Vemurafenib and Obinutuzumab in Treating Patients with Previously Untreated Classical Hairy Cell Leukemia
- Patients must be >= 18 years of age
- Histologically confirmed classical HCL by the enrolling institution
- Has not received any prior therapy for the disease
- Absolute neutrophil count (ANC) =< 1.0
- Hemoglobin (Hgb) =< 10.0 or
- Platelet (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) =< 2.5 x ULN
- Serum creatinine =< 1.5 x 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 women of childbearing potential
- Have had previous treatment for HCL, including purine analogs, rituximab, 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
- Clinically significant history of liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis
- Patients with uncorrectable electrolyte abnormalities with potassium (K) > ULN (upper limit of normal)
- Patients with any active and uncontrolled infections (such as bacterial, fungal, and new or reactivated viral infections)
- Presence of positive test results for hepatitis B virus (HBV), hepatitis B surface antigen (HBsAg) or hepatitis C (HCV) antibody * Patients who are positive for HCV antibody must be negative for HCV by polymerase chain reaction (PCR) to be eligible for study participation * 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
- Known infection with human immunodeficiency virus (HIV) or human T-cell leukemia virus 1 (HTLV-1)
- Invasive malignancy that require active systemic chemotherapy or biologics that may cause significant drug-drug interaction with either vemurafenib or obinutuzumab
- 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
I. To determine the efficacy of vemurafenib in combination with obinutuzumab as assessed by complete response (CR) rates.
I. To assess the safety and tolerability of vemurafenib plus obinutuzumab in patients with previously untreated hairy cell leukemia (HCL).
II. To assess the efficacy of vemurafenib plus obinutuzumab based on duration of response and kinetics of minimal residual disease (MRD) response assessed by immunohistochemistry.
III. To determine the progression-free and overall survival of HCL patients treated with vemurafenib plus obinutuzumab.
IV. To assess the pharmacodynamics of vemurafenib and obinutuzumab via measurement of BRAF downstream targets (MEK, phosphorylated [p]-MEK, ERK, p-ERK) from the peripheral blood and/or bone marrow aspirate samples and by measurement of BRAFV600E allele burden by digital polymerase chain reaction (PCR).
V. To evaluate the potential mechanisms of resistance by assessing secondary BRAF mutations, signaling on the entire MAPK, PI3K and JAK-STAT pathways, and reactivation of MAPK pathways.
Patients receive vemurafenib orally (PO) twice daily (BID) on days 1-28 of all cycles. Beginning cycle 2, patients also receive obinutuzumab intravenously (IV) on days 1, 8, and 15 of cycle 2 and on day 1 of cycle 3 and 4. Treatment repeats every 28 days for up to 4 cycles of vemurafenib and for up to 3 cycles of obinutuzumab in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 4 weeks and every 2-3 months thereafter for 1 year.
Trial Phase Phase II
Trial Type Treatment
Memorial Sloan Kettering Cancer Center
- Primary ID 17-513
- Secondary IDs NCI-2018-00285
- Clinicaltrials.gov ID NCT03410875