Phase II Study of the BRAF Inhibitor, Vemurafenib, in Patients With Relapsed or Refractory Hairy Cell Leukemia ( NCT ) Martin S. Tallman, M.D. Leukemia Service Memorial Sloan Kettering Cancer Center NCT Weill Cornell Medical College New York, NY

Limitations of Purine Analogs Induce high response rates in HCL, but 20-30% relapse May not be curative Limited treatment options for relapsed and/or refractory disease Rates and duration of CR decline with each subsequent line of therapy

Novel Strategies in HCL Immunotoxins: (BL22/HA22) (anti-CD22 + truncated pseudomonas exotoxin A) Monoclonal antibodies: Rituximab Purine analogs + Rituximab Bendamustine + Rituximab Small molecule inhibitors (Vemurafenib, PLX8394) Small molecule inhibitors: Vemurafenib

Rationale for Targeting BRAF in HCL BRAF V600E mutation present in 100% of classical HCL; absent in other B cell lymphoid malignancies Re-appears at disease relapse Trigger for constitutive MEK and ERK activation Treatment of primary HCL cells with the BRAF inhibitor  decrease pMEK and pERK Vemurafenib is an effective and selective BRAF inhibitor, administered orally

Vemurafenib in a Patient With Refractory HCL Peripheral blood counts prior to and post-treatment with vemurafenib Vemurafenib Within 2 days of treatment, spleen started to decrease and WBC & PLT counts increased By day 43, CR achieved as assessed by BMB Dietrich et al. NEJM, 2012; Dietrich et al. J Clin Oncol, 2013

Participating Institutions Memorial Sloan-Kettering Cancer Center (Open) North Shore-LIJ Health System (Open) Dana-Farber Cancer Institute (Open) Scripps Clinic (Open) Northwestern University ( will open in May) Ohio State University (Open)

Key Eligibility Criteria Classical HCL with one of the following: – Intolerance to purine analogs – Failure to achieve any response (CR or PR) to the initial purine analog-based therapy – Relapse ≤ 2 years of purine analog-based therapy – ≥ 2 relapses In need of therapy – ANC ≤1.0, Hgb ≤10.0, or PLT ≤100K QTc < 480msc

Study Objectives Primary Objective – To determine the efficacy as assessed by ORR Secondary Objectives – To assess the safety and tolerability – To assess time to response, duration of response, and MRD kinetics – To determine PFS and OS – To assess the PD via measurement of BRAF downstream targets

Treatment Plan Starting dose: Vemurafenib 960mg orally twice daily MRD assessed by immunohistochemistry

Acknowledgements Jae Park, M.D. Omar Abdel-Wahab, M.D. Stephen Chung, M.D.