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 (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT03410875

Collaborator

Dana-Farber Cancer Institute (Other), Yale University (Other)

Enrollment

Locations

Arm

58.7

Anticipated Duration (Months)

3.3

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Hairy Cell Leukemia Leukemia Leukemia, Hairy Cell	Drug: Vemurafenib Drug: Obinutuzumab	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

30 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Feb 9, 2018

Anticipated Primary Completion Date :

Jan 1, 2023

Anticipated Study Completion Date :

Jan 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Untreated Hairy Cell Leukemia Participants with HCL with no prior treatment for the disease	Drug: 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) for a total of 4 cycles. 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. Drug: Obinutuzumab 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.

Arm

Intervention/Treatment

Experimental: Untreated Hairy Cell Leukemia

Participants with HCL with no prior treatment for the disease

Drug: 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) for a total of 4 cycles. 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.

Drug: Obinutuzumab

Outcome Measures

Primary Outcome Measures

Efficacy of vemurafenib in combination with obinutuzumab [16 weeks]
Efficacy as assessed by complete response (CR) rates of participants

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Yale University	New Haven	Connecticut	United States	06511
2	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02115
3	Memorial Sloan Kettering at Basking Ridge	Basking Ridge	New Jersey	United States	07920
4	Memoral Sloan Kettering Monmouth (Limited Protocol Activities)	Middletown	New Jersey	United States	07748
5	Memorial Sloan Kettering Bergen (Limited Protocol Activities)	Montvale	New Jersey	United States	07645
6	Memorial Sloan Kettering Cancer Center @ Commack (Limited Protocol Activities)	Commack	New York	United States	11725
7	Memoral Sloan Kettering Westchester (Limited Protocol Activities)	Harrison	New York	United States	10604
8	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10021
9	Memorial Sloan Kettering Nassau (Limited Protocol Activities)	Uniondale	New York	United States	11553