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Vemurafenib and Obinutuzumab versus Standard Cladribine and Rituximab of the Treatment of Untreated Hairy Cell Leukemia
Trial Status: active
This phase II trial compares the effect of vemurafenib and obinutuzumab to standard cladribine and rituximab in patients with previously untreated hairy cell leukemia. Vemurafenib is a type of drug called a BRAF inhibitor. BRAF inhibitors target and block BRAF proteins, which are found on cancer cells and play a role in cancer growth and survival. By blocking the BRAF protein, vemurafenib may help slow or stop the growth of cancer. Obinutuzumab and rituximab are both monoclonal antibody drugs that block a protein in the body called CD20 that can cause cancer to grow and spread. Monoclonal antibodies target and destroy only certain cells in the body. This selective targeting may help protect healthy cells from damage. Research studies in patients with other types of cancer have shown that obinutuzumab might be more effective at getting rid of cancer cells compared to rituximab. Rituximab and cladribine are both chemotherapy drugs that stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving vemurafenib and obinutuzumab may kill more cancer cells in patients with previously untreated hairy cell leukemia compared to standard cladribine and rituximab.
Inclusion Criteria
Patients must be >= 18 years of age
Histologically confirmed classical hairy cell leukemia (HCL) by the enrolling institution
Presence of BRAF V600E mutation as confirmed by polymerase chain reaction (PCR), next generation sequencing (NGS) or immunohistochemistry. If patient is known to have negative BRAF mutation, repeat testing is advisable as well as discussion with the main study principal investigator.
Has not received any prior therapy for the disease
Patients who meet the standard treatment initiation criteria, as defined by absolute neutrophil count (ANC) =< 1.0, hemoglobin (Hgb) =< 10.0 or platelets (PLT) =< 100K
Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
Total bilirubin =< 1.5 times the upper limit of normal (ULN)
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5x ULN
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 and cladribine, and 18 months after discontinuation of rituximab and obinutuzumab
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 women of childbearing potential
Exclusion Criteria
Have had previous treatment for HCL, including purine analogs, vemurafenib, rituximab, obinutuzumab, and other investigational agents. Previous treatment with transfusions and other supportive care such as granulocyte colony-stimulating factor (G-CSF) and erythropoietin are allowed
Known hypersensitivity to any of the study drugs
Patients with known long QT syndrome or uncorrectable electrolyte abnormalities
Clinically significant history of liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis
Presence of positive test results for hepatitis B virus (HBV), hepatitis B surface antigen (HBsAg) or hepatitis C (hepatitis C virus [HCV]) antibody
* Patients with occult or prior HBV infection (defined as positive total hepatitis B core antibody [HBcAb] and negative HBsAg) may be included if HBV deoxyribonucleic acid (DNA) is undetectable. These patients must be willing to undergo monthly DNA testing and take HBV viral prophylaxis such as entecavir
Known infection with HIV or human T-cell leukemia virus 1 (HTLV-1)
Active uncontrolled infection, e.g. persistent bacteremia, supplemental oxygen or pressor supports, etc
Live vaccination within 28 days of randomization
Patients with concurrent active malignancies as defined by malignancies requiring any therapy other than expectant observation or hormonal therapy, with the exception of squamous and basal cell carcinoma of the skin, in situ cervical cancer, adequately treated stage I/II cancer from which the patient is current in complete remission, or any other cancer from which the patient has been disease free for five years
Malabsorption syndrome or other condition that precludes enteral route of administration
Patients with HCL variant (as defined by absence of expression of CD25)
Pregnant or lactating, or intending to become pregnant during the study
Additional locations may be listed on ClinicalTrials.gov for NCT06561360.
I. To compare the safety of vemurafenib plus obinutuzumab regimen against the standard of care, cladribine plus rituximab, as assessed by incidences of >= grade 3 treatment-related toxicities per Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0 within first 6 months from the start of the treatment to account delayed toxicities of the treatments.
SECONDARY OBJECTIVES:
I. To assess the efficacy of both intervention arms as defined by rates of complete remission (CR) and partial remission (PR).
II. To assess the rate of minimal residual disease (MRD) response assessed by immunohistochemistry, multiparameter flow cytometry and droplet digital polymerase chain reaction (PCR) for BRAFV600E.
III. To evaluate the progression-free and overall survival in both study arms.
IV. To assess degree of immunosuppression by quantification of peripheral blood B and T cell counts at pre-specified time points in both study arms.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients receive vemurafenib orally (PO) twice daily (BID) on days 1-28 of each cycle. Beginning in cycle 2, patients also receive obinutuzumab intravenously (IV) on days 1, 8, and 15 of cycle 2 and on day 1 of cycles 3 and 4. Cycles repeat every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
ARM II: Patients receive standard of care (SOC) cladribine IV once daily (QD) on days 1-5 of cycle 1 and rituximab IV once a week (QW) on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity.
Patients in both arms also undergo a chest x-ray during screening, a computed tomography (CT) or ultrasound, as well as bone marrow aspiration and biopsy during screening and follow-up, and blood sample collection throughout the trial.
After completion of study treatment, patients are followed up at months 5, 7, 8, 10, 12, 18, and 24 and then yearly for 3 years.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationMemorial Sloan Kettering Cancer Center
