Binimetinib + Imatinib for Melanoma

Recruiting at 1 trial location

Overseen By Sonia Contreras Martinez

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of California, San Francisco

Must not be taking: Investigational agents, Warfarin

Disqualifiers: Cardiovascular disease, Gastrointestinal impairment, 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: 58

Duration: Up to 2 years

25 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies how well binimetinib and imatinib work in treating patients with stage III-IV KIT-mutant melanoma that cannot be removed by surgery (unresectable). Binimetinib and imatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving binimetinib and imatinib may help treat patients with KIT-mutant melanoma.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it mentions that you cannot use certain prohibited medications, including some herbal supplements or foods, that cannot be safely discontinued before starting the study treatment. It's best to discuss your current medications with the study team to see if any adjustments are needed.

What data supports the effectiveness of the drug combination Binimetinib and Imatinib for treating melanoma?

Binimetinib has shown effectiveness in treating melanoma, especially in cases with specific genetic mutations (BRAF and NRAS), when used in combination with other drugs like encorafenib. This suggests potential benefits when combined with other treatments, although direct evidence for its combination with Imatinib in melanoma is not provided. ^{1 2 3 4 5}

What safety data exists for the combination of Binimetinib and Imatinib in humans?

While specific safety data for the combination of Binimetinib and Imatinib is not available, Binimetinib has been studied in combination with other drugs like Encorafenib for melanoma. This combination has been associated with serious side effects such as skin disorders, cardiovascular issues, and gastrointestinal problems. It's important to discuss potential risks with a healthcare provider. ^{1 6 7 8 9}

What makes the drug combination of Binimetinib and Imatinib unique for treating melanoma?

The combination of Binimetinib and Imatinib for melanoma is unique because Binimetinib is a selective inhibitor of MEK, a key protein in a pathway that promotes tumor growth, and it has shown significant efficacy in melanomas with specific mutations. This combination could offer a novel approach for patients with limited options, especially those with NRAS mutations, where traditional treatments may not be as effective. ^{1 2 3 10 11}

Research Team

Katy Tsai, MD

Principal Investigator

University of California, San Francisco

Eligibility Criteria

This trial is for adults with unresectable Stage III-IV KIT-mutant melanoma. Participants must have measurable disease progression after standard therapy or be unable to tolerate it, and have good organ function. HIV-positive individuals on effective therapy can join, as well as those with treated/cured hepatitis C or controlled hepatitis B. Pregnant or breastfeeding women cannot participate, and sexually active participants must use contraception.

Inclusion Criteria

My hepatitis B virus load is undetectable with treatment.

You have a detectable tumor according to specific measurement guidelines.

My blood, liver, and kidney functions are all within normal ranges.

Exclusion Criteria

You are allergic to binimetinib or any of its ingredients.

I have or am at risk for blocked veins in my eye.

I have a digestive condition that affects how I absorb medication.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive binimetinib orally twice daily and imatinib once daily in 28-day cycles

Up to 2 years

Monthly visits for each 28-day cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years

Follow-up at day 30 and 100, then every 3 months

Treatment Details

Interventions

• Binimetinib
• Imatinib

Trial Overview The study tests binimetinib and imatinib's effectiveness in treating advanced KIT-mutant melanoma by blocking enzymes that promote tumor cell growth. This phase II trial aims to determine if this combination treatment can help manage the disease in patients who cannot undergo surgery.

Participant Groups

Group I: Treatment (binimetinib, imatinib) Experimental Treatment 2 Interventions

Patients receive binimetinib PO BID on days 1-28 and imatinib PO QD on days 1-28. Cycles repeat every 28 days

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?

University of California, San Francisco

Lead Sponsor

Trials

2,636

Recruited

19,080,000+

Array BioPharma

Industry Sponsor

Trials

29

Recruited

1,400+

Findings from Research

Binimetinib, an uncompetitive inhibitor of MEK1/2, has shown significant efficacy in treating metastatic melanoma, particularly in combination with encorafenib, resulting in a progression-free survival (PFS) of 14.9 months compared to 7.3 months with vemurafenib alone in Phase 3 trials.

