Clinical Trials - Slide 1

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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
   GOG 111 trial established platinum/taxane
  combination therapy as the standard of care
                  Suboptimal Stage III
                  and any stage IV
                      RANDOMIZE




Cisplatin                      Cisplatin
(75 mg/m2 q21d x 6)            (75 mg/m2 q21d x 6)
PLUS                           PLUS
Cyclophosphamide               Paclitaxel
(750 mg/m2)                    (135 mg/m2/24h)
                  GOG 111: progression-free survival
                                                                Patients (N)
           1.0
                                                     Progression-                        Median     Relative
           0.9                      Treatment        Free               Failure Total    Survival   Risk
           0.8                      Cisplatin/             15             187    202         13.3         –
                                    Cyclophosphamide
           0.7
Proportion                          Cisplatin/Paclitaxel   18             166    184         18.0        0.70
Surviving 0.6
Progression 0.5
Free
            0.4
           0.3
           0.2
           0.1
           0.0
                  0   6   12   18     24     30     36     42      48     54    60      66    72    78     84
                                           Months After Study Entry
   McGuire, NEJM, 1996
                                          GOG 111: overall survival
                       1.0                                                                    No. Pts
                                                                                                               Median            Relative
                       0.9                                  Treatment              Alive       Died      Total Survival (mos)    Risk


                       0.8                                 Cisplatin/               28          174       202        24.8              –
                                                           cyclophosphamide
                       0.7
Proportion surviving




                                                           Cisplatin/paclitaxel     35          150       184        36.9            0.69
                       0.6
                       0.5
                       0.4
                       0.3
                       0.2
                       0.1

                       0.0
                             0   6   12    18   24    30      36      42      48         54     60      66      72    78        84
                                                     Months from entry into study
  McGuire, NEJM, 1996
  Substituting taxol for cytoxan improved survival
                             GOG 111                        OV-10


                                       Cis 75 +                    Cis 75 +
                          Cis 75 +                  Cis 75 +
          Treatment                   Taxol 135                   Taxol 175
                        Cytoxan 750               Cytoxan 750
                                        24 hr                        3hr




         PFS (months)       13          18*          11.5           15.5*




         OS (months)        24          38*           26             36*




          Neuropathy             4%                         14%


McGuire, NEJM, 1996               *p<0.001                      Piccart, JNCI, 2000
         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 111               GOG 158

                                      Cis +      Carbo
                     Cis +    Cis +
      Treatment                       Taxol    (AUC 7.5) +
                    Cytoxan   Taxol
                                      (135)       Taxol



     PFS (months)     13       18      19          21




     OS (months)      24       38      49          57
GOG 182: Is there anything to add to Carbo
    and taxol to improve outcomes?

        Treatment          PFS     OS

  Carbo/Taxol x 8          16.1   40.0

  Carbo/Taxol/Gemzar x 8   16.4   40.4
  Carbo/Taxol/Doxil
  every other x 8          16.4   42.8
  Carbo/Topo x4
  then Carbo/Taxol x 4     15.3   39.1
  Carbo/Gemzar x 4
  then Carbo/Taxol x 4     15.4   40.2
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
       GOG 172: Does IP administration improve
        results with platinum/taxane therapy?
                Stage III, all < 1.0 cm
                      RANDOMIZE



Cisplatin IV
(75 mg/m2)                   Paclitaxel (135 mg/m2) IV Day 1
PLUS                         THEN
Paclitaxel IV                Cisplatin (100 mg/m2) IP Day 2
(135 mg/m2)                  THEN
                             Paclitaxel (60 mg/m2) IP Day 8
             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
                                                            GOG
                  GOG 104               GOG 172
                                                            158

                                               Taxol IV +
               Cytoxan    Cytoxan     Cis IV                Carbo
   Treatment                                    Cis IP +
               + Cis IV   + Cis IP   + Taxol                + Taxol
                                                Taxol IP



     PFS
                 NR         NR         18         24          21
   (months)




     OS
                 41         49         50         66          57
   (months)
   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   • UPCC 11807
  tumors of a survival
  benefit following
  vaccination with
  dendritic cells pulsed
  with tumor lysate
• Demonstration of
  immunomodulatory               Chemo   Bev + CY

  effects of Avastin and
  Cytoxan chemotherapy
Whole tumor antigen vaccine

                -
                        Monocytes

                         GMCSF+IL4


                        Immature DC

                        Pulsing with
                        Tumor antigen



                          Mature DC
            An example of disease regression
      in a patient treated with Avastin and vaccine
Pre-treatment       Pre-treatment            Post-vaccine
  PET scan




                         Nov 2007                Feb 2008
                    L PAoLN - 1.1x1.5 cm   L PAoLN - 0.6 x 1.1 cm

                         11807-01
UPCC-11807: Vaccination was safe and well-
tolerated with evidence of a clinical response

 •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
     Pilot study of T cell transfer following anti-
     tumor vaccination
                                                                UPCC-01808

    UPCC-11807




                                                                   C/F
                                                                             CY   CY




                                                     Phase II
                                           Phase I
  Chemo     Bev + CY      Bev

                                                                    CY       CY   CY




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        • UPCC 11809
  impact of the
  immunosuppressive tumor
  environment                     Cohort   Chemo
                                    1




                                  Cohort   Chemo
                                    2

• Research in the lab
  demonstrates enhanced
  immune function with changes
  in cell preparation             Cohort   Chemo   Bev
                                    3
    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

                GOG 111            GOG 158           GOG 104           GOG 172

                                          Carbo                               Taxol IV
                                Cis +               Cytox    Cytox     Cis
               Cis +    Cis +                                                 + Cis IP
                                Taxol   (AUC 7.5)    an +     an +     IV +
 Treatment    Cytoxan   Taxol                                                 + Taxol
                                (135)    + Taxol    Cis IV   Cis IP   Taxol
                                                                                 IP


   PFS          13       18      19        21        NR       NR       18       24
 (months)



OS (months)     24       38      49        57        41       49       50       66
            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
                                          Susan Mauro RN CCRC
George Coukos, MD, PhD
                                          TRP Clinical Trials Unit
Christina Chu, MD                         3620 Hamilton Walk
Daniel Powell, PhD                        Anatomy-Chemistry Bldg B-24
Lana Kandalaft, PhD                       Philadelphia Pa 19104
                                          P: 215-422-2560
                                          susan.mauro@uphs.upenn.edu

                                         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