THE FUTURE OF CLINICAL TRIALS: NEW MODEL TO ENHANCE EFFICIENCY. Jeff Allen, PhD Executive Director Friends of Cancer Research

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1 THE FUTURE OF CLINICAL TRIALS: NEW MODEL TO ENHANCE EFFICIENCY Jeff Allen, PhD Executive Director Friends of Cancer Research

2 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

3 Design of a Disease-Specific Master Protocol 2012 Conference on Clinical Cancer Research

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

5 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

6 Trial Structure 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: 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

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

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

9 Study Design Within Each Biomarkerdefined Subgroup R a n d o m i z a ti o n Phase II Analysis 56 PFS events Futility established Sto p Phase III Interim Analyses Based on OS Complet e Accrual Final Analysis 210 OS events 12 months follow-up

10 Master Protocol over time Additional drug/biomarker combinations dropped and added to study Trial Start Patient Accrual/ Patient Screening for initial biomarkers Marker/Drug A treatment arm starts A HR=.84, Trial continues A -- 30% events- Interim analysis for OS A %? events- OS analysis Master Protocol Trial Timeline Marker/Drug B treatment arm starts Marker/Drug C apply to trial Marker/Drug C reviewed by steering committee Marker/Drug C added to trial B -- 30% events- Interim analysis for OS Marker/Drug C treatment arm starts B HR=.87- Trial continues C--30% events- Interim analysis for OS

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