Defactinib + VS-6766 for Uveal Melanoma

Overseen By Rino Seedor, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Thomas Jefferson University

Must not be taking: Warfarin, Strong CYP3A4 inhibitors

Disqualifiers: CNS metastases, Hepatitis B, HIV, 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: Up to 2 years

13 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial studies the effect of combining two drugs, defactinib and VS-6766, in patients with metastatic uveal melanoma. These drugs aim to block signals in cancer cells that make them grow and spread, potentially slowing down or stopping the cancer. Everolimus has been studied in combination with other drugs for its potential to inhibit cancer cell growth in various types of tumors, including uveal melanoma.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but it does mention that patients exposed to strong CYP3A4 and CYP2C9 inhibitors within 7 days prior to the first dose are excluded. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

What data supports the effectiveness of the drug Defactinib + VS-6766 for Uveal Melanoma?

Research shows that targeting the Ras/Raf/MEK/ERK pathway, which is active in uveal melanoma, with MEK inhibitors like selumetinib has shown antitumor effects and improved outcomes in pre-clinical models and trials. This suggests that similar drugs, like VS-6766, may also be effective. ^{1 2 3 4 5}

What makes the drug Defactinib + VS-6766 unique for uveal melanoma?

Defactinib + VS-6766 is unique because it combines a FAK inhibitor (Defactinib) with a Raf/MEK inhibitor (VS-6766), targeting specific pathways involved in cancer cell growth and survival, which are not addressed by standard treatments for uveal melanoma. ^{1 2 6 7 8}

Research Team

Rino Seedor, MD

Principal Investigator

Thomas Jefferson University

Eligibility Criteria

Adults with metastatic uveal melanoma, good heart function, and no severe systemic diseases. They must not be pregnant or breastfeeding and agree to use effective contraception. Participants need stable vital signs and blood counts within specific ranges, can't have had recent major surgery or certain treatments, and must not have active infections like hepatitis or HIV.

Inclusion Criteria

My white blood cell count is high enough for the trial.

I have signed and understand the consent form and can follow the treatment plan.

I am fully active or can carry out light work.

Exclusion Criteria

Any other condition which in the Investigator's opinion would not make the patient a good candidate for the clinical trial

I cannot take pills by mouth or have issues absorbing them due to stomach surgery or active bowel inflammation.

I haven't had major surgery in the last 4 weeks or minor surgery in the last 2 weeks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive defactinib orally twice daily and VS-6766 twice a week for 3 weeks in every cycle. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

Up to 2 years

Regular visits for each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up every 3 months until death or up to 2 years after the last patient is enrolled.

Up to 2 years

Every 3 months

Treatment Details

Interventions

• Defactinib Hydrochloride
• Raf/MEK Inhibitor VS-6766

Trial Overview The trial is testing a combination of two drugs: Defactinib Hydrochloride and Raf/MEK Inhibitor VS-6766 on patients with metastatic uveal melanoma. It aims to see if blocking cell signaling pathways slows down cancer growth or shrinks tumors.

Participant Groups

Group I: Treatment (defactinib, VS-6766) Experimental Treatment 3 Interventions

Patients receive defactinib PO BID and VS-6766 PO BIW (Monday and Thursday or Tuesday and Friday) for 3 weeks in every cycle. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

Who Is Running the Clinical Trial?

Thomas Jefferson University

Lead Sponsor

Trials

475

Recruited

189,000+

Verastem, Inc.

Industry Sponsor

Trials

42

Recruited

2,800+

Findings from Research

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 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]

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]

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 of 55 uveal melanoma specimens, 78.2% showed positive expression of the c-kit protein, indicating its potential role in this type of cancer.

Imatinib mesylate significantly reduced the proliferation and invasion of five human uveal melanoma cell lines in vitro, suggesting it could be an effective treatment option and warranting further clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of c-kit and imatinib mesylate in uveal melanoma. Pereira, PR., Odashiro, AN., Marshall, JC., et al.[2020]

A case report demonstrated that the combination of neoadjuvant darovasertib and crizotinib effectively reduced the size of a large uveal melanoma in a patient, allowing for vision-saving treatment instead of enucleation.

After 6 months of treatment, the tumor shrank significantly, enabling the use of plaque brachytherapy, which suggests that this combination therapy could improve visual outcomes for patients with primary uveal melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Globe Salvage and Vision Preservation by Neoadjuvant Darovasertib and Crizotinib in Uveal Melanoma. Hiong, A., O'Day, R., Fog, LS., et al.[2023]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

The multi-kinase inhibitor afatinib serves as a novel candidate for the treatment of human uveal melanoma. [2022]

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. England pubmed.ncbi.nlm.nih.gov

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

4. Switzerland pubmed.ncbi.nlm.nih.gov

Uveal Melanoma: 5-Year Update on Incidence, Treatment, and Survival (SEER 1973-2013). [2022]

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

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

6. Greece pubmed.ncbi.nlm.nih.gov

New therapeutic agents in uveal melanoma. [2012]

7. India pubmed.ncbi.nlm.nih.gov

The role of c-kit and imatinib mesylate in uveal melanoma. [2020]

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

Globe Salvage and Vision Preservation by Neoadjuvant Darovasertib and Crizotinib in Uveal Melanoma. [2023]