Low Dose Vemurafenib and Rituximab in Hairy Cell Leukemia

A Single Arm Phase II Pilot Study of Low Dose Vemurafenib Plus Rituximab in the Front-line and Relapsed/Refractory Treatment of Hairy Cell Leukemia

The current standard-of-care for Hairy Cell Leukemia involves chemotherapy, with agents such as cladribine or pentostatin. Chemotherapy is associated with infection, low blood counts and predisposition to future cancers. This study tests a new yet previously validated drug combination for the treatment of hairy cell leukemia. The treatment involves 8 weeks of treatment with an oral drug called vemurafenib and 8 doses of an intravenous medication called rituximab. The goal of this study is to see whether this treatment is better tolerated and more effective than the currently used treatment in this disease. In addition, this study uses a lower dose of vemurafenib than previous studies have used, with the goal of minimizing side effects from this medication.

Study Overview

• Status: Recruiting
• Conditions: Hairy Cell Leukemia
• Intervention / Treatment: Drug: Low dose vemurafenib plus rituximab

Detailed Description

This is a single-center, open label, single arm, investigator-initiated phase II trial of the oral BRAF inhibitor, vemurafenib, plus rituximab in patients with previously untreated or relapsed and refractory HCL. Eligible patients will receive vemurafenib at a dose of 240 mg orally twice daily (b.i.d.) continuously for 8 weeks. Rituximab 375 mg/m2 will be administered concomitantly with vemurafenib every 2 weeks from the first day of treatment. After completion of vemurafenib, the patient will receive rituximab 375 mg/m2 every 2 weeks for a total of 8 weeks. The entire duration of treatment will be 16 weeks. Six months after the initiation of the treatment, a bone marrow aspirate and biopsy will be performed for assessment of response and evaluation of minimal residual disease (MRD).

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Alan Saven, MD; Phone Number: 8585548788; Email: saven.alan@scrippshealth.org
• Study Contact Backup: Name: David J Hermel, MD; Phone Number: 8585548788; Email: hermel.david@scrippshealth.org

Study Locations

• United States
  • California
    • La Jolla, California, United States, 92037
      • Recruiting
      • Scripps Cancer Center
      • Principal Investigator: Alan Saven, MD
      • Contact: David J Hermel, MD; Phone Number: 858-554-8788; Email: hermel.david@scrippshealth.org
      • Sub-Investigator: David J Hermel, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• ≥ 18 years of age
• Histologically confirmed HCL that are BRAF V600E positive by IHC or NGS
• Patient's must meet the standard treatment initiation criteria, as defined by ANC ≤1.0, Hgb ≤ 10.0 or PLT ≤100K
• Patients can either have (1) not received any prior therapy for the disease or have had (2) failure to achieve any response to the initial purine analog-based therapy or (3) subsequent relapse after any prior therapy.
• ECOG performance status of 0-2
• Acceptable pre-study organ function during screening not exacerbated by Hairy Cell Leukemia. General thresholds should be a 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
• For women of childbearing potential, agreement to use acceptable methods of contraception
• For men with female partners of childbearing potential, agreement to use barrier contraception
• Negative serum pregnancy test within 7 days of commencement of treatment in premenopausal women.
• 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 or intending to become pregnant during the study
• Have had chemotherapy (including purine analogs), rituximab, and other investigational agents within six weeks prior to entering the study. The patients cannot have received BRAF inhibitor therapy within 6 months of 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
• Active HIV, hepatitis B and hepatitis C or any clinically significant history of liver disease. Hepatitis B prior infection is not a contraindication though will require therapy.
• Known hypersensitivity to any of the study drugs
• Patients with HCL that are BRAF V600E mutation negative

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: Low dose Vemurafenib and Rituximab; Eligible patients will receive vemurafenib at a dose of 240 mg orally twice daily (b.i.d.) continuously for 8 weeks. Rituximab 375 mg/m2 will be administered every 2 weeks for a total of 16 weeks. The entire duration of treatment will be 16 weeks.	Drug: Low dose vemurafenib plus rituximab; Vemurafenib 960 mg twice daily for 8 weeks with concurrent rituximab 375 mg/m2 every 2 weeks followed by maintenance consolidative rituximab 4 times every 2 weeks post-vemurafenib; Other Names: Rituximab; Vemurafenib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Response	Resolution of cytopenias and splenomegaly	Up to 2 years from enrollment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to hematologic response	Days until resolution of cytopenias	Up to 2 years from enrollment
MRD Status	At the time of bone marrow assessment by testing for BRAFV600E mutation status	At 6 months, 1 year and 2 years from treatment
Relapse-Free Survival	Reapperance of Hairy-Cell related cytopenia	From start of treatment until 2 years

Collaborators and Investigators

• Sponsor: Scripps Health
• Investigators: Principal Investigator: Alan Saven, MD, Scripps Clinic

Publications and helpful links

General Publications

• Tiacci E, De Carolis L, Simonetti E, Capponi M, Ambrosetti A, Lucia E, Antolino A, Pulsoni A, Ferrari S, Zinzani PL, Ascani S, Perriello VM, Rigacci L, Gaidano G, Della Seta R, Frattarelli N, Falcucci P, Foa R, Visani G, Zaja F, Falini B. Vemurafenib plus Rituximab in Refractory or Relapsed Hairy-Cell Leukemia. N Engl J Med. 2021 May 13;384(19):1810-1823. doi: 10.1056/NEJMoa2031298.
• Grever M, Andritsos L, Banerji V, Barrientos JC, Bhat S, Blachly JS, Call T, Cross M, Dearden C, Demeter J, Dietrich S, Falini B, Forconi F, Gladstone DE, Gozzetti A, Iyengar S, Johnston JB, Juliusson G, Kraut E, Kreitman RJ, Lauria F, Lozanski G, Parikh SA, Park J, Polliack A, Ravandi F, Robak T, Rogers KA, Saven A, Seymour JF, Tadmor T, Tallman MS, Tam CS, Tiacci E, Troussard X, Zent C, Zenz T, Zinzani PL, Wormann B. Hairy cell leukemia and COVID-19 adaptation of treatment guidelines. Leukemia. 2021 Jul;35(7):1864-1872. doi: 10.1038/s41375-021-01257-7. Epub 2021 May 4.

Study record dates

Study Major Dates

• Study Start (Actual): March 2, 2022
• Primary Completion (Estimated): January 1, 2025
• Study Completion (Estimated): January 1, 2025

Study Registration Dates

• First Submitted: May 16, 2022
• First Submitted That Met QC Criteria: May 19, 2022
• First Posted (Actual): May 24, 2022

Study Record Updates

• Last Update Posted (Actual): November 14, 2023
• Last Update Submitted That Met QC Criteria: November 10, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia; Leukemia, Hairy Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Rituximab; Vemurafenib
• Other Study ID Numbers: IRB-21-7787

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Plan to publish aggregate data in manuscript

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes