Binimetinib + Imatinib for Melanoma
Recruiting in Palo Alto (17 mi)
+1 other location
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: University of California, San Francisco
Must not be taking: Investigational agents, Warfarin
Disqualifiers: Cardiovascular disease, Gastrointestinal impairment, others
No Placebo Group
Prior Safety Data
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.
12345What 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.
16789What 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.
1231011Eligibility 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.
+15 more
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.
+12 more
Trial 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
Participant Groups
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.
1Treatment groups
Experimental Treatment
Group I: Treatment (binimetinib, imatinib)Experimental Treatment2 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
UC San Diego Moores Cancer CenterLa Jolla, CA
University of California, San FranciscoSan Francisco, CA
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Who Is Running the Clinical Trial?
University of California, San FranciscoLead Sponsor
Array BioPharmaIndustry Sponsor
References
The discovery and development of binimetinib for the treatment of melanoma. [2021]Label="INTRODUCTION">Binimetinib is an uncompetitive, small-molecule inhibitor of selective mitogen-activated protein kinase (MEK1/2) and was recently approved in 2018 in combination with encorafenib for the treatment of metastatic melanomas. Preclinical and clinical trial data on the drug demonstrate its potent efficacy in cancers, especially melanomas with BRAF and NRAS mutations.
Economic Evaluation of Three BRAF + MEK Inhibitors for the Treatment of Advanced Unresectable Melanoma With BRAF Mutation From a US Payer Perspective. [2023]The combinations of BRAF + MEK inhibitors-encorafenib (ENC) + binimetinib (BIN), cobimetinib (COB) + vemurafenib (VEM), and dabrafenib (DAB) + trametinib (TRA)-are recommended for the treatment of BRAF-mutated advanced melanoma.
Ipilimumab, vemurafenib, dabrafenib, and trametinib: synergistic competitors in the clinical management of BRAF mutant malignant melanoma. [2021]There have been significant advances in the treatment of malignant melanoma with the U.S. Food and Drug Administration approval of two drugs in 2011, the first drugs approved in 13 years. The developments of immune checkpoint modulation via cytotoxic T-lymphocyte antigen-4 blockade, with ipilimumab, and targeting of BRAF(V600), with vemurafenib or dabrafenib, as well as MEK, with trametinib, have been paradigm changing both for melanoma clinical practice and for oncology therapeutic development. These advancements, however, reveal new clinical questions regarding combinations and optimal sequencing of these agents in patients with BRAF mutant disease. We review the development of these agents, putative biomarkers, and resistance mechanisms relevant to their use, and possibilities for sequencing and combining these agents.
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]BRAF/MEK inhibitor combinations are established treatments for BRAF V600-mutant melanoma based on demonstrated benefits on progression-free survival (PFS) and overall survival (OS). Here, we report an updated analysis of the COLUMBUS (COmbined LGX818 [encorafenib] Used with MEK162 [binimetinib] in BRAF mutant Unresectable Skin cancer) trial with long-term follow-up.
Encorafenib and binimetinib for the treatment of BRAF V600E/K-mutated melanoma. [2019]BRAF is a constituent of the mitogen-activated protein kinase (MAPK) signaling pathway, which serves to activate downstream MEK, and is one of the most commonly mutated oncogenes in human tumors. Indeed, BRAF V600 mutations are present in approximately 40% of metastatic melanoma tumors. Encorafenib (LGX-818, Braftovi) and binimetinib (MEK-162, Mektovi) are small-molecule inhibitors of BRAF and MEK, respectively. BRAF and MEK inhibitors have been shown to improve overall and progression-free survival among patients with metastatic melanoma. Of these inhibitors, encorafenib and binimetinib are the newest combination, which received approval by the Food and Drug Administration (FDA) for the treatment of BRAF V600E/K-mutated melanoma in June 2018. This review will focus on the preclinical pharmacology, pharmacokinetics and clinical utility of encorafenib and binimetinib in BRAF V600-mutated melanoma.
Safety of BRAF+MEK Inhibitor Combinations: Severe Adverse Event Evaluation. [2020]Aim: The selective BRAF and MEK inhibitors (BRAFi+MEKi) have substantially improved the survival of melanoma patients with BRAF V600 mutations. However, BRAFi+MEKi can also cause severe or fatal outcomes. We aimed to identify and compare serious adverse events (sAEs) that are significantly associated with BRAFi+MEKi. Methods: In this pharmacovigilance study, we reviewed FDA Adverse Event Reporting System (FAERS) data in order to detect sAE reporting in patients treated with the combination therapies vemurafenib+cobimetinib (V+C), dabrafenib+trametinib (D+T) and encorafenib+binimetinib (E+B). We evaluated the disproportionate reporting of BRAFi+MEKi-associated sAEs. Significant associations were further analyzed to identify combination-specific safety signals among BRAFi+MEKi. Results: From January 2018 through June 2019, we identified 11,721 sAE reports in patients receiving BRAFi+MEKi. Comparison of BRAFi+MEKi combinations demonstrates that skin toxicities, including Stevens-Johnson syndrome, were disproportionally reported using V+C, with an age-adjusted reporting odds ratio (adj. ROR) of 3.4 (95%CI, 2.9-4.0), whereas fever was most significantly associated with D+T treatment with an adj. ROR of 1.9 (95%CI, 1.5-2.4). Significant associations using E+B treatment include peripheral neuropathies (adj. ROR 2.7; 95%CI, 1.2-6.1) and renal disorders (adj. ROR 4.1; 95%CI, 1.3-12.5). Notably, we found an increase in the proportion of Guillain-Barré syndrome reports (adj. ROR 8.5; 95%CI, 2.1-35.0) in patients administered E+B. Conclusion: BRAFi+MEKi combinations share a similar safety profile attributed to class effects, yet concomitantly, these combinations display distinctive effects that can dramatically impact patients' health. Owing to the limitations of pharmacovigilance studies, some findings warrant further validation. However, the possibility of an increased risk for these events should be considered in patient care.
