Binimetinib + Belinostat for Uveal Melanoma

Overseen by Ahmad Tarhini, MD, PhD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

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

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial is testing two drugs, Binimetinib and Belinostat, in people with a type of eye cancer that has spread. The goal is to see if these drugs can stop the cancer from growing or make it shrink.

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.

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

Research shows that MEK inhibitors like Binimetinib can be effective in treating melanomas, and combining them with HDAC inhibitors like Belinostat may enhance their effectiveness by overcoming resistance in uveal melanoma. ^{1 2 3 4 5}

Is the combination of Binimetinib and Belinostat safe for humans?

Binimetinib, a part of this treatment, has been associated with eye-related side effects, such as retinal issues, in some patients. These effects have been observed in studies involving patients with different types of melanoma. ^{1 4 6 7 8}

How is the drug combination of Binimetinib and Belinostat unique for treating uveal melanoma?

The combination of Binimetinib, a MEK inhibitor, and Belinostat, an HDAC inhibitor, is unique for uveal melanoma as it targets specific pathways involved in cancer cell growth and survival, which are not effectively addressed by existing treatments. This approach is novel because there are few approved systemic therapies for uveal melanoma, and their efficacy is often uncertain. ^{6 8 9 10 11}

Research Team

Ahmad Tarhini, MD, PhD

Principal Investigator

Moffitt Cancer Center

Eligibility Criteria

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 18 years old or older.

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.

Trial Timeline

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

Treatment Details

Interventions

• Belinostat (Histone Deacetylase Inhibitor)
• Binimetinib (MEK Inhibitor)

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.

Participant Groups

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.

Who Is Running the Clinical Trial?

H. Lee Moffitt Cancer Center and Research Institute

Lead Sponsor

Trials

576

Recruited

145,000+

Patrick Hwu

H. Lee Moffitt Cancer Center and Research Institute

Chief Executive Officer since 2020

MD from The Medical College of Pennsylvania

Wade J. Sexton

H. Lee Moffitt Cancer Center and Research Institute

Chief Medical Officer

MD

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

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 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 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]

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]

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 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]

References

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

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

2. England 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). [2018]

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

Selumetinib-based therapy in uveal melanoma patient-derived xenografts. [2019]

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

HDAC Inhibition Enhances the In Vivo Efficacy of MEK Inhibitor Therapy in Uveal Melanoma. [2020]

5. England pubmed.ncbi.nlm.nih.gov

Biomarker-driven therapies for metastatic uveal melanoma: A prospective precision oncology feasibility study. [2022]

6. Germany pubmed.ncbi.nlm.nih.gov

A phase I study of binimetinib (MEK162) in Japanese patients with advanced solid tumors. [2022]

7. United States 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. [2023]

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

Serous Retinopathy Associated with Mitogen-Activated Protein Kinase Kinase Inhibition (Binimetinib) for Metastatic Cutaneous and Uveal Melanoma. [2023]

9. Greece pubmed.ncbi.nlm.nih.gov

New therapeutic agents in uveal melanoma. [2012]

10. England 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. [2019]

11. England pubmed.ncbi.nlm.nih.gov

The PEMDAC phase 2 study of pembrolizumab and entinostat in patients with metastatic uveal melanoma. [2021]