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

Inclusion Criteria:

• Age ≥ 18 years at the time of informed consent.

• Provide written informed consent and comply with the study protocol as judged by theInvestigator. Of note, If the subject has an impairment that prevents him/her fromproviding written consent, the site may follow local institutional procedures forobtaining consent.

• Histologically confirmed diagnosis of cutaneous melanoma with radiographicallyconfirmed metastases to the brain.

• Must have a tumor with known RAS, BRAF, and NF1 mutation status using a validatedtesting method prior to enrollment.

• 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 targetlesion) parenchymal brain metastasis with minimal dimensions of ≥ 0.5 cm diameterand maximal dimensions ≤ 4 cm diameter, measured from a gadolinium enhanced MRI T1sequence.

• Note: Subject may have received prior resection or radiation therapy for priorbrain 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 inhibitortherapy.

• 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 orhyperbilirubinemia due to non-hepatic cause (e.g., hemolysis, hematoma) may beenrolled

• Serum creatinine ≤ 1.5 × ULN; OR calculated creatinine clearance > 50 mL/min byCockcroft-Gault formula; OR estimated glomerular filtration rate > 50mL/min/1.73m2.

• International normalized ratio (INR), prothrombin time (PT), or activatedpartial 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/oruterus) and who are sexually active, must have a negative serum pregnancy test andagree to use a highly effective method of contraception for the duration of thestudy and for 90 days following the last dose of study drug.

• Male patients (any individual assigned male at birth) of reproductive potential mustavoid pregnancy in partners who are women of childbearing potential, and suchpartners should not consider getting pregnant during the study and for at least 90days after treatment is discontinued or longer if requested by local authorities.Male patients are considered to be of reproductive potential unless permanentlysterile by bilateral orchidectomy or vasectomized with appropriate post-vasectomydocumentation of absence of sperm in ejaculate.

• Adequate recovery to baseline or ≤ Grade 1 CTCAE v5 from toxicities related to anyprior treatments, unless AE(s) are clinically nonsignificant and/or stable onsupportive therapy per the treating investigator. Exceptions include alopecia andperipheral neuropathy grade ≤ 2.

Exclusion Criteria:

• Receiving other investigational agents.

• Prior systemic anti-cancer therapy or any investigational therapy ≤ 28 days orwithin five half-lives prior to starting study treatment, whichever is shorter.

• Patients with symptomatic brain metastasis, defined as neurologic symptoms withlocalization attributable to an untreated brain metastases with severity >= Grade 2by CTCAE criteria.

• History of allergy or hypersensitivity to any of the study treatments or any oftheir 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 CancerInstitute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) or Grade 2intracranial hemorrhage within 4 weeks prior to the start of study treatment.

• Uncontrolled or severe cardiac disease (eg, history of unstable angina, myocardialinfarction, coronary stenting, or bypass surgery within the last 6 months prior toinitiation of study treatment), symptomatic congestive heart failure, seriousuncontrolled cardiac arrhythmia (including atrial flutter/fibrillation), requirementfor 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 medicalmanagement are to be excluded).

• History of interstitial lung disease, history of slowly progressive dyspnea andunproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonaryhypersensitivity pneumonitis, or symptomatic pleural effusion.

• Active, known, or suspected uncontrolled autoimmune disease, which required therapyin 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 anticipatedstart of treatment. Note: Participants on effective antiretroviral therapy with anundetectable viral load within 6 months of the anticipated start of treatment areeligible for this trial.

• Systemic active infection including tuberculosis (clinical evaluation that includesclinical history, physical examination, radiographic findings, and TB testing inline 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 ofHBsAg) are eligible. Participants positive for hepatitis C (HCV) antibody areeligible only if polymerase chain reaction is negative for HCV RNA.

• History of bleeding diathesis (irrespective of severity) in the absence oftherapeutic anticoagulation.

• Uncontrolled intercurrent illness including, but not limited to ongoing or activeinfection.

• Any condition that could make the patient noncompliant with the study proceduresand/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, uncontrolleddiabetes.

• Patients with history of retinal pathology or evidence of visible retinalpathology that is considered a risk factor for RVO, intraocular pressure > 21mm Hg as measured by tonometry, or other significant ocular pathology, such asanatomical abnormalities that increase the risk for RVO.

• Patients with active or chronic, visually significant corneal disorders, otheractive ocular conditions requiring ongoing therapy or clinically significantcorneal disease that prevents adequate monitoring of drug-induced keratopathy.Examples of visually significant corneal disorders include cornealdegeneration, active or recurrent keratitis, and other forms of serious ocularsurface inflammatory conditions. Visually significant corneal disorders do NOTinclude dry eyes, blepharitis, and uncomplicated corneal erosions.

• 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, herbalremedies, or foods with potential for drug-drug interactions with studyinterventions within 14 days prior to the first dose of study intervention andduring the course of therapy, including:

• Strong CYP3A4 inhibitors or inducers, due to potential drug-drug interactionswith both avutometinib and defactinib.

• Strong CYP2C9 inhibitors or inducers, due to potential drug-drug interactionswith defactinib.

• Strong P-glycoprotein (P-gp) inhibitors or inducers, due to potential drug-druginteractions with both avutometinib and defactinib.

• Strong breast cancer resistance protein (BCRP) inhibitors or inducers, due topotential drug-drug interactions with avutometinib.

• Concomitant treatment with warfarin. Patients who require anticoagulation but cannotdiscontinue warfarin must be excluded from the study.

• Participants taking other prohibited medications in protocol, including anticancertherapy or investigational agents and colony-stimulating factors (CSFs). A washoutperiod of prohibited medications for a period of at least five half-lives or asclinically indicated should occur before the start of treatment.

• The diagnosis of another malignancy within ≤ 2 years before study enrollment, exceptfor those considered to be adequately treated with no evidence of disease orsymptoms and/or will not require therapy during the study duration (i.e., basal cellor squamous cell skin cancer, carcinoma in situ of the breast, bladder or of thecervix, or low-grade prostate cancer with Gleason Score ≤ 6)

• Any other condition that would, in the Investigator's judgment, contraindicate thesubject's participation in the clinical study due to safety concerns or compliancewith clinical study procedures (e.g., infection/inflammation, intestinalobstruction, unable to swallow medication, [subjects may not receive the drugthrough a feeding tube], social/ psychological issues, etc.)

• Medical, psychiatric, cognitive, or other conditions that may compromise thesubject's ability to understand the subject information, give informed consent,comply with the study protocol or complete the study.