NCI Precision Medicine Trial Designs Shakun Malik, M.D. Head, Thoracic and Head & Neck Cancer Therapeutics Cancer Therapy Evaluation Program (CTEP) National Cancer institute/nih 1
Outline Background Current NCI Initiatives/Trials of Personalized therapies/master Protocols 2
Targeted Therapies in Oncology Ideally, a molecular target that drives tumor growth and/or cancer progression is discovered Can be pharmacologically inhibited, inhibition tolerated by normal cells and measurable in tumor tissue. The goal is to identify new antitumor agents with tumor specificity and low systemic toxicity and that can help patients live longer and one day soon cure cancer or at least help make it a chronic disease instead of a fatal one 3
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Lung Cancer Incidence by major histologic types* Small-cell carcinoma Adenocarcinoma 15% Large-cell carcinoma *Numbers do not sum to 100% because of differences in diagnostic criteria From: Ginsberg RJ, et al. Cancer: Principles and Practices of Oncology. 5th ed. 5
NCI-Precision Medicine Initiatives Exceptional Responders Initiative MATCH - Molecular Analysis for Therapy Choice Adjuvant ALCHEMIST (Lung Cancer Enrichment Marker Identification and Sequencing Trial) Lung-MAP (S1400 Lung master Protocol)
NCI EXCEPTIONAL RESPONDERS INITIATIVE PHENOTYPE TO GENOTYPE A Pilot Study
1-10% of patients respond well to drugs that do not go on to receive FDA approval for that indication Molecular mutations or changes in gene expression may explain these exceptional responses Could lead to development of predictive assays Improve biologic understanding for better therapeutics/diagnostic development
Screening of Potential ER Cases Sites Submit Data through the CTSU s OPEN Response Treatment info Copy of consent Pathology Reports Internal NCI review Case is Exceptional Enrollment Request sample and data Submitted through CTSU OPEN Registration Tissue specimen submitted QC Additional clinical data submitted (medidata Rave)
Molecular Analysis for Therapy Choice (NCI MATCH) A Joint NCTN/NCI Clinical Trial
Target: at least 25% of total enrollment to be patients who have rare tumors (Common defined as breast, NSCLC, colon, prostate) Dual Primary Endpoints: Overall Response Rate 5% vs. 25% or Progression Free Survival 6 months 15% (median PFS 2.2 m) vs. 35% (median PFS 4 m) One stage design 31 evaluable patients per arm
ALCHEMIST Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial
The drugs: not very subtle effects Crizotinib (Pfizer): Exceptional Responses mpfs 10 mo survival benefit (retrospective) 2+ line, metastatic RR 57% Erlotinib (Astellas): Initial indication not marker-specific 2 nd line adv/met maintenance in adv/met new: 1 st line with megfr mut EURTAC Phase III 1227 screened 173 randomized Kwak, NEJM 363:1693; 2010 mpfs 9.7 vs 5.2 p < 0.0001 Rosell, Lancet Onc. 13:3; 2012
ALCHEMIST Rationale ALCHEMIST is studying whether or not treatment based on genotype improves cure rates in earlier stage (IB- IIIA) NSCLC cancer patients with nonsquamous tumors that have been completely surgically resected. 16
Lung-MAP (S1400 Lung master Protocol) Phase II/III Biomarker-Driven Master Protocol for Second Line Therapy of Squamous Cell Lung Cancer.
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Future impending study arms of LungMap 1. PARP inhibitor 2. Combination Immunotherapy with PDL1 and anti CTLA 4
SUMMARY Master protocols provide Consistency of drug development approach regardless of intended target Utilize resources (including patient resources) in an efficient manner and have potential of bringing safe and effective drugs to patients faster Able to test multiple drugs for safety and efficacy simultaneously in early drug development studies MS 28 Future Clinical Trials Master Protocols Shakun Malik
SUMMARY On the other hand Master Protocols are Time and resource intense, and Have added need for a high level coordination. MS 28-Future
A Workplace that Supports Cancer Research National Cancer Institute Research Campus Rockville, Maryland, USA