Clinical-Trials-talk-for-Regional-Conf-FINAL-VERSION

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Clinical Trials in Ovarian Cancer
Ovarian Cancer Coalition Regional
Conference
November 5, 2010
Overview
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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
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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
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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
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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
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Informed consent
Confidentiality
Comprehension
Voluntariness
– Beneficience
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Risks-to-Benefit Ratio
Research Design (minimizing risk)
Investigator Qualifications
Conflicts of Interest
– Justice
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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
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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
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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
(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)
1.0
ProgressionFree
Median
Survival
Relative
Risk
0.9
Treatment
0.8
Cisplatin/
Cyclophosphamide
15
187
202
13.3
–
Cisplatin/Paclitaxel
18
166
184
18.0
0.70
54
60
0.7
Proportion
Surviving 0.6
Progression 0.5
Free
0.4
Failure Total
0.3
0.2
0.1
0.0
0
6
12
18
24
30
36
42
48
Months After Study Entry
McGuire, NEJM, 1996
66
72
78
84
GOG 111: overall survival
1.0
No. Pts
0.9
Proportion surviving
0.7
Relative
Risk
Alive
Died
Cisplatin/
cyclophosphamide
28
174
202
24.8
–
Cisplatin/paclitaxel
35
150
184
36.9
0.69
Treatment
0.8
Median
Total Survival (mos)
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
6
12
McGuire, NEJM, 1996
18
24
30
36
42
48
54
60
Months from entry into study
66
72
78
84
Substituting taxol for cytoxan improved survival
GOG 111
OV-10
Treatment
Cis 75 +
Cytoxan 750
Cis 75 +
Taxol 135
24 hr
Cis 75 +
Cytoxan 750
Cis 75 +
Taxol 175
3hr
PFS (months)
13
18*
11.5
15.5*
OS (months)
24
38*
26
36*
Neuropathy
McGuire, NEJM, 1996
4%
*p<0.001
14%
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
Treatment
Cis +
Cytoxan
Cis +
Taxol
Cis +
Taxol
(135)
Carbo
(AUC 7.5) +
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)
PLUS
Paclitaxel IV
(135 mg/m2)
Paclitaxel (135 mg/m2) IV Day 1
THEN
Cisplatin (100 mg/m2) IP Day 2
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 104
GOG 172
GOG
158
Treatment
Cytoxan
+ Cis IV
Cytoxan
+ Cis IP
Cis IV
+ Taxol
Taxol IV +
Cis IP +
Taxol IP
Carbo
+ Taxol
PFS
(months)
NR
NR
18
24
21
OS
(months)
41
49
50
66
57
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
Chemo
Bev + CY
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
Nov 2007
Feb 2008
L PAoLN - 1.1x1.5 cm
L PAoLN - 0.6 x 1.1 cm
PET scan
11807-01
UPCC-11807: Vaccination was safe and welltolerated 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 antitumor vaccination
UPCC-01808
Bev
C/F
Bev + CY
Phase II
Chemo
Phase I
UPCC-11807
CY
CY
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
impact of the
immunosuppressive tumor
environment
• Research in the lab
demonstrates enhanced
immune function with changes
in cell preparation
• UPCC 11809
Cohort
1
Chemo
Cohort
2
Chemo
Cohort
3
Chemo
Bev
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 antitumor 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
(AUC 7.5)
+ Taxol
Cytox
an +
Cis IV
Cytox
an +
Cis IP
Cis
IV +
Taxol
Taxol IV
+ Cis IP
+ Taxol
IP
Cis +
Cytoxan
Cis +
Taxol
Cis +
Taxol
(135)
PFS
(months)
13
18
19
21
NR
NR
18
24
OS (months)
24
38
49
57
41
49
50
66
Treatment
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 [email protected]
– Cathi Ybarra, BSN, RN [email protected]
Acknowledgements
George Coukos, MD, PhD
Christina Chu, MD
Daniel Powell, PhD
Lana Kandalaft, PhD
Susan Mauro RN CCRC
TRP Clinical Trials Unit
3620 Hamilton Walk
Anatomy-Chemistry Bldg B-24
Philadelphia Pa 19104
P: 215-422-2560
[email protected]
Cathi Ybarra, BSN, RN
GOG Research Program Manager
[email protected]
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
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