Binimetinib + Belinostat for Uveal Melanoma

Overseen By Malik Hall

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: H. Lee Moffitt Cancer Center and Research Institute

Must not be taking: MEK inhibitors, HDAC inhibitors

Disqualifiers: Pregnancy, Active infection, Cardiovascular disease, 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: Unknown

Duration: 21 days per cycle

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two drugs, Binimetinib and Belinostat, to determine if they can shrink or halt tumor growth in individuals with metastatic uveal melanoma, a type of eye cancer that has spread. Participants will take Binimetinib orally twice a day and receive Belinostat (also known as Beleodaq) through an IV on specific days each cycle. The trial seeks individuals diagnosed with metastatic uveal melanoma who do not have active brain metastasis. Those who have not previously received similar drugs and meet specific health criteria are suitable candidates for this study. As a Phase 2 trial, this study measures the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important research.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot have had another investigational drug or systemic treatment for uveal melanoma within 4 weeks before starting the study drugs.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that the combination of binimetinib and belinostat is under careful study for safety in people with uveal melanoma, a type of eye cancer that has spread. Previous studies have found that binimetinib is usually well-tolerated in other conditions, with common side effects like tiredness and nausea. Belinostat, used for certain blood cancers, has demonstrated a similar safety profile. In earlier trials, patients experienced side effects such as low blood cell counts and fatigue. The advanced phase of this trial indicates that the treatment has already shown some safety in humans. More detailed safety information will become available as researchers continue their work. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about combining Binimetinib and Belinostat for treating uveal melanoma because these drugs offer a novel approach to targeting cancer cells. Binimetinib works by inhibiting a specific pathway (MEK) that helps cancer cells grow, while Belinostat is a histone deacetylase inhibitor that can alter gene expression to stop cancer cell proliferation. This dual-action strategy differs from the current standard treatments, which mainly involve surgery, radiation, or chemotherapy. By targeting cancer through two distinct mechanisms, there is hope for more effective control of tumor growth and potentially improving patient outcomes.

What evidence suggests that the combination of Binimetinib and Belinostat could be effective for uveal melanoma?

Research has shown that using binimetinib and belinostat together, as studied in this trial, may help shrink tumors or stop them from growing in people with metastatic uveal melanoma. Early results suggest this combination could effectively control the spread of this cancer. Binimetinib targets specific parts of cancer cells, potentially slowing their growth. Belinostat disrupts how cancer cells divide. Together, these drugs may offer a promising treatment for uveal melanoma that has spread to other parts of the body. ^{1 2 4 6 7}

Who Is on the Research Team?

Ahmad Tarhini, MD, PhD

Principal Investigator

Moffitt Cancer Center

Are You a Good Fit for This Trial?

Adults over 18 with metastatic uveal melanoma can join this trial. They should have a life expectancy of more than 3 months, measurable disease, and normal organ/marrow function. Participants must not have had MEK or HDAC inhibitors before and should be free from active brain metastases. Contraception is required during the study.

Inclusion Criteria

I do not have active brain cancer, and any previous brain metastases have been treated.

I have been diagnosed with metastatic uveal melanoma.

I am fully active or can carry out light work.

Exclusion Criteria

I have had serious heart or blood vessel problems in the last 6 months.

I am not currently on IV antibiotics for an infection.

I have had serious eye conditions not fixed by treatment.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive binimetinib by mouth twice daily and belinostat by intravenous infusion on days 1 through 5 of each 21-day cycle

21 days per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Belinostat
• Binimetinib

Trial Overview

The trial is testing a combination of two drugs, Binimetinib and Belinostat, to see if they can shrink or halt the growth of tumors in patients with metastatic uveal melanoma.

How Is the Trial Designed?

Group I: Binimetinib + Belinostat Experimental Treatment 2 Interventions

Participants will receive binimetinib by mouth two times a day, every day during each cycle. Each cycle will last for 21 days. Participants will receive belinostat by intravenous infusion on days 1 through 5 of each cycle.

Belinostat is already approved in United States for the following indications:

Approved in United States as Beleodaq for:

• Peripheral T-cell lymphoma (PTCL)

Who Is Running the Clinical Trial?

H. Lee Moffitt Cancer Center and Research Institute

Lead Sponsor

Trials

576

Recruited

145,000+

Acrotech Biopharma LLC

Industry Sponsor

Trials

28

Recruited

3,800+

Acrotech Biopharma Inc.

Industry Sponsor

Trials

31

Recruited

5,200+

Pfizer

Industry Sponsor

Trials

4,712

Recruited

50,980,000+

Known For

Vaccine Innovations

Top Products

Viagra, Zoloft, Lipitor, Prevnar 13

Albert Bourla

Pfizer

Chief Executive Officer since 2019

PhD in Biotechnology of Reproduction, Aristotle University of Thessaloniki

Patrizia Cavazzoni

Pfizer

Chief Medical Officer

MD from McGill University

Published Research Related to This Trial

Uveal melanoma, the most common eye cancer in adults, has a significant risk of metastasis, with up to 50% of patients developing metastases within 15 years after treatment of the primary tumor.

Current systemic therapies for uveal melanoma have limited efficacy, but ongoing research is exploring new candidate drugs, including bortezomib and MEK inhibitors, to improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New therapeutic agents in uveal melanoma. Velho, TR., Kapiteijn, E., Jager, MJ.[2012]

In a study involving 21 Japanese patients with advanced solid tumors, binimetinib was found to have an acceptable safety profile, with the maximum tolerated dose established at 45 mg taken twice daily, despite some patients experiencing reversible retinal adverse events.

