Inclusion Criteria:
- - 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 known RAS, BRAF, and NF1 mutation status using a validated
testing 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 target lesion)
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 have received at least 1 line of prior systemic immunotherapy.
- - For Cohort B, may have received 1 line 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.
- - INR or PT and aPTT within therapeutic limits (according to the medical
standard in the institution).
- - 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 negative serum pregnancy test and
agree to use a highly effective method of contraception for the duration of the study
and for 30 days following the last dose of study drug.
- - 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 study and for at least 90 days after
treatment is discontinued or longer if requested by local authorities.
Male patients
are considered to be of reproductive potential unless permanently sterile by bilateral
orchidectomy or vasectomized with appropriate post-vasectomy documentation of absence
of sperm in ejaculate.
- - 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.
Exceptions include alopecia and
peripheral neuropathy grade ≤ 2.
Exclusion Criteria:
- - 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.
- - QTc > 450 msec if male and QTc > 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.
- - 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 pathology, such as
anatomical abnormalities that increase the risk for RVO.
- - 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 drug-induced keratopathy.
Examples of visually significant corneal disorders include corneal degeneration,
active or recurrent keratitis, and other forms of serious ocular surface
inflammatory conditions. Visually significant corneal disorders do NOT include
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, herbal remedies,
or foods with potential for drug-drug interactions with study interventions within 14
days prior to the first dose of study intervention and during the course of therapy,
including:
- 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 least five half-lives or as
clinically indicated should occur before the start of treatment.
- - 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 duration (i.e., basal cell or
squamous cell skin cancer, carcinoma in situ of the breast, bladder or of the cervix,
or low-grade prostate cancer with Gleason Score ≤ 6)
- 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., infection/inflammation, intestinal obstruction,
unable to swallow medication, [subjects may not receive the drug through a feeding
tube], social/ psychological issues, etc.)
- 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.
