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.
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.
Cohort A: RAS, BRAF, NF1, or triple wildtype
Receiving other investigational agents.
Prior systemic anti-cancer therapy or any investigational therapy ≤ 28 days or within five half-lives prior to starting study treatment, whichever is shorter.
Patients with symptomatic brain metastasis, defined as neurologic symptoms with localization attributable to an untreated brain metastases with severity >= Grade 2 by CTCAE criteria.
History of allergy or hypersensitivity to any of the study treatments or any of their excipients.
Parallel
Defactinib
DrugDefactinib will be administered at 200 mg twice daily orally per arm description.
Avutometinib
DrugAvutometinib will be administered at 3.2 mg twice a week orally per arm description.
Encorafenib
DrugEncorafinib administered orally per arm description.
Response rate defined as Partial Response (PR) + Complete Response (CR) using Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria of all measurable target lesions present at the time of enrollment on trial.
For Cohort A, the primary objective will be to evaluate preliminary response rate of defactinib and avutometinib in patients with RAS mutant, BRAF mutant, NF1 mutant, and triple RAS/BRAF/NF1 wild type (wt) melanoma (includes RAF fusions). Measurable target lesions to be defined as all untreated and measurable (≥ 0.5 cm by 2 dimensional diameter measurements) present at the time of enrollment on study.
Frequency of dose limiting toxicities (DLTs).The frequency of adverse events (AEs) and serious adverse events (SAEs) characterized by type, severity (as defined by the NIH CTCAE, version 5.0), seriousness, duration, and relationship to study treatment.
For Cohort B, a Phase 1 run-in will be performed with the primary objective of evaluating 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 metastasis.
Response rate defined as Partial Response (PR) + Complete Response (CR) using Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria of all measurable target lesions present at the time of enrollment on trial.
For Cohort B, the primary objective will be to evaluate the preliminary response rate of the three drug combination of defactinib, avutometinib, and encorafenib in patients with BRAF V600E/K mutant melanoma. Measurable target lesions to be defined as all untreated and measurable (≥ 0.5 cm by 2 dimensional diameter measurements) present at the time of enrollment on study.
Duration of response (DoR)
To assess the duration of response (DoR) of the study population. Duration of response is defined as the interval of time from the date of initial documented response (PR or better per Neuro-Oncology Brain Metastases (RANO-BM) criteria) to the time of progression from the best response, the start of a new therapy, or death
Disease control rate as defined by the proportion of subjects achieving a confirmed PR, CR, and SD as defined by Neuro-Oncology Brain Metastases (RANO-BM) criteria.
To assess the disease control rate in the study population.
Progression-free survival (PFS) as defined as the time from study drug initiation to the time documented disease progression (as assessed by Neuro-Oncology Brain Metastases (RANO-BM) criteria) or death from any cause.
To assess progression-free survival (PFS)
Time to development of new brain metastases as defined as the mean time from registration until development of new measurable (≥0.5 cm diameter) brain metastases not present on baseline MRI.
To assess the time to development of new brain metastases in the study population
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University of Utah
Lead sponsor
Verastem, Inc.
Collaborator