While binimetinib has a tolerable safety profile, there is currently no long-term data on durable responses or overall survival benefits compared to other treatments, highlighting the need for individualized treatment plans for patients with BRAF-mutated metastatic melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The discovery and development of binimetinib for the treatment of melanoma. Tran, B., Cohen, MS.[2021]

The combination of encorafenib (ENC) and binimetinib (BIN) was found to be cost-effective compared to cobimetinib (COB) and vemurafenib (VEM) only at a very high willingness-to-pay threshold of $573,000 per quality-adjusted life year (QALY).

The combination of dabrafenib (DAB) and trametinib (TRA) was determined to be the most optimal treatment option for BRAF-mutated advanced melanoma, dominating the COB + VEM combination in terms of cost-effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Economic Evaluation of Three BRAF + MEK Inhibitors for the Treatment of Advanced Unresectable Melanoma With BRAF Mutation From a US Payer Perspective. Halloush, S., Alkhatib, NS., Almutairi, AR., et al.[2023]

The FDA approved two groundbreaking drugs for malignant melanoma in 2011, marking a significant advancement in treatment after a 13-year gap, specifically ipilimumab for immune checkpoint modulation and targeted therapies like vemurafenib and dabrafenib for BRAF(V600) mutations.

These new therapies have changed the landscape of melanoma treatment, but they also raise important questions about how to best combine and sequence these agents for patients with BRAF mutant melanoma to enhance efficacy and manage resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab, vemurafenib, dabrafenib, and trametinib: synergistic competitors in the clinical management of BRAF mutant malignant melanoma. Luke, JJ., Hodi, FS.[2021]

In the COLUMBUS trial involving 577 patients with advanced BRAF V600-mutant melanoma, the combination of encorafenib and binimetinib (COMBO450) significantly improved overall survival (OS) to a median of 33.6 months compared to 16.9 months for vemurafenib (VEM), reducing the risk of death by 39%.

The updated analysis also showed that COMBO450 provided a longer progression-free survival (PFS) of 14.9 months compared to 7.3 months for VEM, indicating that this combination therapy offers substantial long-term benefits for patients with this type of melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Update on tolerability and overall survival in COLUMBUS: landmark analysis of a randomised phase 3 trial of encorafenib plus binimetinib vs vemurafenib or encorafenib in patients with BRAF V600-mutant melanoma. Ascierto, PA., Dummer, R., Gogas, HJ., et al.[2020]

Encorafenib and binimetinib are effective small-molecule inhibitors that target the BRAF and MEK proteins in the MAPK signaling pathway, significantly improving overall and progression-free survival in patients with metastatic melanoma harboring BRAF V600 mutations.

This combination therapy received FDA approval in June 2018 specifically for treating melanoma with BRAF V600E/K mutations, highlighting its clinical utility and relevance in modern cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Encorafenib and binimetinib for the treatment of BRAF V600E/K-mutated melanoma. Rose, AAN.[2019]

A review of 11,721 serious adverse event reports from patients treated with BRAF and MEK inhibitors revealed that different combinations have unique safety profiles, with V+C showing a high incidence of skin toxicities like Stevens-Johnson syndrome.

The combination E+B was notably associated with an increased risk of peripheral neuropathies and renal disorders, as well as a significant rise in reports of Guillain-Barré syndrome, indicating that while these treatments improve survival in melanoma, they also carry serious risks that need careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of BRAF+MEK Inhibitor Combinations: Severe Adverse Event Evaluation. Meirson, T., Asher, N., Bomze, D., et al.[2020]

Recent advances in treating metastatic melanoma have been achieved through targeted therapies using BRAF and MEK inhibitors for patients with the BRAF V600 mutation, with combinations like vemurafenib+cobimetinib and dabrafenib+trametinib showing significant efficacy in clinical trials.

