DESIGN OF A DISEASE SPECIFIC MASTER PROTOCOL Jeff Allen, PhD Executive Director Friends of Cancer Research

Current Challenges Each potential new therapy is typically tested independently from other therapies seeking to treat the same condition For every new trial, the protocol must be reviewed by a number of oversight entities new phase III trials requires an average of 36 administrative or regulatory approvals and averages more than 2 years Approximately 4% of adult cancer patients enroll in clinical trials inability to meet accrual goals is a frequent factor causing trials to close, wasting time, money, and limited patient resources New therapies molecularly targeted against specific mutations may be present in only a fraction of the patient population

Design of a Disease-Specific Master Protocol 2012 Friends/Brookings Conference on Clinical Cancer Research

Major elements Setting: Setting: Squamous cell carcinoma (SCCA), advanced stage, 2 nd line therapy Agents: Agents: Candidate drugs must demonstrate biologic activity against a measurable target with a proposed predictive biomarker Study design: Study design: Multi-arm randomized, controlled phase II/III master registration protocol. Each arm able to open and close independent of other arms

Screening Archival FFPE tumor-common broad testing analytically validated platform suitable for registration purposes Molecule–specific tests, to include IHC, fresh core needle biopsy as appropriate Protocol arm powered for central test+ cases, with subsequent bridging studies as per FDA clearance. Goal is to develop each molecule with a companion diagnostic to support clinical use

Trial Structure Primary Endpoint: Primary Endpoint: Each arm independently powered for OS; interim analysis for PFS. Positive results at “rolling” interim analysis (no temporary closure) determine if a protocol arm proceeds to phase III portion. Goal Goal: minimum of 4 arms open at any time, to ascertain a reasonable chance for patients to be “biomarker positive”. Marker-negative patients enter common control group treated with SoC (vs anti-PD1 agent) to establish annotated repository

Trial operations Operations Management: Operations Management: Neutral 3 rd party - FNIH in collaboration with NCI Cooperative Groups Independent Drug/Biomarker Selection Committee Independent Drug/Biomarker Selection Committee: evaluates each drug-marker pair for suitability Oversight Committee Oversight Committee: Comprised of leaders from NCI, Academia, FDA, industry, advocates, to ensure operational efficacy

CT* TT=Targeted therapy, CT=chemotherapy (docetaxel or gemcitabine), E=erlotinib MASTER PROTOCOL Biomarker C TT C+CT CT* Endpoint (Interim PFS) OS Biomarker Β TT B CT* Endpoint (Interim PFS) OS Biomarker A TT A CT* Endpoint (Interim PFS) OS CNB/CLIA Biomarker Profiling Biomarker D TT D+E E* Endpoint (Interim PFS) OS Anti PD1 Unkn-Negbiomarker Courtesy of: Vali Papadimitrakopoulou

R a n d o m i z a ti o n Complete Accrual Study Design Within Each Biomarker- defined Subgroup Phase II Analysis 56 PFS events Final Analysis 210 OS events Phase III Interim Analyses Based on OS Futility established Stop 12 months follow-up Courtesy of: Mary Redman

Master Protocol over time Additional drug/biomarker combinations dropped and added to study

Benefits of a Master Protocol Enrollment Efficiency: Enrollment Efficiency: Grouping these studies under a single trial reduces the overall screen failure rate Operational Efficiency: Operational Efficiency: single master protocol can be amended as needed as drugs enter and exit the study Consistency: Consistency: every drug entered into the trial would be tested in the identical manner Predictability: Predictability: If pre-specified efficacy and safety criteria are met, the drug and accompanying companion diagnostic will be approved Patient Benefit: Patient Benefit: offers the advantage of bringing safe and effective drugs to patients sooner than they might otherwise be available.

Expert Working Group Roy Herbst – Yale University David Gandara – UC Davis Ellen Sigal – Friends of Cancer Research Vali Papadimitrakopoulou – MD Anderson Fred Hirsch – University of Colorado Mary Redman - Fred Hutchinson Cancer Center Jeff Abrams – National Cancer Institute Jack Welch – National Cancer Institute Shakun Malik – Food and Drug Administration David Wholley – Foundation for the NIH Eric Rubin – Merck Richard Gaynor – Eli Lilly David Chang - Amgen