Encorafenib + Binimetinib for Hairy Cell Leukemia

Overseen By Holly M Eager, R.N.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Chemotherapy, Immunotherapy, Major surgery, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 3

Duration: As long as participants can continue dosing without significant toxicity

45 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of two drugs, encorafenib (Braftovi) and binimetinib (Mektovi), to determine if they outperform the current treatment for people with hairy cell leukemia (HCL) who have a BRAF gene mutation. HCL, a type of cancer, often resists chemotherapy, prompting researchers to seek more effective options. People with HCL that did not respond to treatment or recurred, and who have the BRAF mutation, might be suitable candidates. Participants will take these medications in cycles and attend regular check-ups to monitor their health and treatment progress. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you have taken chemotherapy, immunotherapy, or investigational agents within 4 weeks before starting the study. Also, you cannot take strong CYP3A4 inhibitors or inducers during the trial.

Is there any evidence suggesting that the combination of encorafenib and binimetinib is likely to be safe for humans?

Research has shown that the combination of encorafenib and binimetinib has been tested for safety. In earlier studies, 38% of patients experienced serious side effects, while fatal side effects occurred in 2% of patients. Common side effects included tiredness, nausea, and diarrhea, affecting more than 25% of those taking these drugs together.

This combination has treated other conditions, indicating some known safety from these uses. However, like all treatments, it may carry risks. Participants should discuss these potential side effects with their doctors before joining the trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about the combination of encorafenib and binimetinib for treating Hairy Cell Leukemia because it offers a novel approach compared to standard treatments like purine analogs, which are chemotherapy agents. Encorafenib and binimetinib target specific proteins involved in cancer cell growth, namely BRAF and MEK, offering a more targeted therapy. This mechanism of action could potentially result in fewer side effects and improved effectiveness by directly interfering with the cancer's growth pathways, rather than broadly attacking all rapidly dividing cells.

What evidence suggests that the combination of encorafenib and binimetinib could be an effective treatment for hairy cell leukemia?

Research has shown that treatments targeting the BRAF mutation in hairy cell leukemia (HCL) are promising. In this trial, participants will receive a combination of Encorafenib and Binimetinib, which block signals that promote cancer cell growth. Studies have found that similar drugs, such as vemurafenib, led to complete remission in 30% of patients. However, using Encorafenib and Binimetinib together might prove more effective, as they target multiple pathways, potentially leading to better disease control. ^{1 6 7 8 9}

Who Is on the Research Team?

Robert J Kreitman, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

Adults with Hairy Cell Leukemia (HCL) that have a BRAF V600 mutation and whose disease didn't respond to or returned after treatment. They should not be eligible for certain other treatments, must use effective contraception, and have specific blood count levels. Excluded are those with significant heart disease, gastrointestinal issues affecting drug absorption, recent major surgery recovery, known allergies to trial drugs' components, active infections like HBV or HCV, HIV unless well-managed on medication.

Inclusion Criteria

Your hemoglobin levels are below 10 grams per deciliter.

Co-enrollment in study 10-C-0066

My condition worsened or didn't improve within a year after my first treatment with a purine analog.

Exclusion Criteria

I had major surgery less than 6 weeks ago or am still dealing with its side effects.

I am not taking strong medication that affects liver enzymes.

I have a digestive condition that affects how my body absorbs medication.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive encorafenib daily and binimetinib twice daily in 28-day cycles. They will have at least 1 visit before each cycle, including repeats of some screening tests, abdominal ultrasounds, exercise stress tests, and skin evaluations.

As long as participants can continue dosing without significant toxicity

1 visit per cycle (in-person)

Follow-up

Participants will have a follow-up visit about a month after their last dose of treatment, followed by annual follow-ups.

1 month after treatment, then annually

1 visit (in-person) after treatment, annual visits

What Are the Treatments Tested in This Trial?

Interventions

• Binimetinib
• Encorafenib

Trial Overview The trial is testing the effectiveness of combining two oral medications—encorafenib and binimetinib—in treating BRAF mutant HCL compared to previous vemurafenib treatment alone. Participants will take these drugs in cycles of 28 days while undergoing regular health checks including physical exams and various scans.

How Is the Trial Designed?

Group I: Arm 1/Experimental therapy Experimental Treatment 2 Interventions

Treatment with encorafenib and binimetinib

Binimetinib is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Mektovi for:

• Unresectable or metastatic melanoma with a BRAF V600E or V600K mutation

Approved in European Union as Mektovi for:

• Unresectable or metastatic melanoma with a BRAF V600 mutation

Approved in Canada as Mektovi for:

• Unresectable or metastatic melanoma with a BRAF V600E or V600K mutation

Approved in Japan as Mektovi for:

• Unresectable or metastatic melanoma with a BRAF V600 mutation

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Hairy cell leukemia (HCL) is effectively treated with purine analogs, but about half of patients relapse and may become resistant to these treatments, necessitating alternative therapies.

Targeting the BRAF-V600E mutation with specific inhibitors like vemurafenib or dabrafenib offers a promising chemotherapy-free strategy, especially for patients at risk of severe infections or those with relapsed HCL, and can be combined with rituximab for enhanced efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

How I treat refractory/relapsed hairy cell leukemia with BRAF inhibitors. Falini, B., De Carolis, L., Tiacci, E.[2022]

In a study of 10 patients with hairy cell leukemia treated with recombinant beta-serine-interferon, 63% achieved normalization of blood counts, indicating its efficacy in managing the disease.

