Defactinib and Avutometinib, With or Without Encorafenib, for the Treatment of Patients With Brain Metastases From Cutaneous Melanoma
Trial Parameters
Brief Summary
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.
Eligibility Criteria
Inclusion Criteria: * Age ≥ 18 years at the time of informed consent. * Provide written informed consent and comply with the study protocol as judged by the Investigator. Of note, If the subject has an impairment that prevents him/her from providing written consent, the site may follow local institutional procedures for obtaining consent. * Histologically confirmed diagnosis of cutaneous melanoma with radiographically confirmed metastases to the brain. * Must have a tumor with a known RAS, BRAF, or NF1 mutation or triple wildtype status using validated testing methods prior to enrollment. Cohorts will be assigned as follows: * Cohort A: RAS, BRAF, NF1, or triple wildtype * Cohort B: BRAF V600E or BRAF V600K * Must have at least 1 untreated (no prior resection or radiation of the target lesion) parenchymal brain metastasis with minimal dimensions of ≥ 0.5 cm diameter and maximal dimensions ≤ 4 cm diameter, measured from a gadolinium enhanced MRI T1 sequence. * Note: Subject may have rec