytoxan chemotherapy UPCC 11807 Monocytes GMCSF+IL4 - Whole tumor antigen vaccine Pulsing with Tumor antigen Mature DC Immature DC Pre-treatment Post-vaccine An example of disease regression in a patient treated with Avastin and vaccine Pre-treatment PET scan 11807-01 Nov 2007 L PAoLN - 1.1x1.5 cm Feb 2008 L PAoLN - 0.6 x 1.1 cm Combination therapy was feasible and well tolerated Of the six patients enrolled, two had a partial response (PR), 2 had stable disease (SD), and two had progressive disease (PD) Responses paralleled decreases in serum CA-125 levels. Evidence of vaccine-specific immune responses were demonstrated UPCC-11807: Vaccination was safe and well-tolerated with evidence of a clinical response Pilot study of T cell transfer following anti-tumor vaccination Goal is to amplify anti-tumor T cells in the lab and then administer large numbers of tumor-specific T cells to the subject along with additional vaccinations and metronomic cytoxan chemotherapy. A second-generation whole tumor vaccine Growing evidence of the impact of the immunosuppressive tumor environment Research in the lab demonstrates enhanced immune function with changes in cell preparation UPCC 11809 Vaccine Tumor harvest Apheresis UPCC-11809 Eligibility Women with recurrent ovarian, fallopian tube or primary peritoneal cancer Prior cytoreductive surgery yielding tumor for lysate No residual tumor nodules >4.5 cm Good performance status May have received chemotherapy or other therapy after harvest of tumor and prior to enrollment – subjects without evidence of disease after therapy are still eligible Must recover from any toxicities resulting from chemotherapy prior to receiving the vaccine Future Directions New approaches to vaccine development: Planned clinical trial of intradermal vaccination with killed tumor lysate Transfer of T cells genetically engineered to recognize tumor Preclinical data in a mouse model suggests that an anti-tumor vaccine could be developed using ascites cells This could have the potential to reduce the cost and increase the availability of immune therapy for women with advanced disease Hurdles Differences in the characteristics of clinical trial subjects and the general population Persistent bias Competition for patients Research Funding Outcomes continue to improve
Slide 48 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance HIPAA Health Insurance Portability and Accountability Act, April 2003. Protects information about the physical or mental health of an individual relating to health, health care, or payment for care in the past, present or future. Institutional Review Boards (IRB) Protects the rights and welfare of research subjects Oversees the conduct of all human research Ensures compliance with all federal, state, local and institutional requirements in human subject research. Includes members of the community Principles governing clinical trials Regulatory codes place the responsibility for the ethical conduct of research on the shoulders of researchers Autonomy Informed consent Confidentiality Comprehension Voluntariness Beneficience Risks-to-Benefit Ratio Research Design (minimizing risk) Investigator Qualifications Conflicts of Interest Justice Balance of Burdens/Benefits Population of Inference Eligibility Criteria Representative of Population Equitable Recruitment Methods Informed Consent Purpose Methods and procedures in detail Risks and discomforts Risk of disease vs risk of study participation Benefits Alternatives to participation Voluntary and uncoerced Randomization Provides the best assurance that prognostic factors, both measured and unmeasured, are similar in treatment and control groups Provides the most credible evidence of treatment effects Placebo control is optimal to evaluate new treatments Only appropriate when no known effective treatment is available Blinding Limits possible bias Patient response Physician attitude Outcome evaluation Decision-making during study Single-blind: treating physician knows but patient doesn’t Double-blind: neither the treating physician nor the patient knows Phases Phase I Trials: maximally tolerated dose Safety and tolerability Uncontrolled, unblinded Not randomized Phase II Trials: evaluate for evidence of a clinical effect Dose-finding (and continued safety) (dose dependence) Controlled or uncontrolled; may be blinded or unblinded Randomized or not randomized Phase III Trials: test whether a new treatment is superior Therapeutic ratio (and continued safety) (Drug x compared to drug y) Control is placebo or standard of care. Blinded Randomized Phase IV Trials: post-marketing surveillance (safety) Eligibility Disease type Prior therapy Performance status Evidence of adequate renal and hepatic function Measurable disease Prior malignancies Study Endpoints Adverse events standard criteria to categorize as: none, mild, moderate, severe, life-threatening Response Progressive disease Stable disease Parital response: decrease in the size of measurable disease by 50% Complete response Progression-free survival Overall survival Quality of life Early stopping rules To avoid subjecting participants to ineffective therapy Interim analysis: No effect, stop the trial Significant effect, stop the trial Intermediate, continue accrual. Landmark clinical trials in the treatment of ovarian cancer Suboptimal Stage III and any stage IV GOG 111 trial established platinum/taxane combination therapy as the standard of care RANDOMIZE Cisplatin (75 mg/m2 q21d x 6) PLUS Cyclophosphamide (750 mg/m2) Cisplatin (75 mg/m2 q21d x 6) PLUS Paclitaxel (135 mg/m2/24h) GOG 111: progression-free survival Patients (N) Proportion Surviving Progression Free 6 12 18 24 30 36 42 48 Months After Study Entry 54 60 66 72 78 84 0.8 0.9 0 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Cisplatin/Paclitaxel Cisplatin/ Cyclophosphamide Treatment Progression- Free 18 15 166 187 Failure 184 202 Total Median Survival 18.0 13.3 Relative Risk 0.70 – McGuire, NEJM, 1996 GOG 111: overall survival 0.8 0.9 0 6 12 18 24 30 36 42 48 Months from entry into study Proportion surviving Cisplatin/paclitaxel Cisplatin/ cyclophosphamide 54 60 66 72 78 84 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Treatment Alive 35 28 150 174 Died 184 202 Total Median Survival (mos) 36.9 24.8 Relative Risk 0.69 – No. Pts McGuire, NEJM, 1996 Substituting taxol for cytoxan improved survival Piccart, JNCI, 2000 McGuire, NEJM, 1996 *p<0.001 GOG 158: Is carboplatin as effective as cisplatin? Ozols, JCO, 2003 Outcome is the same, toxicity is different Ozols, JCO, 2003 Carboplatin and Taxol currently are standard chemotherapy for ovarian cancer. GOG 182: Is there anything to add to Carbo and taxol to improve outcomes? Does the route of administration make a difference? GOG 104: patients with optimally debulked stage III disease were randomized to IV cyclophosphamide and IV cisplatin or IV cyclophosphamide and IP cisplatin IP regimen was superior 25 vs 20% reponse rate 49 vs 41 month median survival Not widely adopted because standard of care shifted to carboplatin/taxol Cisplatin IV (75 mg/m2) PLUS Paclitaxel IV (135 mg/m2) Stage III, all < 1.0 cm RANDOMIZE Paclitaxel (135 mg/m2) IV Day 1 THEN Cisplatin (100 mg/m2) IP Day 2 THEN Paclitaxel (60 mg/m2) IP Day 8 GOG 172: Does IP administration improve results with platinum/taxane therapy? Prolonged remission seen with IP administration Armstrong, NEJM, 2006 Overall survival improved with IP administration Armstrong, NEJM, 2006 GOG 172 participation 86/205 = 41.9% 84/205 = 41.0% Armstrong, NEJM, 2006 IP chemotherapy summary Will targeted therapeutics improve response? Bevacizumab (Avastin) is an antibody to the vascular endothelial growth factor (VEGF) which blocks the formation of new blood vessels In phase II trials, Avastin demonstrated significant activity in patients with recurrent ovarian cancer GOG 218 tested Carboplatin/Taxol/Placebo vs Carboplatin/Taxol/Avastin vs Carboplatin/Taxol/Avastin + maintenance Avastin Improved progression free survival was seen in the group that got maintenance Avastin Most patients experience only mild toxicity with Avastin treatment Active GOG trials GOG 262: Does administering dose-dense Taxol improve the response? Weekly Taxol vs every three weeks with carboplatin, with or without Avastin GOG 213: Does Avastin improve the response to chemotherapy for recurrent disease? Does secondary