Drug Combination for Brain Metastases from Melanoma

(DETERMINE Trial)

Recruiting at 1 trial location

Overseen By Yuri Kida

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University of Utah

Must not be taking: Strong CYP3A4, CYP2C9 inhibitors

Disqualifiers: Symptomatic brain metastasis, Uveal melanoma, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 6 months

33 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of drugs—defactinib, avutometinib (also known as VS-6766), and encorafenib—to evaluate their effectiveness and safety for individuals with advanced melanoma that has spread to the brain. Researchers focus on cases with specific mutations, such as BRAF V600E/K, where the cancer has progressed despite other treatments. Suitable candidates for this trial have melanoma that has metastasized to the brain, possess specific genetic mutations, and have at least one brain tumor untreated by surgery or radiation. As a Phase 1 trial, the research aims to understand how the treatment works in people, offering participants the chance to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial requires participants to stop taking certain medications that could interact with the study drugs, such as strong CYP3A4, CYP2C9, P-glycoprotein, and BCRP inhibitors or inducers, as well as warfarin. A washout period (time without taking certain medications) of at least five half-lives or as clinically indicated is required before starting the study treatment.

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

Research has shown that the combination of defactinib and avutometinib has been tested in patients with solid tumors. These early studies indicate that most people tolerate the treatment well. While side effects have been reported, they are usually manageable.

Encorafenib, another treatment in this trial, has already received FDA approval for other conditions. As a result, doctors are familiar with its side effects and know how to manage them.

Since this trial is in the early stages, it focuses on gathering more information about safety and side effects. These initial phases are crucial for understanding treatment tolerance and ensuring safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for brain metastases from melanoma because they target cancer cells in new ways. Unlike standard treatments that often rely on chemotherapy or radiation, Avutometinib, Defactinib, and Encorafenib work together to inhibit specific pathways that help cancer cells grow and spread. Avutometinib and Defactinib block pathways involved in cell growth and survival, while Encorafenib targets the BRAF mutation often found in melanoma, potentially making the combination more effective. This approach aims to attack the cancer from multiple angles, offering hope for improved outcomes compared to existing options.

What evidence suggests that this trial's treatments could be effective for brain metastases from melanoma?

Research has shown that combining the drugs defactinib and avutometinib can target melanoma cells by disrupting pathways crucial for tumor growth. This trial studies the potential of this combination to treat melanoma that has spread to the brain, a condition with limited treatment options. Participants in one arm of the trial will receive defactinib and avutometinib. Studies suggest that blocking certain pathways, called FAK and RAF, can help control tumor spread. Early results are promising, showing potential in reducing these cancerous growths. Another arm of the trial includes adding encorafenib, which targets BRAF mutations, to strengthen this approach for specific tumor types. Although more research is needed, these drugs offer hope for better outcomes in advanced melanoma cases. ^{5 6 7 8 9}

Who Is on the Research Team?

Howard Colman, MD, PhD

Principal Investigator

Huntsman Cancer Institute/ University of Utah

Are You a Good Fit for This Trial?

This trial is for advanced melanoma patients with brain metastases who didn't respond to immune checkpoint inhibitors. It's specifically for those with certain genetic mutations (RAS, BRAF V600E/K, NF1) or without these mutations (triple wild type). Patients must have at least one untreated brain metastasis to qualify.

Inclusion Criteria

I can give written consent and follow the study rules, or someone can do it for me if I'm unable.

I am fully active or able to carry out light work.

My blood tests show my organs and bone marrow are working well.

Exclusion Criteria

I have an eye condition.

I have HIV with a detectable viral load in the last 6 months.

I do not have an active infection like TB, hepatitis B, or C.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive defactinib and avutometinib, with or without encorafenib, in 4-week cycles with 3 weeks of treatment followed by a 1-week rest period

6 months

Biweekly visits for drug administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

up to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Avutometinib
• Defactinib
• Encorafenib

Trial Overview The study tests defactinib and avutometinib's effectiveness on various melanoma genetic types in the brain. For BRAF V600E/K mutants, it also adds encorafenib. The goal is to see how well these drugs work alone or combined and assess their safety.

How Is the Trial Designed?

