Cancer Center Directors Meeting FNLCR Frederick, MD March 11, 2014

1. Cancer Center Directors Meeting FNLCR Frederick, MD March 11, 2014 NCI Clinical Research InitiativesJames H. Doroshow, M.D.Deputy Director for Clinical and Translational ResearchNational Cancer Institute

2. NCI Clinical Research Initiatives • NCTN (Groups); NCORP (CCOP); ETCTN (Phase I) • Update on Status of NCI-supported Precision Medicine Initiatives • NCI-MPACT: Molecular Profiling Based Assignment of Cancer Therapeutics • NCI-MATCH: Molecular Analysis for Therapy Choice • SWOG1400: Biomarker-Driven Master Protocol for Second Line Therapy of Squamous Cell Lung Cancer • ALCHEMIST: Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial • NCI Clinical Trials Reporting Policy

3. NCI Precision Medicine Initiatives • Help to advance molecular profiling from research use into the clinic • Genotype to Phenotype • Develop portfolio of trials across spectrum from early stage to advanced disease • Screen for molecular features that may predict response to a drug with a given mechanism of action • Analyze tumor specimens at relapse to define mechanisms of resistance • Develop public database that links clinical outcomes with molecular tumor characteristics

4. MPACT: Molecular Profiling based Assignment of Cancer TherapeuticsPilot Trial to Assess the Utility of Genetic Sequencing to Determine Therapy and Improve Patient Outcome in Early Phase Trials Independent of Tumor Histology

5. Objective • Assess whether the response rate (CR+PR) and/or 4-month PFS is improved following treatment with agents chosen based on the presence of specific mutations in patient tumors. • Only patients with pre-defined mutations of interest will be eligible • Study treatments, regardless of cohort, will be chosen from the list of regimens defined in the protocol • Arm A: Receive treatment based on an study agent prospectively identified to work on that mutation/pathway • Arm B: Receive treatment with one of the study agents in the complementary set (identified to not work on one of the detected mutations/pathways)

6. MPACT Assay v1.0 Gene Panel

7. MPACT Assay4 Drug Protocols, 3 Pathways, 22 Targeted Genes (392aMOIs)

8. Assign treatment identified to target mutation Arm A RANDOMIZATION Mutation detected DISEASE PROGRESSION Tumor biopsy from all patients for sequencing OR Assign treatment NOT identified to target mutation Arm B Mutation not detected Off-Study NCI MPACT Clinical Trial: Study Design • Fresh tumor biopsy on-study and at progression • Primary endpoint response (CR + PR) and 4-month PFS improved for agents chosen on the basis of specific mutations • Crossover from Arm B (non-mutation–directed) to Arm A (mutation-directed) treatment at progression • Accrual began 1/2014 at NIH Clinical Center—brisk referral and entry • Trial open across NCI’s Phase I/II network (>30 NCI-designated Cancer Centers)

9. Molecular Analysis for Therapy Choice (NCI MATCH) • Umbrella protocol for multiplephase II trials focused on molecular subgroups matched to targeted agents • Fresh screening tumor biopsies : mutations/amplifications or other lesions to establish trial eligibility • NCI IND for protocol template and all drugs • Arms can be added or deleted without affecting other arms • Initially focused on single-agents (commercial or experimental) • Combinations will be considered for targets that have validated combination targeted therapy • Need minimum dose/safety established in phase 1 trials • Study reviewed by the NCI CIRB • Tumor biopsies & sequencing at progression to illuminate resistance mechanisms; de-identified samples submitted to central labs; whole-exome sequencing (research purposes) to detect non-ambiguous variants • Solid tumors and lymphomas that have progressed following at least one line of therapy; exclude histologies if already FDA approved for that indication or lack of efficacy documented; 25% rare tumors

10. NCI MATCH Level of Evidence: Drugs Level 1: FDA approved; evidence of target inhibition, or proof of mechanism; demonstration that patient selection with Dx are more likely to respond Level 2: Agent met a clinical endpoint (objective response, PFS, or OS); with evidence of target inhibition; plausible evidence of a predictive or selection assay/analyte Level 3: Agent demonstrated evidence of clinical activity with evidence of target inhibition; some evidence of a predictive or selection assay/analyte Level 4: Preclinical evidence of anti-tumor activity and evidence of target inhibition; hypothesis for a predictive or selective assay/analyte

