BRAF Inhibitor, Vemurafenib, in Patients With Relapsed or Refractory Hairy Cell Leukemia

A Phase II Study of the BRAF Inhibitor, Vemurafenib, in Patients With Relapsed or Refractory Hairy Cell Leukemia

The purpose of this study is to find out what effects, good and/or bad, treatment with vemurafenib (also known as Zelboraf™) has on the patient and on leukemia. Specifically, the researchers want to know how well vemurafenib eliminates leukemia from the blood.

Study Overview

• Status: Completed
• Conditions: Hairy Cell Leukemia
• Intervention / Treatment: Drug: Vemurafenib

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • La Jolla, California, United States, 92037
      • Scripps Clinic
  • Illinois
    • Evanston, Illinois, United States, 60208
      • Northwestern University
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana Farber Cancer Institute
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• ≥ 18 years of age
• Histologically confirmed classical HCL with one of the following:
• Intolerance to purine analogs or considered to be poor candidates for purine analog-based therapy
• 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 Histologic confirmation of diagnosis will be performed at MSKCC or a participating site.
• Patients who meet the standard treatment initiation criteria, as defined by ANC ≤1.0, Hgb ≤ 10.0 or PLT ≤100K
• ECOG performance status of 0-2
• Acceptable pre-study organ function during screening as defined as: Total bilirubin ≤ 1.5 times the upper limit of normal (ULN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5x ULN, and serum creatinine ≤ 1.5x ULN
• Electrocardiogram (ECG) without evidence of clinically significant ventricular arrhythmias or ischemia as determined by the investigator and a rate-corrected QT interval (QTc, Bazett's formula) of < 480 msec.
• For women of childbearing potential, agreement to the use of two acceptable methods of contraception, including one barrier method, during the study and for 6 months after discontinuation of vemurafenib
• For men with female partners of childbearing potential, agreement to use a latex condom and to advise their female partner to use an additional method of contraception during the study and for 6 months after discontinuation of vemurafenib
• Negative serum pregnancy test within 7 days of commencement of treatment in premenopausal women.
• Agreement not to donate blood or blood products during the study and for at least 6 months after discontinuation of vemurafenib; for male partners, agreement not to donate sperm during the study and for at least 6 months after discontinuation of vemurafenib
• Ability to understand and willingness to sign a written informed consent document.
• Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.

Exclusion Criteria:

• Pregnant or breast-feeding
• Have had chemotherapy (including purine analogs, rituximab, and other investigational agents) within six weeks prior to entering the study
• Major surgery within 4 weeks prior to entering the study
• Invasive malignancy within the past 2 years prior to first study drug administration, except for adequately treated (with curative intent) basal or squamous cell carcinoma, melanoma, in situ carcinoma of the cervix, in situ ductal adenocarcinoma of the breast, in situ prostate cancer, or limited stage bladder cancer or other cancers from which the patient has been disease-free for at least 2 years
• Refractory nausea or vomiting, malabsorption, external biliary shunt, or history of any type of gastrointestinal surgery that would preclude adequate absorption of study drug
• Prior treatment with MEK or BRAF inhibitors
• Active HIV, hepatitis B and hepatitis C
• Patients with HCL variant (as defined by absence of expression of CD25 or absence of BRAF V600E mutation)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Vemurafenib; Eligible patients will receive vemurafenib at a dose of 960mg orally twice daily (b.i.d.) continuously in cycles of 4 weeks (28 days).

Drug: Vemurafenib; Patients will receive vemurafenib at a dose of 960mg orally b.i.d. continuously in cycles of 4 weeks (28 days) as outpatient. A bone marrow aspirate and/or biopsy will be performed after the first cycle for research purposes only. After the completion of the third cycle, a repeat bone marrow aspirate and/or biopsy will be performed for assessment of response and evaluation of MRD. Following the third cycle assessments, patients who achieve complete response (CR) with detectable MRD or partial response (PR) may continue with vemurafenib for up to 3 additional cycles at the treating physician's discretion (Cycles 4-6). Patients who achieve CR without MRD will be observed as part of post-treatment followup, and may be re-treated with vemurafenib after relapse (as per below). Patients who achieve no response (NR) after the initial 3 cycles of vemurafenib will be removed from the study. They will be followed every 3 months as part of posttreatment followup for a total of 12 months.; Other Names: Zelboraf™