Group I: Phase Ib, Defactinib, Avutometinib, and Encorafenib (Cohort B) Experimental Treatment 3 Interventions

Avutometinib will be administered at 3.2 mg biweekly orally (e.g., Monday/Thursday, Tuesday/Friday, or Wednesday/Saturday) for 3 weeks, followed by a 1-week rest period, in each 4-week (28-day) cycle. Defactinib will be administered at 200 mg twice a day orally for 3 weeks, followed by a 1-week rest period, in each 4-week (28-day) cycle. Encorafenib will be administered orally to a small cohort to a limited dose escalation cohort using a Bayesian optimal interval (BOIN) design to evaluate safety, toxicity, and recommended phase II dose for dosage of encorafenib when combined with avutometinib and defactinib. Dose escalation levels for Encorafenib: Dose Level -1: 225 mg Daily (three 75mg capsules) Dose Level 0: 300 mg Daily (four 75mg capsules) Dose Level 1: 450 mg Daily (six 75mg capsules)

Group II: Phase II, Defactinib, Avutometinib, and Encorafenib (Cohort B) Experimental Treatment 3 Interventions

Avutometinib will be administered at 3.2 mg biweekly orally (e.g., Monday/Thursday, Tuesday/Friday, or Wednesday/Saturday) for 3 weeks, followed by a 1-week rest period, in each 4-week (28-day) cycle. Defactinib will be administered at 200 mg twice a day orally for 3 weeks, followed by a 1-week rest period, in each 4-week (28-day) cycle. Encorafinib will be administered orally at doses defined in the dose escalation portion (225mg - 450mg) Daily continuously (days 1-28 of a 28 day cycle) for Cohort B.

Group III: Phase II, Defactinib and Avutometinib (Cohort A) Experimental Treatment 2 Interventions

Avutometinib will be administered at 3.2 mg biweekly orally (e.g., Monday/Thursday, Tuesday/Friday, or Wednesday/Saturday) for 3 weeks, followed by a 1-week rest period, in each 4-week (28-day) cycle. Defactinib will be administered at 200 mg twice a day orally for 3 weeks, followed by a 1-week rest period, in each 4-week (28-day) cycle.

Who Is Running the Clinical Trial?

University of Utah

Lead Sponsor

Trials

1,169

Recruited

1,623,000+

Verastem, Inc.

Industry Sponsor

Trials

42

Recruited

2,800+

Published Research Related to This Trial

In a large study of 856 patients with advanced BRAF V600-mutant melanoma, the combination of dabrafenib and trametinib showed a median progression-free survival (PFS) of 8.02 months, indicating its efficacy in this patient population.

Factors such as elevated lactate dehydrogenase (LDH), poor Eastern Cooperative Oncology Group Performance Status (ECOG PS), and the presence of brain metastasis were associated with shorter PFS, highlighting the importance of these factors in predicting treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy, safety and factors associated with disease progression in patients with unresectable (stage III) or distant metastatic (stage IV) BRAF V600-mutant melanoma: An open label, non-randomized, phase IIIb study of trametinib in combination with dabrafenib. Saiag, P., Robert, C., Grob, JJ., et al.[2021]

The combination of encorafenib and binimetinib has shown a median overall survival of 33.6 months in patients with advanced BRAFV600 mutation-positive melanoma, outperforming other BRAF/MEK inhibitor combinations that achieved 22 months.

Encorafenib's unique pharmacokinetics allow for prolonged binding and greater BRAF inhibition, which may lead to improved efficacy and better tolerability, with fewer side effects like pyrexia and photosensitivity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Encorafenib in combination with binimetinib for unresectable or metastatic melanoma with BRAF mutations. Trojaniello, C., Festino, L., Vanella, V., et al.[2019]

In a study of 10 patients with BRAF-mutant melanoma and untreated brain metastases, BRAF plus MEK inhibitor therapy showed a one-year local failure rate of 17.1%, indicating some effectiveness in controlling local disease.

However, the study also found a high risk of distant intracranial (88.6%) and extracranial (71.4%) progression, suggesting that while local control is achievable, patients with larger brain metastases may require additional local therapies for better outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intracranial Control With Combination BRAF and MEK Inhibitor Therapy in Patients With Metastatic Melanoma. Hui, C., Wu, YF., Liu, K., et al.[2023]

In a real-world study involving 95 patients with metastatic BRAF V600 mutated melanoma, the median overall survival (OS) was significantly higher for patients without brain metastases (21.6 months) compared to those with brain metastases (7.4 months).

The safety profile of cobimetinib/vemurafenib was consistent with previous studies, with high rates of adverse events (83.3% in patients without brain metastases and 87.8% in those with brain metastases), but no new safety concerns were identified.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness, safety and utilization of cobimetinib and vemurafenib in patients with BRAF V600 mutant melanoma with and without cerebral metastasis under real-world conditions in Germany: the non-interventional study coveNIS. Kähler, KC., Debus, D., Schley, G., et al.[2023]

A multicenter study involving 65 patients with BRAF-mutant melanoma and active brain metastases showed that combination therapy with BRAF/MEK inhibitors is safe, with no unexpected treatment-related safety issues observed.

The treatment resulted in a median progression-free survival of 5.3 months and a median overall survival of 9.5 months, indicating that this therapy can be an effective option for patients with challenging brain metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical experience with combination BRAF/MEK inhibitors for melanoma with brain metastases: a real-life multicenter study. Drago, JZ., Lawrence, D., Livingstone, E., et al.[2019]

In the phase 2 COMBI-MB trial involving 125 patients with BRAFV600-mutant melanoma brain metastases, 58% of patients in the asymptomatic cohort (A) achieved an intracranial response, indicating that dabrafenib plus trametinib is effective in this population.

