Slide 51 -
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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
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