AACR Genomics In Clinical Medicine Think Tank NCI’s Precision Medicine Initiative for Oncology – Operationalizing Public- Private Partnerships Jeffrey S. Abrams M.D. Associate Director, CTEP, DCTD Acting Director for Clinical Research, DCTD National Cancer Institute, NIH AACR Genomics In Clinical Medicine Think Tank July 13-14, 2016

NCTN as a Network in the Era of Precision Medicine LAPS Activated: Lung-MAP (S1400) – led by SWOG ALCHEMIST (A151216) – led by Alliance and ECOG-ACRIN Exceptional Responders (9671) – open in NCTN and beyond NCI MATCH –led by ECOG-ACRIN In development: NCI Pediatric MATCH – led by COG … It takes a network …

Key Aspects of NCI Precision Medicine Trials Single IND – multiple company partners working together within NCI IP agreement framework Public- private partnerships to extend the trials’ reach (FNIH, FOCR, Companies) Biopsies, NGS & other diagnostic tests paid for either by NCI or by company partners – trials are very expensive New educational issues for clinicians and patients – significance of diagnostic tests – somatic (variants, allelic fraction) and germline Correlative science: cfDNA, whole exome/genome, RNA seq

NCI Precision Medicine Trials: Lessons Learned Multi-Lab Concordance for NGS testing is achievable Assay turnaround time is adequate Biopsies from sites nationwide are feasible Central IRB is a critical component Pre-screening is valuable Multiple arms can be difficult to manage when new data intrudes Adjuvant studies of rare variants are challenging

NCI’s Early Therapeutics Clinical Trials Network (ETCTN)

NCI-Designated Cancer Centers (clinical) (Red= clinical centers gaining ETCTN opportunity under new program) This map shows in blue stars NCI CC’s that are part of ETCTN and in red stars NCI CC’s that are currently not affiliated with the NCI ETCTN program. Under this proposal, investigators in these cancer centers would now have the opportunity to propose original clinical study ideas to CTEP, and if approved, would have ETCTN sites and infrastructure available for accrual of patients. In addition, many of these centers would now be able to help us recruit patients with rare tumors to our studies.

Recently developed NCI IND agents Agents that have achieved FDA approval based in part on early development in CTEP collaborative early phase programs Bortezomib- Mantle Cell Lymphoma Ipilumumab- Melanoma Lenalidomide and bortezomib- Multiple Myeloma Romidepsin- Peripheral T cell Lymphoma Sorafenib- Thyroid Cancer Ziv-aflibercept- Colorectal Cancer Dinutuximab (ch14.18)- Neuroblastoma Pending FDA approval Nivolumab – Anal and Nasopharyngeal Cancer Pembrolizumab – Merkel Cell, Mycosis Fungoides In pivotal trials based on development in CTEP program Cediranib and Oliparib- Ovarian Cancer Selumetinib- Uveal Melanoma The program has many successes and our trials have contributed to FDA approval of the agents listed here.

Molecularly Targeted Combinations: Accrual Data Active Studies 2011-2016: 263 97 Investigational/Investigational 127 Investigational/Commercial 39 Commercial New indication 29 Trials in review using investigational combinations Total Accrual: 11,432 across all histologies (phase 1, phase 2, and pilot studies only – ETCTN and Cooperative Group Network) http://oma1.od.nih.gov/manualchapters/management/1810-1/ http://oma1.od.nih.gov/manualchapters/grants/4204-204B/

Common Data Sharing and IP Option Agreement Language NCI Drug Formulary Initiative: Industry-NCI/CTEP-Investigator Agreements Common Data Sharing and IP Option Agreement Language Funding Agreement/Protocol Language or MTA (for non-clinical studies) Simplified CRADA Agreement Institutions Collaborator A Investigational Agent A Network Groups NCI/DCTD Collaborator B Investigational Agent B Consortia Agreements encompass multiple trials/studies of mutual interest Framework accepted by Collaborators and Cancer Centers

Recommendations What is the threshold (of rarity) that defines the need for national scale investigation (NCTN or private sector)? Nationwide screening effort is needed to find molecular subtype – new cost sharing structure seems necessary (gov’t, industry, philanthropy) Central IRBs are critical for multi-arm studies and for studies of rare diseases – system depends on volunteers Multiple agents are available for the target – Medical system needs a “bake-off” study to rationalize care