surgical debulking benefit patients? Randomized to secondary debulking or no surgery Randomized to Carboplatin/Taxol/Placebo vs Carboplatin/Taxol/Avastin (concurrent and maintenance) GOG 252: Does Avastin improve response to IP chemotherapy? IV Carboplatin, IV weekly Taxol, Avastin IP Carboplatin, IV weekly Taxol, Avastin IV Taxol (day 1), IP Cisplatin (day 2), IP Taxol (day 8), Avastin GOG 212: Does monthly Taxol improve survival after primary adjuvant chemotherapy? Maintenance therapy with Taxol or CT2103 or no treatment for 12 months after primary adjuvant chemotherapy Evolution of a clinical trial: Penn 2003: T cells in the tumor correlates with improved survival Survival of patients with ovarian cancer: Tumor Infiltrating Lymphocytes (TIL) TIL+ TIL- First Phase I Vaccine Trial 2006: Dendritic cell vaccine Goal: to enhance the anti-tumor T cell response A cellular vaccine comprised of a subject’s own cells primed against ovarian cancer was developed Confirmed the safety of this approach Second Phase I trial: Whole tumor antigen vaccine Evidence in other solid tumors of a survival benefit following vaccination with dendritic cells pulsed with tumor lysate Demonstration of immunomodulatory effects of Avastin and Cytoxan chemotherapy UPCC 11807 Monocytes GMCSF+IL4 - Whole tumor antigen vaccine Pulsing with Tumor antigen Mature DC Immature DC Pre-treatment Post-vaccine An example of disease regression in a patient treated with Avastin and vaccine Pre-treatment PET scan 11807-01 Nov 2007 L PAoLN - 1.1x1.5 cm Feb 2008 L PAoLN - 0.6 x 1.1 cm Combination therapy was feasible and well tolerated Of the six patients enrolled, two had a partial response (PR), 2 had stable disease (SD), and two had progressive disease (PD) Responses paralleled decreases in serum CA-125 levels. Evidence of vaccine-specific immune responses were demonstrated UPCC-11807: Vaccination was safe and well-tolerated with evidence of a clinical response Pilot study of T cell transfer following anti-tumor vaccination Goal is to amplify anti-tumor T cells in the lab and then administer large numbers of tumor-specific T cells to the subject along with additional vaccinations and metronomic cytoxan chemotherapy. A second-generation whole tumor vaccine Growing evidence of the impact of the immunosuppressive tumor environment Research in the lab demonstrates enhanced immune function with changes in cell preparation UPCC 11809 Vaccine Tumor harvest Apheresis UPCC-11809 Eligibility Women with recurrent ovarian, fallopian tube or primary peritoneal cancer Prior cytoreductive surgery yielding tumor for lysate No residual tumor nodules >4.5 cm Good performance status May have received chemotherapy or other therapy after harvest of tumor and prior to enrollment – subjects without evidence of disease after therapy are still eligible Must recover from any toxicities resulting from chemotherapy prior to receiving the vaccine Future Directions New approaches to vaccine development: Planned clinical trial of intradermal vaccination with killed tumor lysate Transfer of T cells genetically engineered to recognize tumor Preclinical data in a mouse model suggests that an anti-tumor vaccine could be developed using ascites cells This could have the potential to reduce the cost and increase the availability of immune therapy for women with advanced disease Hurdles Differences in the characteristics of clinical trial subjects and the general population Persistent bias Competition for patients Research Funding Outcomes continue to improve
Slide 49 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance HIPAA Health Insurance Portability and Accountability Act, April 2003. Protects information about the physical or mental health of an individual relating to health, health care, or payment for care in the past, present or future. Institutional Review Boards (IRB) Protects the rights and welfare of research subjects Oversees the conduct of all human research Ensures compliance with all federal, state, local and institutional requirements in human subject research. Includes members of the community Principles governing clinical trials Regulatory codes place the responsibility for the ethical conduct of research on the shoulders of researchers Autonomy Informed consent Confidentiality Comprehension Voluntariness Beneficience Risks-to-Benefit Ratio Research Design (minimizing risk) Investigator Qualifications Conflicts of Interest Justice Balance of Burdens/Benefits Population of Inference Eligibility Criteria Representative of Population Equitable Recruitment Methods Informed Consent Purpose Methods and procedures in detail Risks and discomforts Risk of disease vs risk of study participation Benefits Alternatives to participation Voluntary and uncoerced Randomization Provides the best assurance that prognostic factors, both measured and unmeasured, are similar in treatment and control groups Provides the most credible evidence of treatment effects Placebo control is optimal to evaluate new treatments Only appropriate when no known effective treatment is available Blinding Limits possible bias Patient response Physician attitude Outcome evaluation Decision-making during study Single-blind: treating physician knows but patient doesn’t Double-blind: neither the treating physician nor the patient knows Phases Phase I Trials: maximally tolerated dose Safety and tolerability Uncontrolled, unblinded Not randomized Phase II Trials: evaluate for evidence of a clinical effect Dose-finding (and continued safety) (dose dependence) Controlled or uncontrolled; may be blinded or unblinded Randomized or not randomized Phase III Trials: test whether a new treatment is superior Therapeutic ratio (and continued safety) (Drug x compared to drug y) Control is placebo or standard of care. Blinded Randomized Phase IV Trials: post-marketing surveillance (safety) Eligibility Disease type Prior therapy Performance status Evidence of adequate renal and hepatic function Measurable disease Prior malignancies Study Endpoints Adverse events standard criteria to categorize as: none, mild, moderate, severe, life-threatening Response Progressive disease Stable disease Parital response: decrease in the size of measurable disease by 50% Complete response Progression-free survival Overall survival Quality of life Early stopping rules To avoid subjecting participants to ineffective therapy Interim analysis: No effect, stop the trial Significant effect, stop the trial Intermediate, continue accrual. Landmark clinical trials in the treatment of ovarian cancer Suboptimal Stage III and any stage IV GOG 111 trial established platinum/taxane combination therapy as the standard of care RANDOMIZE Cisplatin (75 mg/m2 q21d x 6) PLUS Cyclophosphamide (750 mg/m2) Cisplatin (75 mg/m2 q21d x 6) PLUS Paclitaxel (135 mg/m2/24h) GOG 111: progression-free survival Patients (N) Proportion Surviving Progression Free 6 12 18 24 30 36 42 48 Months After Study Entry 54 60 66 72 78 84 0.8 0.9 0 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Cisplatin/Paclitaxel Cisplatin/ Cyclophosphamide Treatment Progression- Free 18 15 166 187 Failure 184 202 Total Median Survival 18.0 13.3 Relative Risk 0.70 – McGuire, NEJM, 1996 GOG 111: overall survival 0.8 0.9 0 6 12 18 24 30 36 42 48 Months from entry into study Proportion surviving Cisplatin/paclitaxel Cisplatin/ cyclophosphamide 54 60 66 72 78 84 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Treatment Alive 35 28 150 174 Died 184 202 Total Median Survival (mos) 36.9 24.8 Relative Risk 0.69 – No. Pts McGuire, NEJM, 1996 Substituting taxol for cytoxan improved survival Piccart, JNCI, 2000 McGuire, NEJM, 1996 *p<0.001 GOG 158: Is carboplatin as effective as cisplatin? Ozols, JCO, 2003 Outcome is the same, toxicity is different Ozols, JCO, 2003 Carboplatin and Taxol currently are standard chemotherapy for ovarian cancer. GOG 182: Is there anything to add to Carbo and taxol to improve outcomes? Does the route of administration make a difference? GOG 104: patients with optimally debulked stage III disease were randomized to IV cyclophosphamide and IV cisplatin or IV cyclophosphamide and IP cisplatin IP regimen was superior 25 vs 20% reponse rate 49 vs 41 month median survival Not widely adopted because standard of care shifted to carboplatin/taxol Cisplatin IV (75 mg/m2) PLUS Paclitaxel IV (135 mg/m2) Stage III, all < 1.0 cm RANDOMIZE