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

Trial Summary

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.

What data supports the effectiveness of the drug combination for brain metastases from melanoma?

Research shows that combinations of BRAF and MEK inhibitors, like dabrafenib and trametinib, have improved outcomes for patients with melanoma that has spread to the brain. These combinations have been effective in increasing survival and reducing symptoms in patients with BRAF-mutant melanoma. ^{1 2 3 4 5}

Is the drug combination for brain metastases from melanoma generally safe in humans?

The combination of BRAF and MEK inhibitors, including encorafenib and binimetinib, has been used in treating melanoma with brain metastases, and studies have not shown any unexpected safety issues. Common side effects include diarrhea and fatigue, but no new safety concerns have been identified in recent studies. ^{2 3 6 7 8}

How is the drug combination of Avutometinib, Defactinib, and Encorafenib unique for treating brain metastases from melanoma?

This drug combination is unique because it includes Avutometinib and Defactinib, which are not typically used in standard BRAF/MEK inhibitor treatments for melanoma with brain metastases. Encorafenib, part of this combination, has shown improved efficacy and tolerability due to its distinct pharmacokinetics, offering a potentially more effective and better-tolerated option compared to other BRAF/MEK inhibitor combinations. ^{2 3 5 6 9}

What is the purpose of this trial?

The goal of this interventional clinical trial is to provide proof-of-principle data for the biologic activity of defactinib in combination with avutometinib in brain metastases from melanoma, and to define the potential role of the combination with mutant BRAF inhibitors or after BRAF/MEK inhibitors in BRAF V600E/K mutant tumors, in individuals with advanced melanoma who experience the development or progression of brain metastases after treatment with immune checkpoint inhibitors. The main questions it aims to answer are: * What is the preliminary response rate of defactinib and avutometinib in patients with RAS mutant, BRAF mutant, NF1 mutant, triple RAS/BRAF/NF1 wild type (wt) melanoma (including RAF fusions)? * What is the safety and tolerability of the combination of defactinib, avutometinib, and encorafenib in patients with BRAF V600E/K mutant melanoma with at least one untreated brain metastases? * What is the preliminary response rate of the three drug combination of defactinib, avutometinib, and encorafenib in patients with BRAF V600E/K mutant melanoma.

Research Team

Howard Colman, MD, PhD

Principal Investigator

Huntsman Cancer Institute/ University of Utah

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

References

1. England 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. [2022]

2. England 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. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Clinical experience with combination BRAF/MEK inhibitors for melanoma with brain metastases: a real-life multicenter study. [2019]

4. England pubmed.ncbi.nlm.nih.gov

How I treat brain metastases of melanoma. [2023]

5. England 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. [2022]

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

Encorafenib and Binimetinib Combination Therapy in Metastatic Melanoma. [2022]

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

Intracranial Control With Combination BRAF and MEK Inhibitor Therapy in Patients With Metastatic Melanoma. [2023]

8. England 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. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Encorafenib in combination with binimetinib for unresectable or metastatic melanoma with BRAF mutations. [2019]