Defactinib and Avutometinib, With or Without Encorafenib, for the Treatment of Patients With Brain Metastases From Cutaneous Melanoma

Part of paid clinical trials in Iowa City, Iowa.

Sponsor
University of Utah
Study ID
NCT06194929
Phase
PHASE1/PHASE2
Status
Recruiting
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Conditions

  • Brain Metastases
  • Cutaneous Melanoma

Eligibility Criteria

Sex
ALL
Age
18 Years - N/A
Healthy Volunteers
Not accepted

Interventions

  • Defactinib — DRUG
    Defactinib will be administered at 200 mg twice daily orally per arm description.
  • Avutometinib — DRUG
    Avutometinib will be administered at 3.2 mg twice a week orally per arm description.
  • Encorafenib — DRUG
    Encorafinib administered orally per arm description.

Study Details

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.

Key Dates

Start date
Mar 20, 2024
Status verified
Nov 2025
Primary completion
Jan 15, 2028
Completion
Jan 15, 2030

Study Design

Enrollment
33 participants (estimated)
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT

Arms

  • Experimental: Phase II, Defactinib and Avutometinib (Cohort A)
    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.
  • Experimental: Phase Ib, Defactinib, Avutometinib, and Encorafenib (Cohort B)
    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 finding 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/de-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)
  • Experimental: Phase II, Defactinib, Avutometinib, and Encorafenib (Cohort B)
    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 finding portion (225mg - 450mg) Daily continuously (days 1-28 of a 28 day cycle) for Cohort B.

Primary Outcome Measure

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. [ Time Frame: 6 months ]

Central Contacts

Locations (2)

FacilityCityStateZIPSite coordinators
University of IowaIowa CityIowa52242
Mohammed Milhem, MD
319-356-2324
Mohammed Milhem, MD (PRINCIPAL_INVESTIGATOR)
Huntsman Cancer InstituteSalt Lake CityUtah84112
Rachel Kingsford
[email protected]
801-585-0115
Howard Colman, MD, PhD (PRINCIPAL_INVESTIGATOR)

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By research site
University of Iowa· Iowa City, IAHuntsman Cancer Institute· Salt Lake City, UT

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