Paclitaxel (135 mg/m2) IV Day 1 THEN Cisplatin (100 mg/m2) IP Day 2 THEN Paclitaxel (60 mg/m2) IP Day 8 GOG 172: Does IP administration improve results with platinum/taxane therapy? Prolonged remission seen with IP administration Armstrong, NEJM, 2006 Overall survival improved with IP administration Armstrong, NEJM, 2006 GOG 172 participation 86/205 = 41.9% 84/205 = 41.0% Armstrong, NEJM, 2006 IP chemotherapy summary Will targeted therapeutics improve response? Bevacizumab (Avastin) is an antibody to the vascular endothelial growth factor (VEGF) which blocks the formation of new blood vessels In phase II trials, Avastin demonstrated significant activity in patients with recurrent ovarian cancer GOG 218 tested Carboplatin/Taxol/Placebo vs Carboplatin/Taxol/Avastin vs Carboplatin/Taxol/Avastin + maintenance Avastin Improved progression free survival was seen in the group that got maintenance Avastin Most patients experience only mild toxicity with Avastin treatment Active GOG trials GOG 262: Does administering dose-dense Taxol improve the response? Weekly Taxol vs every three weeks with carboplatin, with or without Avastin GOG 213: Does Avastin improve the response to chemotherapy for recurrent disease? Does secondary surgical debulking benefit patients? Randomized to secondary debulking or no surgery Randomized to Carboplatin/Taxol/Placebo vs Carboplatin/Taxol/Avastin (concurrent and maintenance) GOG 252: Does Avastin improve response to IP chemotherapy? IV Carboplatin, IV weekly Taxol, Avastin IP Carboplatin, IV weekly Taxol, Avastin IV Taxol (day 1), IP Cisplatin (day 2), IP Taxol (day 8), Avastin GOG 212: Does monthly Taxol improve survival after primary adjuvant chemotherapy? Maintenance therapy with Taxol or CT2103 or no treatment for 12 months after primary adjuvant chemotherapy Evolution of a clinical trial: Penn 2003: T cells in the tumor correlates with improved survival Survival of patients with ovarian cancer: Tumor Infiltrating Lymphocytes (TIL) TIL+ TIL- First Phase I Vaccine Trial 2006: Dendritic cell vaccine Goal: to enhance the anti-tumor T cell response A cellular vaccine comprised of a subject’s own cells primed against ovarian cancer was developed Confirmed the safety of this approach Second Phase I trial: Whole tumor antigen vaccine Evidence in other solid tumors of a survival benefit following vaccination with dendritic cells pulsed with tumor lysate Demonstration of immunomodulatory effects of Avastin and Cytoxan chemotherapy UPCC 11807 Monocytes GMCSF+IL4 - Whole tumor antigen vaccine Pulsing with Tumor antigen Mature DC Immature DC Pre-treatment Post-vaccine An example of disease regression in a patient treated with Avastin and vaccine Pre-treatment PET scan 11807-01 Nov 2007 L PAoLN - 1.1x1.5 cm Feb 2008 L PAoLN - 0.6 x 1.1 cm Combination therapy was feasible and well tolerated Of the six patients enrolled, two had a partial response (PR), 2 had stable disease (SD), and two had progressive disease (PD) Responses paralleled decreases in serum CA-125 levels. Evidence of vaccine-specific immune responses were demonstrated UPCC-11807: Vaccination was safe and well-tolerated with evidence of a clinical response Pilot study of T cell transfer following anti-tumor vaccination Goal is to amplify anti-tumor T cells in the lab and then administer large numbers of tumor-specific T cells to the subject along with additional vaccinations and metronomic cytoxan chemotherapy. A second-generation whole tumor vaccine Growing evidence of the impact of the immunosuppressive tumor environment Research in the lab demonstrates enhanced immune function with changes in cell preparation UPCC 11809 Vaccine Tumor harvest Apheresis UPCC-11809 Eligibility Women with recurrent ovarian, fallopian tube or primary peritoneal cancer Prior cytoreductive surgery yielding tumor for lysate No residual tumor nodules >4.5 cm Good performance status May have received chemotherapy or other therapy after harvest of tumor and prior to enrollment – subjects without evidence of disease after therapy are still eligible Must recover from any toxicities resulting from chemotherapy prior to receiving the vaccine Future Directions New approaches to vaccine development: Planned clinical trial of intradermal vaccination with killed tumor lysate Transfer of T cells genetically engineered to recognize tumor Preclinical data in a mouse model suggests that an anti-tumor vaccine could be developed using ascites cells This could have the potential to reduce the cost and increase the availability of immune therapy for women with advanced disease Hurdles Differences in the characteristics of clinical trial subjects and the general population Persistent bias Competition for patients Research Funding Outcomes continue to improve
Slide 50 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance HIPAA Health Insurance Portability and Accountability Act, April 2003. Protects information about the physical or mental health of an individual relating to health, health care, or payment for care in the past, present or future. Institutional Review Boards (IRB) Protects the rights and welfare of research subjects Oversees the conduct of all human research Ensures compliance with all federal, state, local and institutional requirements in human subject research. Includes members of the community Principles governing clinical trials Regulatory codes place the responsibility for the ethical conduct of research on the shoulders of researchers Autonomy Informed consent Confidentiality Comprehension Voluntariness Beneficience Risks-to-Benefit Ratio Research Design (minimizing risk) Investigator Qualifications Conflicts of Interest Justice Balance of Burdens/Benefits Population of Inference Eligibility Criteria Representative of Population Equitable Recruitment Methods Informed Consent Purpose Methods and procedures in detail Risks and discomforts Risk of disease vs risk of study participation Benefits Alternatives to participation Voluntary and uncoerced Randomization Provides the best assurance that prognostic factors, both measured and unmeasured, are similar in treatment and control groups Provides the most credible evidence of treatment effects Placebo control is optimal to evaluate new treatments Only appropriate when no known effective treatment is available Blinding Limits possible bias Patient response Physician attitude Outcome evaluation Decision-making during study Single-blind: treating physician knows but patient doesn’t Double-blind: neither the treating physician nor the patient knows Phases Phase I Trials: maximally tolerated dose Safety and tolerability Uncontrolled, unblinded Not randomized Phase II Trials: evaluate for evidence of a clinical effect Dose-finding (and continued safety) (dose dependence) Controlled or uncontrolled; may be blinded or unblinded Randomized or not randomized Phase III Trials: test whether a new treatment is superior Therapeutic ratio (and continued safety) (Drug x compared to drug y) Control is placebo or standard of care. Blinded Randomized Phase IV Trials: post-marketing surveillance (safety) Eligibility Disease type Prior therapy Performance status Evidence of adequate renal and hepatic function Measurable disease Prior malignancies Study Endpoints Adverse events standard criteria to categorize as: none, mild, moderate, severe, life-threatening Response Progressive disease Stable disease Parital response: decrease in the size of measurable disease by 50% Complete response Progression-free survival Overall survival Quality of life Early stopping rules To avoid subjecting participants to ineffective therapy Interim analysis: No effect, stop the trial Significant effect, stop the trial Intermediate, continue accrual. Landmark clinical trials in the treatment of ovarian cancer Suboptimal Stage III and any stage IV GOG 111 trial established platinum/taxane combination therapy as the standard of care RANDOMIZE Cisplatin (75 mg/m2 q21d x 6) PLUS Cyclophosphamide (750 mg/m2) Cisplatin (75 mg/m2 q21d x 6) PLUS Paclitaxel (135 mg/m2/24h) GOG 111: progression-free survival Patients (N) Proportion Surviving Progression Free 6 12 18 24 30 36 42 48 Months After Study Entry 54 60 66 72 78 84 0.8 0.9 0 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Cisplatin/Paclitaxel Cisplatin/ Cyclophosphamide Treatment Progression- Free 18 15 166 187 Failure 184 202 Total Median