While no complete or partial responses were observed, 67% of patients achieved stable disease for over 180 days, indicating that binimetinib can effectively stabilize tumor growth in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study of binimetinib (MEK162) in Japanese patients with advanced solid tumors. Watanabe, K., Otsu, S., Hirashima, Y., et al.[2022]

MEK inhibitors show very low efficacy in treating metastatic uveal melanoma, with an overall response rate averaging only 2.5% across six studies involving various combinations of drugs.

Severe treatment-related adverse events were common, particularly with combinations like selumetinib plus dacarbazine (62%) and binimetinib plus sotrastaurin (75%), indicating safety concerns that further discourage the use of MEK inhibitors in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

How to MEK the best of uveal melanoma: A systematic review on the efficacy and safety of MEK inhibitors in metastatic or unresectable uveal melanoma. Steeb, T., Wessely, A., Ruzicka, T., et al.[2019]

In the PEMDAC phase 2 clinical trial involving 29 patients with metastatic uveal melanoma, the combination of the HDAC inhibitor entinostat and the PD-1 inhibitor pembrolizumab achieved an objective response rate of 14% and a clinical benefit rate of 28% at 18 weeks.

The treatment was generally safe, with manageable toxicities and no treatment-related deaths, and showed promising results particularly in patients with specific tumor characteristics, such as BAP1 wildtype tumors and low baseline ctDNA levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The PEMDAC phase 2 study of pembrolizumab and entinostat in patients with metastatic uveal melanoma. Ny, L., Jespersen, H., Karlsson, J., et al.[2021]

In a study of 11 patients with metastatic BRAF mutant melanoma, the combination of BRAF and MEK inhibitors with hydroxychloroquine showed no significant ocular toxicity or inflammation, indicating a favorable safety profile for this treatment regimen.

However, 82% of patients experienced a subclinical separation of the photoreceptor outer segment from the retinal pigment epithelium, suggesting potential interference with retinal maintenance functions, although this did not affect visual acuity or sensitivity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FREQUENT SUBCLINICAL MACULAR CHANGES IN COMBINED BRAF/MEK INHIBITION WITH HIGH-DOSE HYDROXYCHLOROQUINE AS TREATMENT FOR ADVANCED METASTATIC BRAF MUTANT MELANOMA: Preliminary Results From a Phase I/II Clinical Treatment Trial. Nti, AA., Serrano, LW., Sandhu, HS., et al.[2023]

The study identified key escape pathways, such as PI3K/AKT and YAP signaling, that allow uveal melanoma cells to resist MEK inhibitors, highlighting the complexity of treatment resistance in this cancer.

Combining MEK inhibitors with the pan-HDAC inhibitor panobinostat showed enhanced efficacy in reducing tumor growth in uveal melanoma models, suggesting this combination could be a promising strategy to overcome resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HDAC Inhibition Enhances the In Vivo Efficacy of MEK Inhibitor Therapy in Uveal Melanoma. Faião-Flores, F., Emmons, MF., Durante, MA., et al.[2020]

The study evaluated the effectiveness of the MEK inhibitor selumetinib in combination with various drugs for treating metastatic uveal melanoma, finding that combining selumetinib with the chemotherapy drug DTIC did not enhance its antitumor effects, aligning with previous clinical trial results.

However, combinations of selumetinib with ERK and mTORC1/2 inhibitors showed promising efficacy in patient-derived xenograft models, suggesting these combinations may be more effective treatment strategies for this aggressive cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selumetinib-based therapy in uveal melanoma patient-derived xenografts. Decaudin, D., El Botty, R., Diallo, B., et al.[2019]

The SUMIT trial is a phase III study involving 128 patients with metastatic uveal melanoma, testing the combination of selumetinib (a MEK1/2 inhibitor) and dacarbazine, aiming to improve progression-free survival compared to dacarbazine alone.

Previous studies indicated that selumetinib showed antitumor effects in pre-clinical models and improved outcomes in a phase II trial, making this combination a promising approach for patients who have not received prior systemic therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Study design and rationale for a randomised, placebo-controlled, double-blind study to assess the efficacy of selumetinib (AZD6244; ARRY-142886) in combination with dacarbazine in patients with metastatic uveal melanoma (SUMIT). Carvajal, RD., Schwartz, GK., Mann, H., et al.[2018]

In a study of 35 patients with metastatic cutaneous melanoma and uveal melanoma treated with the MEK inhibitor binimetinib, 20% of cutaneous melanoma patients and 40% of uveal melanoma patients reported mild and transient visual symptoms, typically occurring within 3.5 days of starting treatment.

The study found that 77% of cutaneous melanoma patients and 60% of uveal melanoma patients developed subretinal fluid, indicating a reversible serous retinopathy associated with binimetinib, potentially linked to medication toxicity and the presence of autoantibodies against retinal proteins.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Serous Retinopathy Associated with Mitogen-Activated Protein Kinase Kinase Inhibition (Binimetinib) for Metastatic Cutaneous and Uveal Melanoma. van Dijk, EH., van Herpen, CM., Marinkovic, M., et al.[2023]

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]

In the Treat20 Plus study, a precision oncology approach was successfully implemented for 45 patients with metastatic uveal melanoma, with 60% receiving therapies matched to their specific molecular profiles, demonstrating the feasibility of this strategy in clinical practice.

The matched therapies led to a clinical benefit in 56% of patients, with a median overall survival of 13.9 months, highlighting the potential effectiveness of personalized treatment based on tumor mutational burden.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biomarker-driven therapies for metastatic uveal melanoma: A prospective precision oncology feasibility study. Leyvraz, S., Konietschke, F., Peuker, C., et al.[2022]

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Overall survival (OS)

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