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New treatment option for Cutaneous Melanoma
Official title Defactinib and Avutometinib, With or Without Encorafenib, for the Treatment of Patients With Brain Metastases From Cutaneous Melanoma
ClinicalTrials.gov ID: NCT06194929
What this study is testing
What is Defactinib?
Defactinib is an investigational medicine, given as an once-daily pill taken by mouth, being studied as a potential treatment for cutaneous melanoma.
Plain-language explanation of the investigational treatment - it is being studied and is not an approved or proven therapy. The study team can confirm the details.
- What it's testing
- 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)?
- Phase 2: a mid-size study of how well it works
A plain-language read of the study's public ClinicalTrials.gov listing. The study team confirms the details.
Who can take part
Ages 18 and older
You may be able to join 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...
- 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...
- Cohort A: RAS, BRAF, NF1, or triple wildtype
You likely can't join 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...
- Patients with symptomatic brain metastasis, defined as neurologic symptoms with localization attributable to an untreated brain metastases with...
- 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.
See the full eligibility criteria
Who can join
- 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...
- 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...
- 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;
- AST and ALT ≤ 2.5 × ULN; in patients with liver metastases ≤ 5 × ULN;
- Total bilirubin ≤ 1.5 × ULN; NOTE: Patients with documented Gilbert syndrome or hyperbilirubinemia due to non-hepatic cause (e.g., hemolysis, hematoma) may be enrolled
- Serum creatinine ≤ 1.5 × ULN; OR calculated creatinine clearance \> 50 mL/min by Cockcroft-Gault formula; OR estimated glomerular filtration rate \> 50 mL/min/1.73m2.
- International normalized ratio (INR), prothrombin time (PT), or activated partial thromboplastin time (aPTT) as follows:
- In the absence of therapeutic intent to anticoagulate the patient:
- INR \< 1.5 × ULN.
- PT \< 1.5 × ULN.
- aPTT \< 1.5 × ULN.
- Adequate cardiac function with left ventricular ejection fraction ≥ 55% by echocardiography (ECHO) or multiple-gated acquisition (MUGA) scan.
- For women (any individual assigned female at birth) who are not postmenopausal (ie, \< 2 years after last menstruation) or surgically sterile (absence of ovaries and/or uterus) and who are sexually active, must have a...
- Male patients (any individual assigned male at birth) of reproductive potential must avoid pregnancy in partners who are women of childbearing potential, and such partners should not consider getting pregnant during the...
- Adequate recovery to baseline or ≤ Grade 1 CTCAE v5 from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy per the treating investigator...
What rules you out
- 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...
- 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...
- History of interstitial lung disease, history of slowly progressive dyspnea and unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonary hypersensitivity pneumonitis, or symptomatic pleural...
- 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...
- 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...
- 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...
- History of bleeding diathesis (irrespective of severity) in the absence of therapeutic anticoagulation.
- Uncontrolled intercurrent illness including, but not limited to ongoing or active infection.
- Any condition that could make the patient noncompliant with the study procedures and/or study requirements, as judged by the Investigator.
- Active skin disorder that has required systemic therapy within the past 1 year.
- History of rhabdomyolysis.
- Concurrent ocular disorders:
- Patients with history of glaucoma, history of retinal vein occlusion (RVO), predisposing factors for RVO, including uncontrolled hypertension, uncontrolled diabetes.
- Patients with history of retinal pathology or evidence of visible retinal pathology that is considered a risk factor for RVO, intraocular pressure \> 21 mm Hg as measured by tonometry, or other significant ocular...
- Patients with active or chronic, visually significant corneal disorders, other active ocular conditions requiring ongoing therapy or clinically significant corneal disease that prevents adequate monitoring of...
- Patients with a history of hypersensitivity to any of the active (avutometinib, defactinib, encorafenib) or inactive ingredients of the investigational products.
- Exposure to medications (with or without prescriptions), supplements, herbal remedies, or foods with potential for drug-drug interactions with study interventions within 14 days prior to the first dose of study...
- Strong CYP3A4 inhibitors or inducers, due to potential drug-drug interactions with both avutometinib and defactinib.
- Strong CYP2C9 inhibitors or inducers, due to potential drug-drug interactions with defactinib.
- Strong P-glycoprotein (P-gp) inhibitors or inducers, due to potential drug-drug interactions with both avutometinib and defactinib.
- Strong breast cancer resistance protein (BCRP) inhibitors or inducers, due to potential drug-drug interactions with avutometinib.
- Concomitant treatment with warfarin. Patients who require anticoagulation but cannot discontinue warfarin must be excluded from the study.
- Participants taking other prohibited medications in protocol, including anticancer therapy or investigational agents and colony-stimulating factors (CSFs). A washout period of prohibited medications for a period of at...
- The diagnosis of another malignancy within ≤ 2 years before study enrollment, except for those considered to be adequately treated with no evidence of disease or symptoms and/or will not require therapy during the study...
- Any other condition that would, in the Investigator's judgment, contraindicate the subject's participation in the clinical study due to safety concerns or compliance with clinical study procedures (e.g...
- Medical, psychiatric, cognitive, or other conditions that may compromise the subject's ability to understand the subject information, give informed consent, comply with the study protocol or complete the study.
The study team makes the final eligibility decision.
Where it's taking place
- Iowa City, Iowa, United States
- Salt Lake City, Utah, United States
Questions & answers
Do participants get paid in this trial?
This listing doesn't specify compensation. Many trials still reimburse travel or offer a stipend, so it's worth asking the study team when you connect.
Is it free to join, and do I need insurance?
Searching and applying through BridgeMD is free. In clinical trials the study-related treatment and visits are generally provided at no cost to you. You usually don't need insurance to take part - confirm specifics with the study team.
How long does this study last?
The listing doesn't state an exact length. The study team walks you through the schedule and number of visits before you decide to enroll.
Who can join this trial?
This study is enrolling all sexes, 18 years and older. The study team makes the final eligibility decision.
Where is this trial taking place?
Study sites include Iowa City, Iowa, United States; Salt Lake City, Utah, United States. Enter your location above to see the nearest site and check your eligibility.
Explore other conditions
BridgeMD is an information and trial-matching tool - not medical advice, and not the study sponsor. Details come from ClinicalTrials.gov; the study team decides eligibility.