Survival 18.0 13.3 Relative Risk 0.70 – McGuire, NEJM, 1996 GOG 111: overall survival 0.8 0.9 0 6 12 18 24 30 36 42 48 Months from entry into study Proportion surviving Cisplatin/paclitaxel Cisplatin/ cyclophosphamide 54 60 66 72 78 84 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Treatment Alive 35 28 150 174 Died 184 202 Total Median Survival (mos) 36.9 24.8 Relative Risk 0.69 – No. Pts McGuire, NEJM, 1996 Substituting taxol for cytoxan improved survival Piccart, JNCI, 2000 McGuire, NEJM, 1996 *p<0.001 GOG 158: Is carboplatin as effective as cisplatin? Ozols, JCO, 2003 Outcome is the same, toxicity is different Ozols, JCO, 2003 Carboplatin and Taxol currently are standard chemotherapy for ovarian cancer. GOG 182: Is there anything to add to Carbo and taxol to improve outcomes? Does the route of administration make a difference? GOG 104: patients with optimally debulked stage III disease were randomized to IV cyclophosphamide and IV cisplatin or IV cyclophosphamide and IP cisplatin IP regimen was superior 25 vs 20% reponse rate 49 vs 41 month median survival Not widely adopted because standard of care shifted to carboplatin/taxol Cisplatin IV (75 mg/m2) PLUS Paclitaxel IV (135 mg/m2) Stage III, all < 1.0 cm RANDOMIZE Paclitaxel (135 mg/m2) IV Day 1 THEN Cisplatin (100 mg/m2) IP Day 2 THEN Paclitaxel (60 mg/m2) IP Day 8 GOG 172: Does IP administration improve results with platinum/taxane therapy? Prolonged remission seen with IP administration Armstrong, NEJM, 2006 Overall survival improved with IP administration Armstrong, NEJM, 2006 GOG 172 participation 86/205 = 41.9% 84/205 = 41.0% Armstrong, NEJM, 2006 IP chemotherapy summary Will targeted therapeutics improve response? Bevacizumab (Avastin) is an antibody to the vascular endothelial growth factor (VEGF) which blocks the formation of new blood vessels In phase II trials, Avastin demonstrated significant activity in patients with recurrent ovarian cancer GOG 218 tested Carboplatin/Taxol/Placebo vs Carboplatin/Taxol/Avastin vs Carboplatin/Taxol/Avastin + maintenance Avastin Improved progression free survival was seen in the group that got maintenance Avastin Most patients experience only mild toxicity with Avastin treatment Active GOG trials GOG 262: Does administering dose-dense Taxol improve the response? Weekly Taxol vs every three weeks with carboplatin, with or without Avastin GOG 213: Does Avastin improve the response to chemotherapy for recurrent disease? Does secondary surgical debulking benefit patients? Randomized to secondary debulking or no surgery Randomized to Carboplatin/Taxol/Placebo vs Carboplatin/Taxol/Avastin (concurrent and maintenance) GOG 252: Does Avastin improve response to IP chemotherapy? IV Carboplatin, IV weekly Taxol, Avastin IP Carboplatin, IV weekly Taxol, Avastin IV Taxol (day 1), IP Cisplatin (day 2), IP Taxol (day 8), Avastin GOG 212: Does monthly Taxol improve survival after primary adjuvant chemotherapy? Maintenance therapy with Taxol or CT2103 or no treatment for 12 months after primary adjuvant chemotherapy Evolution of a clinical trial: Penn 2003: T cells in the tumor correlates with improved survival Survival of patients with ovarian cancer: Tumor Infiltrating Lymphocytes (TIL) TIL+ TIL- First Phase I Vaccine Trial 2006: Dendritic cell vaccine Goal: to enhance the anti-tumor T cell response A cellular vaccine comprised of a subject’s own cells primed against ovarian cancer was developed Confirmed the safety of this approach Second Phase I trial: Whole tumor antigen vaccine Evidence in other solid tumors of a survival benefit following vaccination with dendritic cells pulsed with tumor lysate Demonstration of immunomodulatory effects of Avastin and Cytoxan chemotherapy UPCC 11807 Monocytes GMCSF+IL4 - Whole tumor antigen vaccine Pulsing with Tumor antigen Mature DC Immature DC Pre-treatment Post-vaccine An example of disease regression in a patient treated with Avastin and vaccine Pre-treatment PET scan 11807-01 Nov 2007 L PAoLN - 1.1x1.5 cm Feb 2008 L PAoLN - 0.6 x 1.1 cm Combination therapy was feasible and well tolerated Of the six patients enrolled, two had a partial response (PR), 2 had stable disease (SD), and two had progressive disease (PD) Responses paralleled decreases in serum CA-125 levels. Evidence of vaccine-specific immune responses were demonstrated UPCC-11807: Vaccination was safe and well-tolerated with evidence of a clinical response Pilot study of T cell transfer following anti-tumor vaccination Goal is to amplify anti-tumor T cells in the lab and then administer large numbers of tumor-specific T cells to the subject along with additional vaccinations and metronomic cytoxan chemotherapy. A second-generation whole tumor vaccine Growing evidence of the impact of the immunosuppressive tumor environment Research in the lab demonstrates enhanced immune function with changes in cell preparation UPCC 11809 Vaccine Tumor harvest Apheresis UPCC-11809 Eligibility Women with recurrent ovarian, fallopian tube or primary peritoneal cancer Prior cytoreductive surgery yielding tumor for lysate No residual tumor nodules >4.5 cm Good performance status May have received chemotherapy or other therapy after harvest of tumor and prior to enrollment – subjects without evidence of disease after therapy are still eligible Must recover from any toxicities resulting from chemotherapy prior to receiving the vaccine Future Directions New approaches to vaccine development: Planned clinical trial of intradermal vaccination with killed tumor lysate Transfer of T cells genetically engineered to recognize tumor Preclinical data in a mouse model suggests that an anti-tumor vaccine could be developed using ascites cells This could have the potential to reduce the cost and increase the availability of immune therapy for women with advanced disease Hurdles Differences in the characteristics of clinical trial subjects and the general population Persistent bias Competition for patients Research Funding Outcomes continue to improve For more information Department of Health and Human Services www.dhhs.gov FDA (U.S. Food and Drug Administration) www.fda.gov FDA Center for Drug Evaluation and Research www.fda.gov/cder/ National Institutes of Health www.nih.gov/ or https://clinicaltrials.gov NIH: National Cancer Institute www.nci.nih.gov/ Office of Human Research Protections http://www.hhs.gov/ohrp/ The University of Pennsylvania Susan Mauro RN CCRCsusan.mauro@uphs.upenn.edu Cathi Ybarra, BSN, RN ybarrac@obgyn.upenn.edu
Slide 51 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance HIPAA Health Insurance Portability and Accountability Act, April 2003. Protects information about the physical or mental health of an individual relating to health, health care, or payment for care in the past, present or future. Institutional Review Boards (IRB) Protects the rights and welfare of research subjects Oversees the conduct of all human research Ensures compliance with all federal, state, local and institutional requirements in human subject research. Includes members of the community Principles governing clinical trials Regulatory codes place the responsibility for the ethical conduct of research on the shoulders of researchers Autonomy Informed consent Confidentiality Comprehension Voluntariness Beneficience Risks-to-Benefit Ratio Research Design (minimizing risk) Investigator Qualifications Conflicts of Interest Justice Balance of Burdens/Benefits Population of Inference Eligibility Criteria Representative of Population Equitable Recruitment Methods Informed Consent Purpose Methods and procedures in detail Risks and discomforts Risk of disease vs risk of study participation Benefits Alternatives to participation Voluntary and uncoerced Randomization Provides the best assurance that prognostic factors, both measured and unmeasured, are similar in treatment and control groups Provides the most credible evidence of treatment effects Placebo control is optimal to evaluate new treatments Only appropriate when no known effective treatment is available Blinding Limits possible bias Patient response Physician attitude Outcome evaluation Decision-making during study Single-blind: treating physician knows but patient doesn’t Double-blind: neither the treating physician nor the patient knows Phases Phase I Trials: maximally tolerated dose Safety and tolerability Uncontrolled, unblinded Not randomized