Clinical trial NCT03410875: A Phase II Study of the BRAF Inhibitor, Vemurafenib, Plus Obinutuzumab in Patients With Previously Untreated Classical Hairy Cell Leukemia
Official title: A Phase II Study of the BRAF Inhibitor, Vemurafenib, Plus Obinutuzumab in Patients With Previously Untreated Classical Hairy Cell Leukemia
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Hairy Cell Leukemia
Leukemia
Leukemia, Hairy Cell
Keywords: Leukemia
Hairy Cell Leukemia
BRAF
vemurafenib
obinutuzumab
Memorial Sloan Kettering Cancer Center
17-513
Lead sponsor: Memorial Sloan Kettering Cancer Center
Sponsor class: OTHER
Collaborators: name: Dana-Farber Cancer Institute
name: Yale University
First posted: 2018-01-25
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Efficacy of vemurafenib in combination with obinutuzumab
timeFrame: 16 weeks
Secondary outcomes:
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Basking Ridge
country: United States
facility: Memorial Sloan Kettering at Basking Ridge
state: New Jersey
city: Middletown
country: United States
facility: Memorial Sloan Kettering Monmouth (Limited Protocol Activities)
state: New Jersey
city: Montvale
country: United States
facility: Memorial Sloan Kettering Bergen (Limited Protocol Activities)
state: New Jersey
city: Commack
country: United States
facility: Memorial Sloan Kettering Cancer Center @ Commack (Limited Protocol Activities)
state: New York
city: Harrison
country: United States
facility: Memorial Sloan Kettering Westchester (Limited Protocol Activities)
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Uniondale
country: United States
facility: Memorial Sloan Kettering Nassau (Limited Protocol Activities)
state: New York
Study officials:
affiliation: Memorial Sloan Kettering Cancer Center
name: Jae Park, MD
role: PRINCIPAL_INVESTIGATOR
References: