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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.