Phase II Trials: evaluate for evidence of a clinical effect Dose-finding (and continued safety) (dose dependence) Controlled or uncontrolled; may be blinded or unblinded Randomized or not randomized Phase III Trials: test whether a new treatment is superior Therapeutic ratio (and continued safety) (Drug x compared to drug y) Control is placebo or standard of care. Blinded Randomized Phase IV Trials: post-marketing surveillance (safety) Eligibility Disease type Prior therapy Performance status Evidence of adequate renal and hepatic function Measurable disease Prior malignancies Study Endpoints Adverse events standard criteria to categorize as: none, mild, moderate, severe, life-threatening Response Progressive disease Stable disease Parital response: decrease in the size of measurable disease by 50% Complete response Progression-free survival Overall survival Quality of life Early stopping rules To avoid subjecting participants to ineffective therapy Interim analysis: No effect, stop the trial Significant effect, stop the trial Intermediate, continue accrual. Landmark clinical trials in the treatment of ovarian cancer Suboptimal Stage III and any stage IV GOG 111 trial established platinum/taxane combination therapy as the standard of care RANDOMIZE Cisplatin (75 mg/m2 q21d x 6) PLUS Cyclophosphamide (750 mg/m2) Cisplatin (75 mg/m2 q21d x 6) PLUS Paclitaxel (135 mg/m2/24h) GOG 111: progression-free survival Patients (N) Proportion Surviving Progression Free 6 12 18 24 30 36 42 48 Months After Study Entry 54 60 66 72 78 84 0.8 0.9 0 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Cisplatin/Paclitaxel Cisplatin/ Cyclophosphamide Treatment Progression- Free 18 15 166 187 Failure 184 202 Total Median Survival 18.0 13.3 Relative Risk 0.70 – McGuire, NEJM, 1996 GOG 111: overall survival 0.8 0.9 0 6 12 18 24 30 36 42 48 Months from entry into study Proportion surviving Cisplatin/paclitaxel Cisplatin/ cyclophosphamide 54 60 66 72 78 84 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Treatment Alive 35 28 150 174 Died 184 202 Total Median Survival (mos) 36.9 24.8 Relative Risk 0.69 – No. Pts McGuire, NEJM, 1996 Substituting taxol for cytoxan improved survival Piccart, JNCI, 2000 McGuire, NEJM, 1996 *p<0.001 GOG 158: Is carboplatin as effective as cisplatin? Ozols, JCO, 2003 Outcome is the same, toxicity is different Ozols, JCO, 2003 Carboplatin and Taxol currently are standard chemotherapy for ovarian cancer. GOG 182: Is there anything to add to Carbo and taxol to improve outcomes? Does the route of administration make a difference? GOG 104: patients with optimally debulked stage III disease were randomized to IV cyclophosphamide and IV cisplatin or IV cyclophosphamide and IP cisplatin IP regimen was superior 25 vs 20% reponse rate 49 vs 41 month median survival Not widely adopted because standard of care shifted to carboplatin/taxol Cisplatin IV (75 mg/m2) PLUS Paclitaxel IV (135 mg/m2) Stage III, all < 1.0 cm RANDOMIZE Paclitaxel (135 mg/m2) IV Day 1 THEN Cisplatin (100 mg/m2) IP Day 2 THEN Paclitaxel (60 mg/m2) IP Day 8 GOG 172: Does IP administration improve results with platinum/taxane therapy? Prolonged remission seen with IP administration Armstrong, NEJM, 2006 Overall survival improved with IP administration Armstrong, NEJM, 2006 GOG 172 participation 86/205 = 41.9% 84/205 = 41.0% Armstrong, NEJM, 2006 IP chemotherapy summary Will targeted therapeutics improve response? Bevacizumab (Avastin) is an antibody to the vascular endothelial growth factor (VEGF) which blocks the formation of new blood vessels In phase II trials, Avastin demonstrated significant activity in patients with recurrent ovarian cancer GOG 218 tested Carboplatin/Taxol/Placebo vs Carboplatin/Taxol/Avastin vs Carboplatin/Taxol/Avastin + maintenance Avastin Improved progression free survival was seen in the group that got maintenance Avastin Most patients experience only mild toxicity with Avastin treatment Active GOG trials GOG 262: Does administering dose-dense Taxol improve the response? Weekly Taxol vs every three weeks with carboplatin, with or without Avastin GOG 213: Does Avastin improve the response to chemotherapy for recurrent disease? Does secondary surgical debulking benefit patients? Randomized to secondary debulking or no surgery Randomized to Carboplatin/Taxol/Placebo vs Carboplatin/Taxol/Avastin (concurrent and maintenance) GOG 252: Does Avastin improve response to IP chemotherapy? IV Carboplatin, IV weekly Taxol, Avastin IP Carboplatin, IV weekly Taxol, Avastin IV Taxol (day 1), IP Cisplatin (day 2), IP Taxol (day 8), Avastin GOG 212: Does monthly Taxol improve survival after primary adjuvant chemotherapy? Maintenance therapy with Taxol or CT2103 or no treatment for 12 months after primary adjuvant chemotherapy Evolution of a clinical trial: Penn 2003: T cells in the tumor correlates with improved survival Survival of patients with ovarian cancer: Tumor Infiltrating Lymphocytes (TIL) TIL+ TIL- First Phase I Vaccine Trial 2006: Dendritic cell vaccine Goal: to enhance the anti-tumor T cell response A cellular vaccine comprised of a subject’s own cells primed against ovarian cancer was developed Confirmed the safety of this approach Second Phase I trial: Whole tumor antigen vaccine Evidence in other solid tumors of a survival benefit following vaccination with dendritic cells pulsed with tumor lysate Demonstration of immunomodulatory effects of Avastin and Cytoxan chemotherapy UPCC 11807 Monocytes GMCSF+IL4 - Whole tumor antigen vaccine Pulsing with Tumor antigen Mature DC Immature DC Pre-treatment Post-vaccine An example of disease regression in a patient treated with Avastin and vaccine Pre-treatment PET scan 11807-01 Nov 2007 L PAoLN - 1.1x1.5 cm Feb 2008 L PAoLN - 0.6 x 1.1 cm Combination therapy was feasible and well tolerated Of the six patients enrolled, two had a partial response (PR), 2 had stable disease (SD), and two had progressive disease (PD) Responses paralleled decreases in serum CA-125 levels. Evidence of vaccine-specific immune responses were demonstrated UPCC-11807: Vaccination was safe and well-tolerated with evidence of a clinical response Pilot study of T cell transfer following anti-tumor vaccination Goal is to amplify anti-tumor T cells in the lab and then administer large numbers of tumor-specific T cells to the subject along with additional vaccinations and metronomic cytoxan chemotherapy. A second-generation whole tumor vaccine Growing evidence of the impact of the immunosuppressive tumor environment Research in the lab demonstrates enhanced immune function with changes in cell preparation UPCC 11809 Vaccine Tumor harvest Apheresis UPCC-11809 Eligibility Women with recurrent ovarian, fallopian tube or primary peritoneal cancer Prior cytoreductive surgery yielding tumor for lysate No residual tumor nodules >4.5 cm Good performance status May have received chemotherapy or other therapy after harvest of tumor and prior to enrollment – subjects without evidence of disease after therapy are still eligible Must recover from any toxicities resulting from chemotherapy prior to receiving the vaccine Future Directions New approaches to vaccine development: Planned clinical trial of intradermal vaccination with killed tumor lysate Transfer of T cells genetically engineered to recognize tumor Preclinical data in a mouse model suggests that an anti-tumor vaccine could be developed using ascites cells This could have the potential to reduce the cost and increase the availability of immune therapy for women with advanced disease Hurdles Differences in the characteristics of clinical trial subjects and the general population Persistent bias Competition for patients Research Funding Outcomes continue to improve For more information Department of Health and Human Services www.dhhs.gov FDA (U.S. Food and Drug Administration) www.fda.gov FDA Center for Drug Evaluation and Research www.fda.gov/cder/ National Institutes of Health www.nih.gov/ or https://clinicaltrials.gov NIH: National Cancer Institute www.nci.nih.gov/ Office of Human Research Protections http://www.hhs.gov/ohrp/ The University of Pennsylvania Susan Mauro RN CCRCsusan.mauro@uphs.upenn.edu Cathi Ybarra, BSN, RN ybarrac@obgyn.upenn.edu Acknowledgements George Coukos, MD, PhD Christina Chu, MD Daniel Powell, PhD Lana Kandalaft, PhD Cathi Ybarra, BSN, RN GOG Research Program Manager ybarrac@obgyn.upenn.edu The Sandy Rollman Ovarian Cancer Foundation Kaleidoscope of Hope Foundation AACR Scholar-in-Training Award ASCO Young Investigators Award Ovarian Cancer SPORE Paul Calebressi NIH K12 Training Grant The Florence and Marshall Schwid Ovarian Cancer Research Grant from the Gynecologic Cancer Foundation Susan Mauro RN CCRC TRP Clinical Trials Unit 3620 Hamilton Walk Anatomy-Chemistry Bldg B-24 Philadelphia Pa 19104 P: 215-422-2560 susan.mauro@uphs.upenn.edu
