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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two drugs, defactinib (a cancer treatment) and VS-6766 (a Raf/MEK inhibitor), to determine their effectiveness in treating uveal melanoma, a type of eye cancer that has metastasized. The researchers aim to block certain pathways in cancer cells, potentially shrinking or halting cancer growth and extending survival. Suitable participants have confirmed metastatic uveal melanoma and can manage daily activities independently. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group of participants.

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.

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

Research has shown that the combination of defactinib and VS-6766 is under study for treating metastatic uveal melanoma. Although still in testing, some safety information is available. Previous studies suggest that patients might tolerate these drugs well together.

As with most cancer treatments, some side effects have been noted, such as tiredness, nausea, or a skin rash. Serious side effects, however, are less common. Importantly, this treatment is in Phase 2, indicating it has already passed initial safety tests in humans. This suggests the treatment is generally safe for further testing, but more information is needed to fully understand its long-term safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Defactinib and VS-6766 for uveal melanoma because these treatments offer a new approach by targeting specific pathways involved in cancer growth. Unlike traditional treatments like surgery, radiation, or chemotherapy, Defactinib works by inhibiting a protein called FAK, which plays a role in cancer cell survival and spread. Meanwhile, VS-6766 is a Raf/MEK inhibitor, disrupting the MAPK pathway that many cancers rely on for growth. Together, these drugs may offer a more targeted attack on the cancer cells, potentially leading to better outcomes with fewer side effects.

What evidence suggests that this combination treatment could be effective for uveal melanoma?

Research has shown that using the drugs defactinib and VS-6766 together might help treat uveal melanoma, especially when it has spread to other parts of the body. In this trial, participants will receive both defactinib and VS-6766 as part of the treatment regimen. These drugs block certain signals in cancer cells that promote growth and spread. Early findings suggest that this combination could shrink the cancer or halt its growth. This approach might slow the disease and possibly extend patients' lives. While more information is needed, these early results are promising for those with metastatic uveal melanoma. ^{1 2 3 4 6}

Who Is on the Research Team?

Rino Seedor, MD

Principal Investigator

Thomas Jefferson University

Are You a Good Fit for This Trial?

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 have had issues like a hole in my stomach or intestines or severe gut infections.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04720417

Study Details | NCT04720417 | Defactinib and VS-6766 for ... Giving defactinib together with VS-6766 may block pathways that are important for the growth of uveal melanoma cells, and may result in shrinkage or ...

2. withpower.com withpower.com/trial/phase-3-melanoma-2021-9edcd

Defactinib + VS-6766 for Uveal Melanoma 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 ...

3. asco.org asco.org/abstracts-presentations/ABSTRACT335655

Phase II trial of defactinib (VS-6063) combined with ... Background: Despite successful treatment of primary uveal melanomas (UM), up to 50% of patients subsequently develop systemic metastasis, with the liver ...

4. clinicaltrial.be clinicaltrial.be/nl/details/48463?per_page=100&only_recruiting=0&enrolling_by_invitation=1&active_not_recruiting=1&completed=0&only_eligible=0&only_active=0

Defactinib and VS-6766 for the Treatment of Patients With... To assess the effectiveness of defactinib in combination with VS-6766 in patients with metastatic uveal melanoma (MUM). II. To assess the safety and toxicity ...

5. investor.verastem.com investor.verastem.com/node/12081/pdf

June 22, 2020 - Verastem, Inc. a Phase II investigator-initiated study of the combination of VS-6766 and defactinib in uveal melanoma anticipated to begin in late 2020.

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2025/219616Orig1s000MultidisciplineR.pdf

219616Orig1s000 - accessdata.fda.gov RAMP-201 (NCT04625270) is a randomized, multicenter trial assessing the combination of avutometinib and defactinib versus avutometinib ...