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Kinase Inhibitor

Drug Combination for Brain Metastases from Melanoma (DETERMINE Trial)

Phase 1 & 2

Recruiting

Led By Howard Colman, MD, PhD

Research Sponsored by University of Utah

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Must have a tumor with known RAS, BRAF, and NF1 mutation status using a validated testing method prior to enrollment

Must have at least 1 untreated parenchymal brain metastasis with minimal dimension of ≥ 0.5 cm diameter and maximal dimension ≤ 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 not have

Inability to swallow and retain study treatment

Systemic active infection including tuberculosis, hepatitis B, or hepatitis C

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 5 years

Awards & highlights

No Placebo-Only Group

Summary

This trial is testing a combination of drugs (defactinib, avutometinib, and encorafenib) in patients with advanced melanoma that has spread to the brain. The

Who is the study for?

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.

What is being tested?

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.

What are the potential side effects?

While specific side effects aren't listed here, common ones may include fatigue, nausea, skin reactions from targeted therapies like rash or dryness, liver function changes, and potential bleeding or swelling in the brain from tumor treatment.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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My tumor's RAS, BRAF, and NF1 mutation status is known.

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I have at least one brain tumor that hasn't been treated, measuring between 0.5 and 4 cm.

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I am fully active or able to carry out light work.

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My skin cancer has spread to my brain.

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I have had at least one immunotherapy treatment before.

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I am 18 years old or older.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I cannot swallow or keep down the medication.

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I do not have an active infection like TB, hepatitis B, or C.

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I have a history of bleeding disorders without being on blood thinners.

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I have an eye condition.

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I have had rhabdomyolysis in the past.

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I have a history of lung conditions like interstitial lung disease or sarcoidosis.

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I have or had cancer spread to the lining of my brain and spinal cord.

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I do not have severe or uncontrolled heart problems.

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I have not had severe bleeding or a serious brain bleed in the last month.

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I do not have any uncontrolled illnesses or active infections.

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My melanoma is in the eye (uveal) or in mucous membranes.

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I haven't taken any medications or supplements that could interfere with the study treatment in the last 14 days.

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I have brain metastasis causing noticeable symptoms.

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I have an autoimmune disease that needed treatment in the last 2 years.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 5 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 5 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 5 years for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

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.

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.

Secondary study objectives

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.

Duration of response (DoR)

Overall survival (OS) defined as the time of study drug initiation until death from any cause

+3 more

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

3Treatment groups

Experimental Treatment

Group I: Phase Ib, Defactinib, Avutometinib, and Encorafenib (Cohort B)Experimental Treatment3 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 Treatment3 Interventions

Group III: Phase II, Defactinib and Avutometinib (Cohort A)Experimental Treatment2 Interventions

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Encorafenib

2022

Completed Phase 3

~970

Defactinib

2013