Slide 52 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance HIPAA Health Insurance Portability and Accountability Act, April 2003. Protects information about the physical or mental health of an individual relating to health, health care, or payment for care in the past, present or future. Institutional Review Boards (IRB) Protects the rights and welfare of research subjects Oversees the conduct of all human research Ensures compliance with all federal, state, local and institutional requirements in human subject research. Includes members of the community Principles governing clinical trials Regulatory codes place the responsibility for the ethical conduct of research on the shoulders of researchers Autonomy Informed consent Confidentiality Comprehension Voluntariness Beneficience Risks-to-Benefit Ratio Research Design (minimizing risk) Investigator Qualifications Conflicts of Interest Justice Balance of Burdens/Benefits Population of Inference Eligibility Criteria Representative of Population Equitable Recruitment Methods Informed Consent Purpose Methods and procedures in detail Risks and discomforts Risk of disease vs risk of study participation Benefits Alternatives to participation Voluntary and uncoerced Randomization Provides the best assurance that prognostic factors, both measured and unmeasured, are similar in treatment and control groups Provides the most credible evidence of treatment effects Placebo control is optimal to evaluate new treatments Only appropriate when no known effective treatment is available Blinding Limits possible bias Patient response Physician attitude Outcome evaluation Decision-making during study Single-blind: treating physician knows but patient doesn’t Double-blind: neither the treating physician nor the patient knows Phases Phase I Trials: maximally tolerated dose Safety and tolerability Uncontrolled, unblinded Not randomized Phase II Trials: evaluate for evidence of a clinical effect Dose-finding (and continued safety) (dose dependence) Controlled or uncontrolled; may be blinded or unblinded Randomized or not randomized Phase III Trials: test whether a new treatment is superior Therapeutic ratio (and continued safety) (Drug x compared to drug y) Control is placebo or standard of care. Blinded Randomized Phase IV Trials: post-marketing surveillance (safety) Eligibility Disease type Prior therapy Performance status Evidence of adequate renal and hepatic function Measurable disease Prior malignancies Study Endpoints Adverse events standard criteria to categorize as: none, mild, moderate, severe, life-threatening Response Progressive disease Stable disease Parital response: decrease in the size of measurable disease by 50% Complete response Progression-free survival Overall survival Quality of life Early stopping rules To avoid subjecting participants to ineffective therapy Interim analysis: No effect, stop the trial Significant effect, stop the trial Intermediate, continue accrual. Landmark clinical trials in the treatment of ovarian cancer Suboptimal Stage III and any stage IV GOG 111 trial established platinum/taxane combination therapy as the standard of care RANDOMIZE Cisplatin (75 mg/m2 q21d x 6) PLUS Cyclophosphamide (750 mg/m2) Cisplatin (75 mg/m2 q21d x 6) PLUS Paclitaxel (135 mg/m2/24h) GOG 111: progression-free survival Patients (N) Proportion Surviving Progression Free 6 12 18 24 30 36 42 48 Months After Study Entry 54 60 66 72 78 84 0.8 0.9 0 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Cisplatin/Paclitaxel Cisplatin/ Cyclophosphamide Treatment Progression- Free 18 15 166 187 Failure 184 202 Total Median Survival 18.0 13.3 Relative Risk 0.70 – McGuire, NEJM, 1996 GOG 111: overall survival 0.8 0.9 0 6 12 18 24 30 36 42 48 Months from entry into study Proportion surviving Cisplatin/paclitaxel Cisplatin/ cyclophosphamide 54 60 66 72 78 84 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Treatment Alive 35 28 150 174 Died 184 202 Total Median Survival (mos) 36.9 24.8 Relative Risk 0.69 – No. Pts McGuire, NEJM, 1996 Substituting taxol for cytoxan improved survival Piccart, JNCI, 2000 McGuire, NEJM, 1996 *p<0.001 GOG 158: Is carboplatin as effective as cisplatin? Ozols, JCO, 2003 Outcome is the same, toxicity is different Ozols, JCO, 2003 Carboplatin and Taxol currently are standard chemotherapy for ovarian cancer. GOG 182: Is there anything to add to Carbo and taxol to improve outcomes? Does the route of administration make a difference? GOG 104: patients with optimally debulked stage III disease were randomized to IV cyclophosphamide and IV cisplatin or IV cyclophosphamide and IP cisplatin IP regimen was superior 25 vs 20% reponse rate 49 vs 41 month median survival Not widely adopted because standard of care shifted to carboplatin/taxol Cisplatin IV (75 mg/m2) PLUS Paclitaxel IV (135 mg/m2) Stage III, all < 1.0 cm RANDOMIZE Paclitaxel (135 mg/m2) IV Day 1 THEN Cisplatin (100 mg/m2) IP Day 2 THEN Paclitaxel (60 mg/m2) IP Day 8 GOG 172: Does IP administration improve results with platinum/taxane therapy? Prolonged remission seen with IP administration Armstrong, NEJM, 2006 Overall survival improved with IP administration Armstrong, NEJM, 2006 GOG 172 participation 86/205 = 41.9% 84/205 = 41.0% Armstrong, NEJM, 2006 IP chemotherapy summary Will targeted therapeutics improve response? Bevacizumab (Avastin) is an antibody to the vascular endothelial growth factor (VEGF) which blocks the formation of new blood vessels In phase II trials, Avastin demonstrated significant activity in patients with recurrent ovarian cancer GOG 218 tested Carboplatin/Taxol/Placebo vs Carboplatin/Taxol/Avastin vs Carboplatin/Taxol/Avastin + maintenance Avastin Improved progression free survival was seen in the group that got maintenance Avastin Most patients experience only mild toxicity with Avastin treatment Active GOG trials GOG 262: Does administering dose-dense Taxol improve the response? Weekly Taxol vs every three weeks with carboplatin, with or without Avastin GOG 213: Does Avastin improve the response to chemotherapy for recurrent disease? Does secondary surgical debulking benefit patients? Randomized to secondary debulking or no surgery Randomized to Carboplatin/Taxol/Placebo vs Carboplatin/Taxol/Avastin (concurrent and maintenance) GOG 252: Does Avastin improve response to IP chemotherapy? IV Carboplatin, IV weekly Taxol, Avastin IP Carboplatin, IV weekly Taxol, Avastin IV Taxol (day 1), IP Cisplatin (day 2), IP Taxol (day 8), Avastin GOG 212: Does monthly Taxol improve survival after primary adjuvant chemotherapy? Maintenance therapy with Taxol or CT2103 or no treatment for 12 months after primary adjuvant chemotherapy Evolution of a clinical trial: Penn 2003: T cells in the tumor correlates with improved survival Survival of patients with ovarian cancer: Tumor Infiltrating Lymphocytes (TIL) TIL+ TIL- First Phase I Vaccine Trial 2006: Dendritic cell vaccine Goal: to enhance the anti-tumor T cell response A cellular vaccine comprised of a subject’s own cells primed against ovarian cancer was developed Confirmed the safety of this approach Second Phase I trial: Whole tumor antigen vaccine Evidence in other solid tumors of a survival benefit following vaccination with dendritic cells pulsed with tumor lysate Demonstration of immunomodulatory effects of Avastin and Cytoxan chemotherapy UPCC 11807 Monocytes GMCSF+IL4 - Whole tumor antigen vaccine Pulsing with Tumor antigen Mature DC Immature DC Pre-treatment Post-vaccine An example of disease regression in a patient treated with Avastin and vaccine Pre-treatment PET scan 11807-01 Nov 2007 L PAoLN - 1.1x1.5 cm Feb 2008 L PAoLN - 0.6 x 1.1 cm Combination therapy was feasible and well tolerated Of the six patients enrolled, two had a partial response (PR), 2 had stable disease (SD), and two had progressive disease (PD) Responses paralleled decreases in serum CA-125 levels. Evidence of vaccine-specific immune responses were