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy of Vemurafenib	as assessed by overall response rates after three months of treatment in patients with relapsed or refractory HCL. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxicity (Safety and Tolerability)	Toxicity will be graded and recorded using the NCI Common Toxicology Criteria version 4.0.	2 years
To Assess the Pharmacodynamics Change From Baseline	Peripheral blood and/or bone marrow aspirate samples from pretreatment and post-treatment at specified time points will be assessed by Western Blot or by phospho-flow for the downstream targets of BRAF (MEK, pMEK, ERK, pERK) to assess the ontarget effect of the Vemurafenib. The droplet digital PCR assay was performed to quantify the concentration of molecules with mutated BRAF V600E DNA at baseline and again at 12 weeks of vermurafenib therapy.	2 years
Evaluate Biomarkers of Resistance	Reactivation of MAPK pathways: Increased expression of the other RAF isoforms CRAF and ARAF), and MAPK (MAPK8 or COT) will be analyzed by Western Blot and/or real-time PCR39,40. Secondary BRAF mutations (all 18 BRAF exons) and RAS mutations40 will be analyzed by bidirectional Sanger sequencing and by Raindance multiplex PCR and Illumina next generation sequencing, respectively. Activation of RTKs (i.e. PDGFRβ and IGF-IR) will be assessed by Western Blot. Cell Biosciences NanoPro 1000 technology will be used to examine quantitative signaling on the entire MAPK, PI3K and JAK-STAT pathways41.	2 years

Collaborators and Investigators

• Sponsor: Memorial Sloan Kettering Cancer Center
• Collaborators: National Cancer Institute (NCI); Northwestern University; Northwell Health; Dana-Farber Cancer Institute; Ohio State University; Scripps Clinic
• Investigators: Principal Investigator: Jae H. Park, MD, Memorial Sloan Kettering Cancer Center

Publications and helpful links

General Publications

• Tiacci E, Park JH, De Carolis L, Chung SS, Broccoli A, Scott S, Zaja F, Devlin S, Pulsoni A, Chung YR, Cimminiello M, Kim E, Rossi D, Stone RM, Motta G, Saven A, Varettoni M, Altman JK, Anastasia A, Grever MR, Ambrosetti A, Rai KR, Fraticelli V, Lacouture ME, Carella AM, Levine RL, Leoni P, Rambaldi A, Falzetti F, Ascani S, Capponi M, Martelli MP, Park CY, Pileri SA, Rosen N, Foa R, Berger MF, Zinzani PL, Abdel-Wahab O, Falini B, Tallman MS. Targeting Mutant BRAF in Relapsed or Refractory Hairy-Cell Leukemia. N Engl J Med. 2015 Oct 29;373(18):1733-47. doi: 10.1056/NEJMoa1506583. Epub 2015 Sep 9.
• Handa S, Lee JO, Derkach A, Stone RM, Saven A, Altman JK, Grever MR, Rai KR, Shukla M, Vemuri S, Montoya S, Taylor J, Abdel-Wahab O, Tallman MS, Park JH. Long-term outcomes in patients with relapsed or refractory hairy cell leukemia treated with vemurafenib monotherapy. Blood. 2022 Dec 22;140(25):2663-2671. doi: 10.1182/blood.2022016183.

Helpful Links

• Memorial Sloan Kettering Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2012
• Primary Completion (Actual): August 16, 2024
• Study Completion (Actual): August 16, 2024

Study Registration Dates

• First Submitted: October 17, 2012
• First Submitted That Met QC Criteria: October 18, 2012
• First Posted (Estimated): October 22, 2012

Study Record Updates

• Last Update Posted (Estimated): October 20, 2025
• Last Update Submitted That Met QC Criteria: October 7, 2025
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: BRAF Inhibitor; VEMURAFENIB; 12-200; Zelboraf™
• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Leukemia; Hemic and Lymphatic Diseases; Leukemia, Hairy Cell; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Amides; Indoles; Sulfonamides; Sulfones; Vemurafenib
• Other Study ID Numbers: 12-200