The treatment had a manageable safety profile, with common serious adverse events including pyrexia and decreased ejection fraction, consistent with previous studies in patients without brain metastases, although the median duration of response was relatively short.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib plus trametinib in patients with BRAFV600-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. Davies, MA., Saiag, P., Robert, C., et al.[2022]

Recent advancements in systemic treatments, such as immune checkpoint inhibitors and BRAF/MEK inhibitors, have significantly improved survival rates and tumor response in patients with brain metastases from advanced melanoma, moving median survival from approximately 4 months to longer durations.

Despite previous concerns about the blood-brain barrier limiting treatment effectiveness, studies now show that systemic therapies can provide substantial benefits, with treatment decisions influenced by factors like neurologic symptoms, the characteristics of brain metastases, and BRAF mutation status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

How I treat brain metastases of melanoma. Eroglu, Z., Topcu, TO., Yu, HM., et al.[2023]

Encorafenib and binimetinib, approved by the FDA in 2018, significantly improve progression-free and overall survival in patients with metastatic melanoma harboring BRAF V600E or V600K mutations, based on the COLUMBUS trial results.

This combination therapy is the third BRAF plus MEK inhibitor regimen approved, highlighting the need for careful consideration of clinical and practical differences when choosing treatment options for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Encorafenib and Binimetinib Combination Therapy in Metastatic Melanoma. Davis, J., Wayman, M.[2022]

Dabrafenib demonstrated significant efficacy in treating patients with Val600Glu BRAF-mutant melanoma and brain metastases, with 39.2% of previously untreated patients achieving an overall intracranial response, and 30.8% of those with progressive disease after prior treatment responding as well.

The treatment had an acceptable safety profile, with 22% of patients experiencing grade 3 or worse adverse events, including serious issues like squamous-cell carcinoma and intracranial hemorrhage, indicating that while effective, monitoring for side effects is crucial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Long, GV., Trefzer, U., Davies, MA., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06194929

NCT06194929 | Defactinib and Avutometinib, With or ... What is the preliminary response rate of the three drug combination of defactinib, avutometinib, and encorafenib in patients with BRAF V600E/K mutant melanoma.

2. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2023-09548

Defactinib and Avutometinib with or without Encorafenib for ... Melanoma patients with brain metastases have little chance of a successful outcome and median overall survival for these patients is less than 2 years from the ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11866499/

Combined inhibition of focal adhesion kinase and RAF ... This study addresses the urgent need for effective therapies for patients with brain metastases from cutaneous melanoma, a major cause of ...

4. onclive.com onclive.com/view/avutometinib-defactinib-combo-could-fill-sizeable-unmet-need-in-lgsoc

Avutometinib/Defactinib Combo Could Fill Sizeable Unmet ... Ritu Salani, MD, MBA, details the significance of trials examining avutometinib plus defactinib and enthusiasm for ADCs in ovarian cancer.

5. docwirenews.com docwirenews.com/post/distant-brain-metastases-in-cutaneous-melanoma-may-be-mitigated-with-multiple-pathway-inhibitors

Distant Brain Metastases in Cutaneous Melanoma May Be ... This provides rationale for the clinical evaluation of defactinib and avutometinib in the treatment of melanoma metastases.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06194929

NCT06194929 | Defactinib and Avutometinib, With or ... What is the preliminary response rate of the three drug combination of defactinib, avutometinib, and encorafenib in patients with BRAF V600E/K mutant melanoma.

7. clinicaltrials.uihealthcare.org clinicaltrials.uihealthcare.org/studies/determine-phase-1b2-trial-defactinib-and-avutometinib-or-without-encorafenib-treatment

DETERMINE: Phase 1b/2 Trial of Defactinib and Avutometinib ... The goal of this interventional clinical trial is to provide proof-of-principle data for the biologic activity of defactinib in combination with avutometinib ...

8. nature.com nature.com/articles/s41591-025-03763-y

Defactinib with avutometinib in patients with solid tumors We describe the first-in-human trial of avutometinib (RAF–MEK clamp) and defactinib (focal adhesion kinase inhibitor) in patients with solid tumors.

9. centerwatch.com centerwatch.com/clinical-trials/listings/NCT06194929/defactinib-and-avutometinib-with-or-without-encorafenib-for-the-treatment-of-patients-with-brain-metastases-from-cutaneous-melanoma

Defactinib and Avutometinib, With or Without Encorafenib, ... Histologically confirmed diagnosis of cutaneous melanoma with radiographicallyconfirmed metastases to the brain. Must have a tumor with known ...