Encorafenib + Binimetinib for Hairy Cell Leukemia

Overseen By Holly Eager (DiFebo), 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

Trial Summary

What is the purpose of this trial?

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....

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.

What evidence supports the effectiveness of the drugs Encorafenib and Binimetinib for treating Hairy Cell Leukemia?

Research shows that targeting the BRAF-V600E mutation, which is common in Hairy Cell Leukemia, with BRAF inhibitors like vemurafenib can lead to high response rates, including complete remission in some cases. Combining BRAF inhibitors with MEK inhibitors, like Binimetinib, may enhance the treatment's effectiveness by overcoming resistance and promoting cancer cell death. ^{1 2 3 4 5}

How is the drug Encorafenib + Binimetinib unique for treating hairy cell leukemia?

Encorafenib and Binimetinib target the BRAF-V600E mutation, a key driver in hairy cell leukemia, by inhibiting the RAF-MEK-ERK signaling pathway, which is not addressed by traditional treatments like purine analogs. This combination offers a novel approach by directly targeting the genetic mutation responsible for the disease, potentially leading to better outcomes for patients who relapse or are resistant to standard therapies. ^{1 2 4 5 6}

Research Team

Robert J Kreitman, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

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

I am 18 years old or older.

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

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

2. England pubmed.ncbi.nlm.nih.gov

A population-based study of hairy cell leukemia over a period of 20 years. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

How I treat refractory/relapsed hairy cell leukemia with BRAF inhibitors. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Genomics of Hairy Cell Leukemia. [2018]

5. United States pubmed.ncbi.nlm.nih.gov

BRAF inhibitors reverse the unique molecular signature and phenotype of hairy cell leukemia and exert potent antileukemic activity. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Recombinant beta-serine-interferon in hairy cell leukemia compared prospectively with results with recombinant alpha-interferon. [2019]