A Phase II Study of the BRAF Inhibitor, Vemurafenib, Plus Obinutuzumab in Patients With Previously Untreated Classical Hairy Cell Leukemia

Sponsor: Memorial Sloan Kettering Cancer Center

Sponsor score: 60

ClinicalTrials ID:NCT03410875

This Phase II trial evaluates vemurafenib and obinutuzumab in untreated classical HCL patients. Using a Simon mini-max two-stage design, it involves 28 patients. Eligibility includes age ≥18, confirmed HCL, no prior therapy, and specific organ function criteria. Vemurafenib is given orally, with dose adjustments for toxicity, while obinutuzumab is infused starting cycle 2.

Patient Parameters

Program Overview

This is a multi-center, open label, single arm, phase II trial of the oral BRAF inhibitor, vemurafenib, plus obinutuzumab in patients with previously untreated HCL. A Simon mini-max two-stage design will be employed to assess the efficacy of the combination treatment of vemurafenib and obinutuzumab. In the first stage of the protocol, 9 patients will be treated. If fewer than 6 CRs are seen among the first 9 patients, the study will be closed for lack of efficacy. If at least 7 patients respond to the treatment, then an additional 19 patients will be accrued to the second stage, for a total of 28 patients.

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

Obinutuzumab will be administered concomitantly with vemurafenib starting at cycle 2 of treatment in cycles of 4 weeks. Obinutuzumab infusions will be administered at 1000mg per day on days 1, 8 and 15 during the cycle 2 and 1000mg per day every 4 weeks during the cycle 3 and 4 of treatment. After the completion of the treatment (i.e. after 4 cycles), a bone marrow aspirate and biopsy will be performed for assessment of response and evaluation of minimal residual disease (MRD). In case of certain defined toxicities, dose reductions of vemurafenib by 50% (480mg b.i.d.) or interruptions of up to 15 days are permitted. If additional dose reduction is required, vemurafenib may be reduced to 240mg oral b.i.d.

Eligibility Criteria

Inclusion Criteria

  • Patients must be >/= 18 years of age

  • Histologically confirmed classical HCL by the enrolling institution

  • Has not received any prior therapy for the disease

  • 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
    • 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 (QT 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 with 7 days of commencement of treatment in women of childbearing potential

Exclusion Criteria

  • Have had previous treatment for HCL, including purine analogs, rituximab, and other investigational agents. Previous treatment with transfusions and other supportive care such as 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 DNA is undetectable. These patients must be willing to undergo monthly DNA testing.

  • Known infection with 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

Locations

FACILITYZIPCITYSTATE
Yale University06511New HavenConnecticut
Dana Farber Cancer Institute02115BostonMassachusetts
Memorial Sloan Kettering at Basking Ridge07920Basking RidgeNew Jersey
Memorial Sloan Kettering Monmouth (Limited Protocol Activities)07748MiddletownNew Jersey
Memorial Sloan Kettering Bergen (Limited Protocol Activities)07645MontvaleNew Jersey
Memorial Sloan Kettering Cancer Center @ Commack (Limited Protocol Activities)11725CommackNew York
Memorial Sloan Kettering Westchester (Limited Protocol Activities)10604HarrisonNew York
Memorial Sloan Kettering Cancer Center10021New YorkNew York
Memorial Sloan Kettering Nassau (Limited Protocol Activities)11553UniondaleNew York

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