Phase II Study of the BRAF Inhibitor, Vemurafenib, in

Patients With Relapsed or Refractory

Hairy Cell Leukemia (NCT01711632 )

Martin S. Tallman, M.D. Leukemia Service

Memorial Sloan Kettering Cancer CenterNCT01711632 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.