[Management of toxicities of BRAF inhibitors and MEK inhibitors in advanced melanoma]. [2021]Major therapeutic advances have been made recently in the treatment of metastatic melanoma, due to the development of targeted therapies, namely BRAF and MEK inhibitors, in patients with BRAF V600 mutation. Combinations of vemurafenib+cobimetinib, dabrafenib+trametinib, et encorafenib+binimetinib, evaluated in coBRIM, COMBI-d/COMBI-v and COLUMBUS trials respectively have been approved in this indication. Toxicities induced by combination therapies are different from those reported with monotherapies, in terms of frequency and intensity. Physicians who treat melanoma patients thus face news issues relating to prevention, detection and treatment of these adverse events. This paper summarizes tolerance data from the three pivotal trials (coBRIM, COMBI-v and COLUMBUS) and issues recommendations for the specific management of main toxicities, based on experts' opinion. We discuss dermatological, ophthalmological, cardiovascular, digestive, musculoskeletal, renal and general toxicities and propose a timetable for examinations to be performed before and during treatment.
Treatment experience with encorafenib plus binimetinib for BRAF V600-mutant metastatic melanoma: management insights for clinical practice. [2023]For patients with locally advanced or metastatic melanoma who have BRAF V600 activating mutations, combination therapy with BRAF and MEK inhibitors is now the standard of care. The combination of encorafenib, a highly selective adenosine triphosphate-competitive BRAF inhibitor, plus binimetinib, a potent, selective, allosteric, non-adenosine triphosphate-competitive MEK1/2 inhibitor, was approved by the US Food and Drug Administration for unresectable or metastatic melanoma with BRAF V600E or V600K mutations based on data from the phase III COLUMBUS study (NCT01909453). Clinical data evaluating BRAF and MEK inhibitor combinations in advanced melanoma indicate a specific profile of adverse events that includes serious retinopathy, skin disorders, and cardiovascular toxicities. Here we provide an overview of the rationale for combining BRAF and MEK inhibitors for the treatment of melanoma, long-term safety results from COLUMBUS, and guidance on managing the most common adverse events associated with this combination based on clinical experience. Proactive and appropriate management of adverse events can allow for longer treatment durations and may result in better treatment outcomes.
[Treatment combinations in BRAF-mutant metastatic melanoma.] [2022]Combinations of BRAF and MEK inhibitors are now the standard treatment in patients with BRAF V600-mutant metastatic melanoma. Three combination treatments with BRAF and MEK inhibitors are available for thetreatment of metastatic melanoma: vemurafenib + cobimetinib, dabrafenib + trametinib, encorafenib + binimetinib. These 3 combination treatments have distinct safety profiles as evidenced by the data from the phase III studies. For example, fever was observed more frequently in patients treated with dabrafenib and trametinib, photosensitivity in patients treated with vemurafenib and cobimetinib while patients treated with the encorafenib + binimetinib combination have a higher incidence of adverse events related to gastrointestinal system. Considering the similar clinical efficacy demonstrated by the three BRAFi + MEKi combinations, the therapeutic decision is often based on the side effect profile that characterizes each of the combinations.
A review of binimetinib for the treatment of mutant cutaneous melanoma. [2023]Although significant progress has been made in the treatment of unresectable or metastatic melanoma, at least half of all advanced melanoma patients eventually progress and pass away due to their disease. In particular, patients with NRAS-mutated melanoma still face limited therapeutic options, with immunotherapy being the current treatment type of choice. Binimetinib is a selective inhibitor of MEK, a central kinase in the tumor-promoting MAPK pathway. The results of a recent Phase III trial rendered binimetinib the first targeted therapy agent to significantly improve progression-free survival in NRAS-mutated melanoma. This review will summarize the development and clinical data of binimetinib in melanoma in general and also explore the potential future role of this substance as single agent or combination therapy.
Systemic Therapy of Metastatic Melanoma: On the Road to Cure. [2021]This decade has brought significant survival improvement in patients with metastatic melanoma with targeted therapies and immunotherapies. As our understanding of the mechanisms of action of these therapeutics evolves, even more impressive therapeutic success is being achieved through various combination strategies, including combinations of different immunotherapies as well as with other modalities. This review summarizes prospectively and retrospectively generated clinical evidence on modern melanoma therapy, focusing on immunotherapy and targeted therapy with BRAF kinase inhibitors and MEK kinase inhibitors (BRAF/MEK inhibitors), including recent data presented at major conference meetings. The combination of the anti-PD-1 directed monoclonal antibody nivolumab and of the CTLA-4 antagonist ipilimumab achieves unprecedented 5-year overall survival (OS) rates above 50%; however, toxicity is high. For PD-1 monotherapy (nivolumab or pembrolizumab), toxicities are in general well manageable. Today, novel combinations of such immune checkpoint inhibitors (ICIs) are under investigation, for example with cytokines and oncolytic viruses (i.e., pegylated interleukin-2, talimogene laherparepvec). Furthermore, current studies investigate the combined or sequential use of ICIs plus BRAF/MEK inhibitors. Several studies focus particularly on poor prognosis patients, as e.g., on anti-PD-1 refractory melanoma, patients with brain metastases, or uveal melanoma. It is hoped, on the road to cure, that these new approaches further improve long term survival in patients with advanced or metastatic melanoma.