Encorafenib Plus Binimetinib for People With BRAF V600 Mutated Relapsed/Refractory HCL

Hairy Cell Leukemia Clinical Trial

Official title: Phase 2 Trial of Encorafenib Plus Binimetinib for Patients With BRAF V600 Mutated Relapsed/Refractory HCL

Status Recruiting

Clinical Trial Summary

Background:

Hairy cell leukemia (HCL) does not usually respond to chemotherapy. Most people with HCL have a BRAF gene mutation. This can increase the growth of cancer cells. Vemurafenib has been tested to treat these people. However, researchers think a combination of drugs might work better.

Objective:

To test if treatment with a combination of encorafenib and binimetinib in BRAF mutant

HCL is more effective than treatment with vemurafenib.

Eligibility:

People ages 18 and older with BRAF mutant HCL that did not respond to or came back after treatment

Design:

Participants will be screened with:

Medical history

Physical exam

Bone marrow biopsy: A needle will be injected through the participant s skin and into a bone to remove liquid.

Blood and urine tests

Heart and lung function tests

CT or MRI scan: Participants will lie in a machine that takes pictures of the body. They may have a contrast agent injected into a vein.

Eye exam

Participants will take the study drugs by mouth in 28-day cycles. They will take encorafenib daily. They will take binimetinib twice daily. They will keep a pill diary.

Participants will take their temperature daily.

Participants will have at least 1 visit before each cycle. Visits will include repeats of some screening tests. They will also include abdominal ultrasounds, exercise stress tests, and skin evaluations.

Participants may continue treatment as long as their disease does not get worse and they do not have bad side effects.

About a month after their last dose of treatment, participants will have a follow-up visit. Then they will have annual follow-ups....

Clinical Trial Description

Background:

• Hairy cell leukemia (HCL) is an indolent B-cell leukemia comprising 2% of all leukemias, or approximately 1900 new cases/year in the US. The nucleoside analogs cladribine and pentostatin are highly active as monotherapy with complete remission (CR) rates of 80 to 90%. However, there is no cure from chemotherapy and patients eventually relapse with worse efficacy and cumulative toxicity (stem cell damage and neuropathy) with each repeated chemotherapy course.

• About 90% of classic HCL patients have the BRAF V600E mutation, which leads to Ras-independent activation of the MAPK pathway, causing increased phosphorylation (hyper-activation) of MEK, followed by ERK, therefore promoting the proliferation and survival of HCL cells.

• The BRAF inhibitor, vemurafenib, when used as a single agent for the treatment of HCL achieved high response rate with CR rate of 38% in 50 patients reported from 2 trials, however, treatment was limited to several months and responses lacked durability, with median CR duration of 19 months in 1 trial. In this trial, 100% of the CRs were positive for minimal residual disease (MRD) by immunohistochemistry (IHC), and failure to eradicate MRD after several months of vemurafenib likely lead to the lack of CR durability.

• In a recent trial of combined inhibition of BRAF and MEK using dabrafenib and trametinib treatment, 49% of 41 evaluable patients achieved CR, and MRD was eradicated in 15% of patients on this trial. At NIH, we enrolled a total of 28 HCL patients on this trial and achieved a CR rate of 68% amongst our patients by managing toxicity and allowing patients to remain on treatment.

• A major challenge in the long-term treatment of HCL patients with dabrafenib and trametinib is managing fever, which has necessitated long-term or intermittent steroids use for most patients.

• In the COLOMBUS trial, the combination of the BRAF inhibitor, encorafenib and the MEK inhibitor, binimetinib was found to be superior to vemurafenib for BRAF V600E+ melanoma with respect to PFS and OS and was well tolerated with low rates of toxicities including pyrexia.

• To our knowledge, neither encorafenib nor binimetinib has been tested in HCL, but the low rate of pyrexia with encorafenib plus binimetinib in melanoma suggests that this combination may be well tolerated in HCL.

Objective:

• To determine if treatment with combination encorafenib and binimetinib in BRAF V600 mutant + HCL is associated with a CR rate which exceeds that of vemurafenib.

Eligibility:

• BRAF V600 mutant HCL with at least 1 prior purine analog treatment

• Need for treatment, as evidenced by any one of the following: ANC <1 x10^3/mcL, Hgb <10g/dL, Platelet count <100 x10^3/mcL, leukemia cell count >5 x10^3/mcL, symptomatic splenomegaly, enlarging HCL mass > 2cm in short axis

• Greater than or equal to 18 years of age

• No uncontrolled infection, cardiopulmonary dysfunction, or secondary malignancy requiring treatment.

• No chemotherapy, immunotherapy, investigational agent or radiotherapy within 4 weeks prior to the start of study treatment.

Design:

• Phase 2 trial, single arm, non-randomized trial to determine if the combination of encorafenib and binimetinib achieves a CR rate in HCL which is historically higher than that of vemurafenib.

• Simon optimal 2-phase design will be used to rule out an unacceptable CR rate of 35% in favor of an improved 55% CR rate.

• Initially 12 evaluable participants will be enrolled. If 5 or more achieve CR, then accrual will continue to a total of 32 evaluable participants

• Encorafenib will be given at a dose of 450mg QD and binimetinib at a dose of 45mg BID for as long as participants can continue dosing chronically without significant toxicity or a trial off therapy due to achievement of MRD negative complete remission or PR/CR in which they would like a trial off therapy. Participants may return to therapy within 2 years of stopping treatment if evidence of disease returns. ;

Related Conditions & MeSH terms

• Hairy Cell Leukemia
• Leukemia, Hairy Cell

• NCT number: NCT04324112
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Contact: Holly Eager (DiFebo), R.N.
• Phone: (240) 858-7229
• Email: holly.eager@nih.gov
• Status: Recruiting
• Phase: Phase 2
• Start date: October 28, 2020
• Completion date: July 31, 2028