demonstrated UPCC-11807: Vaccination was safe and well-tolerated with evidence of a clinical response Pilot study of T cell transfer following anti-tumor vaccination Goal is to amplify anti-tumor T cells in the lab and then administer large numbers of tumor-specific T cells to the subject along with additional vaccinations and metronomic cytoxan chemotherapy. A second-generation whole tumor vaccine Growing evidence of the impact of the immunosuppressive tumor environment Research in the lab demonstrates enhanced immune function with changes in cell preparation UPCC 11809 Vaccine Tumor harvest Apheresis UPCC-11809 Eligibility Women with recurrent ovarian, fallopian tube or primary peritoneal cancer Prior cytoreductive surgery yielding tumor for lysate No residual tumor nodules >4.5 cm Good performance status May have received chemotherapy or other therapy after harvest of tumor and prior to enrollment – subjects without evidence of disease after therapy are still eligible Must recover from any toxicities resulting from chemotherapy prior to receiving the vaccine Future Directions New approaches to vaccine development: Planned clinical trial of intradermal vaccination with killed tumor lysate Transfer of T cells genetically engineered to recognize tumor Preclinical data in a mouse model suggests that an anti-tumor vaccine could be developed using ascites cells This could have the potential to reduce the cost and increase the availability of immune therapy for women with advanced disease Hurdles Differences in the characteristics of clinical trial subjects and the general population Persistent bias Competition for patients Research Funding Outcomes continue to improve For more information Department of Health and Human Services www.dhhs.gov FDA (U.S. Food and Drug Administration) www.fda.gov FDA Center for Drug Evaluation and Research www.fda.gov/cder/ National Institutes of Health www.nih.gov/ or https://clinicaltrials.gov NIH: National Cancer Institute www.nci.nih.gov/ Office of Human Research Protections http://www.hhs.gov/ohrp/ The University of Pennsylvania Susan Mauro RN CCRCsusan.mauro@uphs.upenn.edu Cathi Ybarra, BSN, RN ybarrac@obgyn.upenn.edu Acknowledgements George Coukos, MD, PhD Christina Chu, MD Daniel Powell, PhD Lana Kandalaft, PhD Cathi Ybarra, BSN, RN GOG Research Program Manager ybarrac@obgyn.upenn.edu The Sandy Rollman Ovarian Cancer Foundation Kaleidoscope of Hope Foundation AACR Scholar-in-Training Award ASCO Young Investigators Award Ovarian Cancer SPORE Paul Calebressi NIH K12 Training Grant The Florence and Marshall Schwid Ovarian Cancer Research Grant from the Gynecologic Cancer Foundation Susan Mauro RN CCRC TRP Clinical Trials Unit 3620 Hamilton Walk Anatomy-Chemistry Bldg B-24 Philadelphia Pa 19104 P: 215-422-2560 susan.mauro@uphs.upenn.edu
Slide 53 - Clinical Trials in Ovarian Cancer Ovarian Cancer Coalition Regional Conference November 5, 2010 Overview Preclinical drug development Regulations to protect participants Goals of clinical trials Landmark clinical trials in ovarian cancer Evolution of a phase I trial of immune therapy at Penn Where to get more information Clinical trials vs. standard health care Clinical care: interventions designed solely to enhance the well-being of the patient that have a reasonable expectation of success Research: an activity designed to test a hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge Drug Development Serendipity Broad search and screen Design based on natural substances Molecular knowledge of a receptor Pre-clinical drug development Maximum tolerated dose Route of administration Bioavailability and metabolism studies Characterization of toxicity Acute toxicity Subacute toxicity Chronic toxicity Teratogenicity and carcinogenicity History of Clinical Trials 1747 James Lind, Naval physician, tests therapies for scurvy Declaration of Helsinki Developed by the World Medical Association as a set of ethical principles for human experimentation Established Institutional Review Boards (IRB) Emphasizes informed consent Defined vulnerable populations Regulates the inclusion and selection of placebo groups Regulatory Agencies in the US Food and Drug Administration Research 21 CFR 50.3(c) defines research as an experiment that involves a test article and one or more human subjects that is subject to the IND or IDE regulations or which collects data to be submitted to or held for inspection by FDA. Research is subject to the IND regulations when it involves any use of a drug except for the use of a marketed drug in the course of medical practice (21 CFR §312.3) Human Subject 21 CFR 50.3(e) defines human subject as an individual who is or becomes a participant in research, either as a recipient of a test article or as a control. In the case of research involving a medical device, a human subject also includes an individual on whose specimen a medical device is used. Test Article 21 CFR 50.3(j) defines test article as any drug (including a biological product for human use, medical device for human use, human food additive, color, adaptive, electronic product, or any other article subject to regulation under the jurisdiction of the FDA Office for Human Research Protections: The Common Rule Research 45 CFR 46.102(d) defines research as a systematic investigation, including research development, and testing and evaluation, designed to develop or contribute to generalizable knowledge. Human Subject 45 CFR 102(f) defines a human subject as an individual about whom an investigator conducting research obtains data through intervention or interaction with individual or identifiable private information. Intervention or Interaction includes physical procedures performed on an individual, manipulation, communication or interpersonal contact with an individual or manipulation of an individual's environment. Private information includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Identifiable means that the identity of the individual is or may be readily ascertained by the investigator or associated with the information. www.hhs.gov/ohrs;/humansubjects/guidance HIPAA Health Insurance Portability and Accountability Act, April 2003. Protects information about the physical or mental health of an individual relating to health, health care, or payment for care in the past, present or future. Institutional Review Boards (IRB) Protects the rights and welfare of research subjects Oversees the conduct of all human research Ensures compliance with all federal, state, local and institutional requirements in human subject research. Includes members of the community Principles governing clinical trials Regulatory codes place the responsibility for the ethical conduct of research on the shoulders of researchers Autonomy Informed consent Confidentiality Comprehension Voluntariness Beneficience Risks-to-Benefit Ratio Research Design (minimizing risk) Investigator Qualifications Conflicts of Interest Justice Balance of Burdens/Benefits Population of Inference Eligibility Criteria Representative of Population Equitable Recruitment Methods Informed Consent Purpose Methods and procedures in detail Risks and discomforts Risk of disease vs risk of study participation Benefits Alternatives to participation Voluntary and uncoerced Randomization Provides the best assurance that prognostic factors, both measured and unmeasured, are similar in treatment and control groups Provides the most credible evidence of treatment effects Placebo control is optimal to evaluate new treatments Only appropriate when no known effective treatment is available Blinding Limits possible bias Patient response Physician attitude Outcome evaluation Decision-making during study Single-blind: treating physician knows but patient doesn’t Double-blind: neither the treating physician nor the patient knows Phases Phase I Trials: maximally tolerated dose Safety and tolerability Uncontrolled, unblinded Not randomized Phase II Trials: evaluate for evidence of a clinical effect Dose-finding (and continued safety) (dose dependence) Controlled or uncontrolled; may be blinded or unblinded Randomized or not randomized Phase III Trials: test whether a new treatment is superior Therapeutic ratio (and continued safety) (Drug x compared to drug y) Control is placebo or standard of care. Blinded Randomized Phase IV Trials: post-marketing surveillance (safety) Eligibility Disease type Prior therapy Performance status Evidence of adequate renal and hepatic function Measurable disease Prior malignancies Study Endpoints Adverse events standard criteria to categorize as: none, mild, moderate, severe, life-threatening Response Progressive disease Stable disease Parital response: decrease in the size of measurable disease by 50% Complete response Progression-free survival Overall survival Quality of life Early stopping rules To avoid subjecting participants to ineffective therapy Interim analysis: No effect, stop the trial Significant effect, stop the trial Intermediate, continue accrual. Landmark clinical trials in the treatment of ovarian cancer Suboptimal Stage III and any stage IV GOG 111 trial established platinum/taxane combination therapy as the standard of care RANDOMIZE Cisplatin (75 mg/m2 q21d x 6) PLUS Cyclophosphamide (750 mg/m2) Cisplatin (75 mg/m2 q21d x 6) PLUS Paclitaxel (135 mg/m2/24h) GOG 111: progression-free survival Patients (N) Proportion Surviving Progression Free 6 12 18 24 30 36 42 48 Months After Study Entry 54 60 66 72 78 84 0.8 0.9 0 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Cisplatin/Paclitaxel Cisplatin/ Cyclophosphamide Treatment Progression- Free 18 15 166 187 Failure 184 202 Total Median Survival 18.0 13.3 Relative Risk 0.70 – McGuire, NEJM, 1996 GOG 111: overall survival 0.8 0.9 0 6 12 18 24 30 36 42 48 Months from entry into study Proportion surviving Cisplatin/paclitaxel Cisplatin/ cyclophosphamide 54 60 66 72 78 84 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Treatment Alive 35 28 150 174 Died 184 202 Total Median Survival (mos) 36.9 24.8 Relative Risk 0.69 – No. Pts McGuire, NEJM, 1996 Substituting taxol for cytoxan improved survival Piccart, JNCI, 2000 McGuire, NEJM, 1996 *p<0.001 GOG 158: Is carboplatin as effective as cisplatin? Ozols, JCO, 2003 Outcome is the same, toxicity is different Ozols, JCO, 2003 Carboplatin and Taxol currently are standard chemotherapy for ovarian cancer. GOG 182: Is there anything to add to Carbo and taxol to improve outcomes? Does the route of administration make a difference? GOG 104: patients with optimally debulked stage III disease were randomized to IV cyclophosphamide and IV cisplatin or IV cyclophosphamide and IP cisplatin IP regimen was superior 25 vs 20% reponse rate 49 vs 41 month median survival Not widely adopted because standard of care shifted to carboplatin/taxol Cisplatin IV (75 mg/m2) PLUS Paclitaxel IV (135 mg/m2) Stage III, all < 1.0 cm RANDOMIZE Paclitaxel (135 mg/m2) IV Day 1 THEN Cisplatin (100 mg/m2) IP Day 2 THEN Paclitaxel (60 mg/m2) IP Day 8 GOG 172: Does IP administration improve results with platinum/taxane therapy? Prolonged remission seen with IP administration Armstrong, NEJM, 2006 Overall survival improved with IP administration Armstrong, NEJM, 2006 GOG 172 participation 86/205 = 41.9% 84/205 = 41.0% Armstrong, NEJM, 2006 IP chemotherapy summary Will targeted therapeutics improve response? Bevacizumab (Avastin) is an antibody to the vascular endothelial growth factor (VEGF) which blocks the formation of new blood vessels In phase II trials, Avastin demonstrated significant activity in patients with recurrent ovarian cancer GOG 218 tested Carboplatin/Taxol/Placebo vs Carboplatin/Taxol/Avastin vs Carboplatin/Taxol/Avastin + maintenance Avastin Improved progression free survival was seen in the group that got maintenance Avastin Most patients experience only mild toxicity with Avastin treatment Active GOG trials GOG 262: Does administering dose-dense Taxol improve the response? Weekly Taxol vs every three weeks with carboplatin, with or without Avastin GOG 213: Does Avastin improve the response to chemotherapy for recurrent disease? Does secondary surgical debulking benefit patients? Randomized to secondary debulking or no surgery Randomized to Carboplatin/Taxol/Placebo vs Carboplatin/Taxol/Avastin (concurrent and maintenance) GOG 252: Does Avastin improve response to IP chemotherapy? IV Carboplatin, IV weekly Taxol, Avastin IP Carboplatin, IV weekly Taxol, Avastin IV Taxol (day 1), IP Cisplatin (day 2), IP Taxol (day 8), Avastin GOG 212: Does monthly Taxol improve survival after primary adjuvant chemotherapy? Maintenance therapy with Taxol or CT2103 or no treatment for 12 months after primary adjuvant chemotherapy Evolution of a clinical trial: Penn 2003: T cells in the tumor correlates with improved survival Survival of patients with ovarian cancer: Tumor Infiltrating Lymphocytes (TIL) TIL+ TIL- First Phase I Vaccine Trial 2006: Dendritic cell vaccine Goal: to enhance the anti-tumor T cell response A cellular vaccine comprised of a subject’s own cells primed against ovarian cancer was developed Confirmed the safety of this approach Second Phase I trial: Whole tumor antigen vaccine Evidence in other solid tumors of a survival benefit following vaccination with dendritic cells pulsed with tumor lysate Demonstration of immunomodulatory effects of Avastin and Cytoxan chemotherapy UPCC 11807 Monocytes GMCSF+IL4 - Whole tumor antigen vaccine Pulsing with Tumor antigen Mature DC Immature DC Pre-treatment Post-vaccine An example of disease regression in a patient treated with Avastin and vaccine Pre-treatment PET scan 11807-01 Nov 2007 L PAoLN - 1.1x1.5 cm Feb 2008 L PAoLN - 0.6 x 1.1 cm Combination therapy was feasible and well tolerated Of the six patients enrolled, two had a partial response (PR), 2 had stable disease (SD), and two had progressive disease (PD) Responses paralleled decreases in serum CA-125 levels. Evidence of vaccine-specific immune responses were demonstrated UPCC-11807: Vaccination was safe and well-tolerated with evidence of a clinical response Pilot study of T cell transfer following anti-tumor vaccination Goal is to amplify anti-tumor T cells in the lab and then administer large numbers of tumor-specific T cells to the subject along with additional vaccinations and metronomic cytoxan chemotherapy. A second-generation whole tumor vaccine Growing evidence of the impact of the immunosuppressive tumor environment Research in the lab demonstrates enhanced immune function with changes in cell preparation UPCC 11809 Vaccine Tumor harvest Apheresis UPCC-11809 Eligibility Women with recurrent ovarian, fallopian tube or primary peritoneal cancer Prior cytoreductive surgery yielding tumor for lysate No residual tumor nodules >4.5 cm Good performance status May have received chemotherapy or other therapy after harvest of tumor and prior to enrollment – subjects without evidence of disease after therapy are still eligible Must recover from any toxicities resulting from chemotherapy prior to receiving the vaccine Future Directions New approaches to vaccine development: Planned clinical trial of intradermal vaccination with killed tumor lysate Transfer of T cells genetically engineered to recognize tumor Preclinical data in a mouse model suggests that an anti-tumor vaccine could be developed using ascites cells This could have the potential to reduce the cost and increase the availability of immune therapy for women with advanced disease Hurdles Differences in the characteristics of clinical trial subjects and the general population Persistent bias Competition for patients Research Funding Outcomes continue to improve For more information Department of Health and Human Services www.dhhs.gov FDA (U.S. Food and Drug Administration) www.fda.gov FDA Center for Drug Evaluation and Research www.fda.gov/cder/ National Institutes of Health www.nih.gov/ or https://clinicaltrials.gov NIH: National Cancer Institute www.nci.nih.gov/ Office of Human Research Protections http://www.hhs.gov/ohrp/ The University of Pennsylvania Susan Mauro RN CCRCsusan.mauro@uphs.upenn.edu Cathi Ybarra, BSN, RN ybarrac@obgyn.upenn.edu Acknowledgements George Coukos, MD, PhD Christina Chu, MD Daniel Powell, PhD Lana Kandalaft, PhD Cathi Ybarra, BSN, RN GOG Research Program Manager ybarrac@obgyn.upenn.edu The Sandy Rollman Ovarian Cancer Foundation Kaleidoscope of Hope Foundation AACR Scholar-in-Training Award ASCO Young Investigators Award Ovarian Cancer SPORE Paul Calebressi NIH K12 Training Grant The Florence and Marshall Schwid Ovarian Cancer Research Grant from the Gynecologic Cancer Foundation Susan Mauro RN CCRC TRP Clinical Trials Unit 3620 Hamilton Walk Anatomy-Chemistry Bldg B-24 Philadelphia Pa 19104 P: 215-422-2560 susan.mauro@uphs.upenn.edu