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

NCT06194929 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: HCI168254
• Study Type: interventional
• Target: 33
• Locations: 1 country
• Sites: 2

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.

Conditions

Cutaneous Melanoma; Brain Metastases

Outcome Measures

Primary Outcomes (3)

• 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.

  6 months

• 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.

  4 weeks

• 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.

  6 months

Secondary Outcomes (6)

• Duration of response (DoR)

  up to 5 years

• 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.

  6 months

• 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.

  up to 5 years

• 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.

  up to 5 years

• Rate of new brain metastases defined as percent of study population that develop new measurable brain metastases between time of enrollment and time of documented progression (target or new lesions).

  up to 5 years

Study Arms (3)

Phase II, Defactinib and Avutometinib (Cohort A)

EXPERIMENTAL

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.

Drug: Defactinib; Drug: Avutometinib

Phase Ib, Defactinib, Avutometinib, and Encorafenib (Cohort B)

EXPERIMENTAL

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)

Drug: Defactinib; Drug: Avutometinib; Drug: Encorafenib

Phase II, Defactinib, Avutometinib, and Encorafenib (Cohort B)

EXPERIMENTAL

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.

Drug: Defactinib; Drug: Avutometinib; Drug: Encorafenib

Interventions

Defactinib DRUG

Defactinib will be administered at 200 mg twice daily orally per arm description.

Phase II, Defactinib and Avutometinib (Cohort A); Phase II, Defactinib, Avutometinib, and Encorafenib (Cohort B); Phase Ib, Defactinib, Avutometinib, and Encorafenib (Cohort B)

Avutometinib DRUG

Avutometinib will be administered at 3.2 mg twice a week orally per arm description.

Phase II, Defactinib and Avutometinib (Cohort A); Phase II, Defactinib, Avutometinib, and Encorafenib (Cohort B); Phase Ib, Defactinib, Avutometinib, and Encorafenib (Cohort B)

Encorafenib DRUG

Encorafinib administered orally per arm description.

Phase II, Defactinib, Avutometinib, and Encorafenib (Cohort B); Phase Ib, Defactinib, Avutometinib, and Encorafenib (Cohort B)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 received prior resection or radiation therapy for prior brain metastases.
• Must have received at least 1 line of prior systemic immunotherapy.
• For Cohort B, may have received 1 or more lines of prior BRAF or MEK inhibitor therapy.
• An ECOG Performance Status of 0 or 1, or Karnofsky score \>= 70
• Adequate bone marrow, organ function and laboratory parameters:
• ANC ≥ 1.5 × 109/L;
• Hemoglobin ≥ 9 g/dL with or without transfusions;
• Platelets ≥100,000/mm2;

You may not qualify if:

• 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.
• Inability to swallow and retain study treatment.
• Uveal or mucosal melanoma.
• History of or current leptomeningeal metastases.
• QTcF \> 450 msec if male and QTcF \> 470 msec if female.
• Any hemorrhage or bleeding event that is ≥ Grade 3 based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) or Grade 2 intracranial hemorrhage within 4 weeks prior to the start of study treatment.
• Uncontrolled or severe cardiac disease (eg, history of unstable angina, myocardial infarction, coronary stenting, or bypass surgery within the last 6 months prior to initiation of study treatment), symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia (including atrial flutter/fibrillation), requirement for inotropic support or use of devices for cardiac conditions (eg, pacemakers/defibrillators), or hypertension (patients with systolic blood pressure \[BP\] of \> 160 mm Hg or diastolic BP of \> 100 mm Hg despite optimal medical management are to be excluded).
• History of interstitial lung disease, history of slowly progressive dyspnea and unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonary hypersensitivity pneumonitis, or symptomatic pleural effusion.
• Active, known, or suspected uncontrolled autoimmune disease, which required therapy in the past 2 years, including but not limited to systemic lupus erythematosus, Hashimotos thyroiditis, scleroderma, polyarteritis nodosa, or autoimmune hepatitis.
• Known HIV infection with a detectable viral load within 6 months of the anticipated start of treatment. Note: Participants on effective antiretroviral therapy with an undetectable viral load within 6 months of the anticipated start of treatment are eligible for this trial.
• Systemic active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination, radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), or hepatitis C. Note: Participants with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody \[anti-HBc\] and absence of HBsAg) are eligible. Participants positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
• History of bleeding diathesis (irrespective of severity) in the absence of therapeutic anticoagulation.

Sponsors & Collaborators

• University of Utah: lead
• Verastem, Inc.: collaborator

Study Sites (2)

University of Iowa

Iowa City, Iowa, 52242, United States

RECRUITING

Huntsman Cancer Institute

Salt Lake City, Utah, 84112, United States

RECRUITING

MeSH Terms

Conditions

Melanoma; Brain Neoplasms

Interventions

defactinib; encorafenib

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases; Central Nervous System Neoplasms; Nervous System Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Study Officials

• Howard Colman, MD, PhD

  Huntsman Cancer Institute/ University of Utah

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Rachel Kingsford

CONTACT

801-585-0115; rachel.kingsford@hci.utah.edu

Yuri Kida

CONTACT

801-646-4397; yuri.kida@hci.utah.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Cohort A will evaluate the hypothesis that avutometinib and defactinib will have clinical benefit in terms of response rate and/or for prolonging organ specific PFS in patients with cutaneous melanoma and at least one untreated brain metastases after at least one line of immunotherapy (Cohort A), compared to historical controls. Cohort B will evaluate the hypotheses that avutometinib, defactinib, and encorafenib will have clinical benefit in terms of response rate and/or for prolonging organ specific PFS in patients who have received at least one prior line of immunotherapy and also may have received at least one line of prior BRAF/MEK therapy, compared to historical controls. Cohort B will also include a limited dose escalation cohort using a BOIN design

Study Record Dates

• First Submitted: December 20, 2023
• First Posted: January 8, 2024
• Study Start: March 20, 2024
• Primary Completion (Estimated): January 15, 2028
• Study Completion (Estimated): January 15, 2030
• Last Updated: December 3, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)