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

• ClinicalTrials.gov Identifier: NCT01711632
• Recruitment Status: Active, not recruiting
• First Posted: October 22, 2012
• Last Update Posted: August 1, 2023
• Sponsor: Memorial Sloan Kettering Cancer Center
• Collaborators: National Cancer Institute (NCI); Northwestern University; Ohio State University; Dana-Farber Cancer Institute; Scripps Clinic; Northwell Health
• Information provided by (Responsible Party): Memorial Sloan Kettering Cancer Center

Tracking Information

• First Submitted Date: October 17, 2012
• First Posted Date: October 22, 2012
• Last Update Posted Date: August 1, 2023
• Actual Study Start Date: October 2012
• Estimated Primary Completion Date: October 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 18, 2012)

efficacy of vemurafenib [ Time Frame: 3 months ]

as assessed by overall response rates after three months of treatment in patients with relapsed or refractory HCL.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: October 18, 2012)

• Toxicity (safety and tolerability) [ Time Frame: 2 years ]
  Toxicity will be graded and recorded using the NCI Common Toxicology Criteria version 4.0.
• To assess the pharmacodynamics [ Time Frame: 2 years ]
  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.
• evaluate biomarkers [ Time Frame: 2 years ]
  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.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: BRAF Inhibitor, Vemurafenib, in Patients With Relapsed or Refractory Hairy Cell Leukemia
• Official Title: A Phase II Study of the BRAF Inhibitor, Vemurafenib, in Patients With Relapsed or Refractory Hairy Cell Leukemia
• Brief Summary: 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Hairy Cell Leukemia

Intervention

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 Name: Zelboraf™

Study Arms

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).

Intervention: Drug: Vemurafenib

• 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.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: October 18, 2012): 36
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: October 2025
• Estimated Primary Completion Date: October 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

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)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01711632
• Other Study ID Numbers: 12-200
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Memorial Sloan Kettering Cancer Center
• Original Responsible Party: Same as current
• Current Study Sponsor: Memorial Sloan Kettering Cancer Center
• Original Study Sponsor: Same as current

Collaborators

• National Cancer Institute (NCI)
• Northwestern University
• Ohio State University
• Dana-Farber Cancer Institute
• Scripps Clinic
• Northwell Health

Investigators

• Principal Investigator: Jae H. Park, MD; Memorial Sloan Kettering Cancer Center

• PRS Account: Memorial Sloan Kettering Cancer Center
• Verification Date: July 2023