Combination therapies have different toxicity profiles compared to single-agent treatments, necessitating new strategies for prevention, detection, and management of adverse events, as outlined in the tolerance data from pivotal trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Management of toxicities of BRAF inhibitors and MEK inhibitors in advanced melanoma]. Sibaud, V., Baric, L., Cantagrel, A., et al.[2021]

The combination of encorafenib and binimetinib is now the standard treatment for patients with advanced melanoma harboring BRAF V600 mutations, based on the phase III COLUMBUS study.

While this combination therapy is effective, it is associated with specific adverse events such as serious retinopathy and cardiovascular toxicities, highlighting the importance of proactive management to improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment experience with encorafenib plus binimetinib for BRAF V600-mutant metastatic melanoma: management insights for clinical practice. Augustyn, K., Joseph, J., Patel, AB., et al.[2023]

Combination treatments of BRAF and MEK inhibitors, specifically vemurafenib + cobimetinib, dabrafenib + trametinib, and encorafenib + binimetinib, are the standard care for patients with BRAF V600-mutant metastatic melanoma, showing similar clinical efficacy across the board.

Each combination has unique safety profiles, with specific side effects such as fever with dabrafenib + trametinib, photosensitivity with vemurafenib + cobimetinib, and gastrointestinal issues with encorafenib + binimetinib, influencing treatment choices based on patient tolerance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Treatment combinations in BRAF-mutant metastatic melanoma.] Depenni, R.[2022]

Binimetinib is the first targeted therapy that has shown a significant improvement in progression-free survival for patients with NRAS-mutated melanoma, addressing a critical need in this patient population.

This review highlights the potential of binimetinib not only as a standalone treatment but also in combination therapies, which could enhance its effectiveness in managing melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A review of binimetinib for the treatment of mutant cutaneous melanoma. Koelblinger, P., Dornbierer, J., Dummer, R.[2023]

The combination of nivolumab and ipilimumab has achieved over 50% 5-year overall survival rates in patients with metastatic melanoma, although this combination is associated with high toxicity.

Current research is exploring new combinations of immune checkpoint inhibitors with other treatments, such as BRAF/MEK inhibitors and oncolytic viruses, aiming to improve long-term survival, especially in patients with poor prognosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic Therapy of Metastatic Melanoma: On the Road to Cure. Steininger, J., Gellrich, FF., Schulz, A., et al.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

The discovery and development of binimetinib for the treatment of melanoma. [2021]

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

Economic Evaluation of Three BRAF + MEK Inhibitors for the Treatment of Advanced Unresectable Melanoma With BRAF Mutation From a US Payer Perspective. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Ipilimumab, vemurafenib, dabrafenib, and trametinib: synergistic competitors in the clinical management of BRAF mutant malignant melanoma. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Update on tolerability and overall survival in COLUMBUS: landmark analysis of a randomised phase 3 trial of encorafenib plus binimetinib vs vemurafenib or encorafenib in patients with BRAF V600-mutant melanoma. [2020]

5. Spain pubmed.ncbi.nlm.nih.gov

Encorafenib and binimetinib for the treatment of BRAF V600E/K-mutated melanoma. [2019]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Safety of BRAF+MEK Inhibitor Combinations: Severe Adverse Event Evaluation. [2020]

7. France pubmed.ncbi.nlm.nih.gov

[Management of toxicities of BRAF inhibitors and MEK inhibitors in advanced melanoma]. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Treatment experience with encorafenib plus binimetinib for BRAF V600-mutant metastatic melanoma: management insights for clinical practice. [2023]

9. Italy pubmed.ncbi.nlm.nih.gov

[Treatment combinations in BRAF-mutant metastatic melanoma.] [2022]

10. England pubmed.ncbi.nlm.nih.gov

A review of binimetinib for the treatment of mutant cutaneous melanoma. [2023]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Systemic Therapy of Metastatic Melanoma: On the Road to Cure. [2021]