While all patients experienced mild influenza-like symptoms and some had injection site reactions, these side effects were manageable and did not limit the treatment, suggesting a favorable safety profile for rIFN-beta ser.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recombinant beta-serine-interferon in hairy cell leukemia compared prospectively with results with recombinant alpha-interferon. Glaspy, JA., Marcus, SG., Ambersley, J., et al.[2019]

BRAF and MEK inhibitors, such as vemurafenib and trametinib, effectively target the BRAF-V600E mutation in hairy cell leukemia (HCL), leading to significant dephosphorylation of the MEK/ERK pathway and inducing apoptosis in leukemic cells from 26 patients.

The study highlights that combining BRAF and MEK inhibitors can overcome protective effects from bone marrow stromal cells, suggesting a promising therapeutic strategy for improving treatment outcomes in HCL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BRAF inhibitors reverse the unique molecular signature and phenotype of hairy cell leukemia and exert potent antileukemic activity. Pettirossi, V., Santi, A., Imperi, E., et al.[2022]

The discovery of the BRAF-V600E mutation in nearly all patients with hairy cell leukemia (HCL) provides a genetic basis for the disease and allows for a genetics-based differential diagnosis, distinguishing HCL from similar B-cell neoplasms.

Treatment with the BRAF inhibitor vemurafenib has shown an almost 100% response rate in patients with relapsed HCL, achieving complete remission in 35% to 42% of cases, and importantly, this treatment does not cause myelotoxicity, making it a promising therapeutic option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genomics of Hairy Cell Leukemia. Tiacci, E., Pettirossi, V., Schiavoni, G., et al.[2018]

In a study involving 64 patients with hairy cell leukemia, 89% responded positively to treatment with interferon alfa-2b, indicating its high efficacy in managing this condition.

The treatment led to a significant reduction in hairy cells in the blood within one month and improved blood counts over nine months, which correlated with fewer serious infections and reduced need for blood transfusions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The treatment of hairy cell leukemia with recombinant alfa interferon: a multi-institutional study. Thompson, JA., Fefer, A.[2019]

In a study of 123 patients with hairy cell leukemia (HCL) diagnosed between 1996 and 2016, cladribine as a first-line treatment resulted in a high hematological complete response rate of 92%, demonstrating its efficacy in managing this rare cancer.

The median overall survival for HCL patients was over 15 years, with 5-year and 10-year survival rates of 84% and 70.5%, indicating a favorable long-term prognosis, especially compared to other treatments like IFN-α which had a higher relapse rate.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A population-based study of hairy cell leukemia over a period of 20 years. Wiber, M., Maitre, E., Poncet, JM., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04324112

Encorafenib Plus Binimetinib for People With BRAF V600 ... The nucleoside analogs cladribine and pentostatin are highly active as monotherapy with complete remission (CR) rates of 80 to 90%.

2. withpower.com withpower.com/trial/phase-3-leukemia-hairy-cell-9-2020-1c47b

Encorafenib + Binimetinib for Hairy Cell Leukemia Trial Overview The trial is testing the effectiveness of combining two oral medications—encorafenib and binimetinib—in treating BRAF mutant HCL compared to ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12270311/

Complete Response in Hairy Cell Leukemia to Anti-CD22 ... Purine analogs cladribine and pentostatin achieve complete remissions (CR), but relapse occurs at a median 4.5-16 years depending on age and ...

4. hairycellleukemia.org hairycellleukemia.org/may-2024-clinical-trials-nci

HCL Clinical Trials at the National Cancer Institute (NCI)-NIH The BRAF inhibitor dabrafenib alone gives 30% complete remissions in HCL. Dabrafenib and trametinib have been shown to be more effective and ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9815161/

Novel targeted treatments in hairy cell leukemia and other ... In recent multicenter cohorts with a long-term follow-up over 10 years, outcomes for HCL patients treated with PNA were impressive. Thus, in the ...

6. braftovi.pfizerpro.com braftovi.pfizerpro.com/mektovi-n/adverse-reactions

Adverse Reactions Serious ARs occurred in 38% of patients who received BRAFTOVI + MEKTOVI. · Fatal ARs occurred in 2% of patients who received BRAFTOVI + MEKTOVI, including ...

7. braftovi.com braftovi.com/m

BRAFTOVI® (encorafenib) + MEKTOVI® (binimetinib) IMPORTANT SAFETY INFORMATION. BRAFTOVI (encorafenib) and MEKTOVI (binimetinib) may cause serious side effects, including: Risk of new skin cancers. BRAFTOVI, ...

8. ema.europa.eu ema.europa.eu/en/documents/product-information/braftovi-epar-product-information_en.pdf

Braftovi, INN-encorafenib - EMA The most common adverse reactions (>25%) occurring in patients treated with encorafenib 300 mg administered with binimetinib were fatigue, nausea and diarrhoea.

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9818023/

BRAF and MEK Inhibitors and Their Toxicities: A Meta-Analysis Our study provides comprehensive data on treatment-related adverse events of BRAFi and MEKi combination therapies, showing related toxicity profiles.