11. NCI MATCH: Assays • NGS: Ion Torrent PGM with custom Ampliseq panel of 200-300 actionable genes • Validation in network of CLIA certified labs: • MD Anderson; Yale; MGH; FNLCR • IHC, FISH? • Rule driven treatment assignment

12. NCI MATCH 2 1CR, PR, SD, and PD as defined by RECIST 2Stable disease is assessed relative to tumor status at re-initiation of study agent 3Rebiopsy; if additional mutations, offer new targeted therapy • Conduct across NCTN: 3000 NCI-supported sites • Pay for on-study and at progression biopsies • Initial estimate: screen 3000 patients to complete • 20 phase II trials

13. NCI MATCH Over 40 drugs Pledged by Companies: • Abbvie • Amgen • Ariad • Biomarin • BMS • BoehringerIngelheim • Clovis • Genentech • JNJ • Millenium • Pfizer • Sanofi • Tesaro • Tracon • Verastem

14. Phase II/III Biomarker-Driven Master Protocol for Second Line Therapy of Squamous Cell Lung Cancer (SCCA) Study Chair: Vali Papadimitrakopoulou, MD UT/MDACC, Dept of Thoracic/Head & Neck Med Oncology Cooperative Groups Co-chairs: Alliance: Everett Vokes, MD ECOG: Suresh Ramalingam, MD NCI Co-Chair: Jack Welch, MD NCIC: Glenwood Goss, MD NRG: Jeff Bradley, MD SWOG: David R. Gandara, MD Steering Committee Co-Chair: Roy S. Herbst, MD, PhD Statistical Co-chair: Mary W. Redman, Ph.D. Molecular Pathology co-Chair: Ignacio Wistuba, MD Correlative Science co-Chair: F Hirsch MD, PhD, P Mack PhD

15. Significantly Mutated Genes in Lung SQCC PS Hammerman et al. Nature000, 1-7 (2012) doi:10.1038/nature11404

16. S1400: Rationale for Master Protocol Design • Adenocarcinoma: multiple and often independent mutations and potential therapeutic targets. • Lung SCCA “orphan” group- substantial developments in therapeutics have yet to be seen. • Subgroup selection (genotype or phenotype-driven) refined strategy in a Multi-arm Master Protocol with improved operational efficiency: homogeneous patient populations & consistency in eligibility from arm to arm. Phase II-III design: rapid drug/biomarker testing for detection of “large effects” • Grouping multiple studies: reduces overall screen failure rate , multi-target screening by NGS platform: sufficient “hit rate” uninterrupted accrual. • Bring safe and effective drugs to patients faster, ineffective drugs are replaced by new improved candidates. • Designed to allow FDA approval of new therapeutics

17. Assign treatment Arm by marker Patient Registration Consent Randomization Tumor Collection Treatment NGS/IHC (Foundation Medicine) Investigational Targeted Therapy Genomic Screening <2 weeks Interim Endpoint: PFS Primary Endpoint: OS Genomic “Pre-screening” In selected patients Standard of Care Therapy • Organizers: FOCR,NCI-TMSC, FDA, FNIH • Participants: Entire North American Lung Intergroup • (SWOG, Alliance, ECOG-Acrin, NRG, NCI-Canada) • Screening: 500-1,000 patients/year • With 4-6 arms open simultaneously, “hit” rate ~70% in matching a patient with a drug/biomarker arm.

18. MASTER PROTOCOL S1400 Common Broad Platform CLIA Biomarker Profiling* CT* Non-match Anti-PD-L1: MEDI4736 FGFR M: FGFRampl, mut, fusion CDK4/6 M: CCND1, cdk4/6 ampl, CDKN2 del/mut, Rbwt HGF M:Met Expr PI3K M:PIK3CAmut AZD4547 +CT CT* E* CT* CT* GDC-0032 AMG102 +E PD-0332991 Endpoint (Interim PFS) PFS/OS Endpoint (Interim PFS) PFS/OS Endpoint (Interim PFS) PFS/OS Endpoint (Interim PFS) PFS/OS TT=Targeted therapy, CT=chemotherapy (docetaxel or gemcitabine), E=erlotinib *Archival FFPE tumor, fresh CNB if needed Target/M: Drug target and biomarker

19. S1400 Master ProtocolUnique Private-Public Partnerships with the NCTN National Clinical Trials Network S1400 Master Protocol

20. NCI Clinical Trials Reporting Policy: Premise • Fundamental premise (ample precedent) that results of all NIH-funded research must be shared to contribute to the general body of science, and ultimately, to the public health • Grantee/contracteeinstitutions are expected to make the results of their activities available to the research community and to the public at large • Problem: --Long lag time to publication of results, even for positive studies --Negative studies or incomplete studies are frequently never published due to lack of journal and/or investigator interest --Limits in FDAAA (FDA Amendment Act) legislation leave out certain studies from the requirement to publish results in clinicaltrials.gov

21. FDAAA Reporting Requirements • Registration required for: • Phase 2-4 trials • Drug, device, or biologic • IND/IDE or one site in U.S. • Includes IND exempt studies • Results reporting required, in general, within 12 months of the earlier of estimated/actual primary completion date • Results reporting required for studies of approved products (or products that become approved) •  Enforcement Provisions, including • Withholding of NIH grant funding • Up to $10,000/day fines

22. FDAAA: Gaps in Results Reporting • Phase 0 – 1 trials • Results required ONLY for studies of APPROVED PRODUCTS • Some surgical trials are not covered as only devices under FDA jurisdiction are subject to FDAAA • Proposed NCI Policy applies to diagnostic, preventive, behavioral and supportive care studies, some of which may not use agents/devices under FDA jurisdiction

23. 100 Months after Completion: Two Thirds of NIH-Supported Clinical Trials Published BMJ 2011;344:d7292 doi 432 published

24. Why Publish Incomplete Studies? • Studies stopped for toxicity, poor accrual, or other reasons may still prove valuable to other researchers and patients, even if only to avoid duplication, wasted effort, or to improve knowledge of side effects

25. Proposed NCI Clinical Trials Reporting Policy Principle Rapid, public access to final trial results for investigators, clinicians, and patients is particularly important for cancer research trials because the results of such research have the potential to directly affect patient care • Covered Trials • All NCI-supported interventional clinical trials whether extra-mural or intramural, across all disciplines and trial phases, whether completed or not • Excluded Studies • Observational studies and any interventional clinical trial in which no subjects are enrolled

26. NCI-Supported: Definition • All trials financially supported – whether in whole or in part – by NCI. In the case of NCI-designated Cancer Centers, the Policy does not apply to the subset of trials which, although they may benefit from core support from a Center grant, are funded privately and in which the data from the trial belong to the private funder. However, NCI-support does include those Cancer Center trials, funded at least in part by NCI, where the data resides with the academic investigator

27. When Must Trials Be Reported? • NCI will align its policy with clinicaltrials.gov to avoid confusion • Results are expected to be published within twelve (12) months of a trial’s Primary Completion Date • Primary Completion Date: date final subject had final collection of data for the primary outcome. Data from incomplete trials must also be reported within 12 months of the date the last subject had data collected even if the trial does not achieve its primary aim

28. What Must Be Reported? (all results reported by arm) • Participant Flow • Number Started • Number Completed • Baseline Characteristics • Number of Participants • Age and Gender • Outcome Measures • Summary results for primary and secondary outcome measures • Statistical analyses, as appropriate • Adverse Events • “Serious” and “Other” by Organ System

29. Where Must Trials Be Reported? • Final Trial Results must be reported in a publicly accessibly manner • Peer-reviewed scientific journal (in print or on-line) • On-line registration and reporting with a publicly accessible registry dedicated to the dissemination of clinical trial information such as ClinicalTrials.gov. • Journals willing to publish in abbreviated format, esp. negative or incomplete trials with less rigorous peer review than full-length articles • NCI not mandating a particular mechanism; eitherjournal publication or registry submission acceptable;the goal must be public accessibility • If publication is selected, then the NIH Public Access Policy (http://publicaccess.nih.gov/) requires submission to PubMed upon acceptance;public availability no later than 12 mos. after publication

30. Compliance & Public Input • Term of award for grants or deliverable for contracts • NCI Program/Project Officers will enforce this policy at time of final progress report or an alternative date for larger grants to trial networks • Non-compliance may result in funds recovery or withholding future support • Proposed policy published in NIH Guide: NOT-CA-14-005 • Comments were uniformly supportive • NIH Guide Notice was shared with CTEP clinical investigator distribution list • Most comments were positive although one respondent was concerned about the added workload