A Study of Binimetinib and Encorafenib in Advanced BRAF Mutant Cancers

Inclusion Criteria: * Patient has signed the Informed Consent (ICF) prior to any screening procedures being performed and is able to comply with protocol requirements * Age ≥ 18 years at the time of informed consent * Metastatic or advanced-stage malignant tumors confirmed histologically for whom no standard therapy is considered to be appropriate by the investigator * Patients must have at least one other lesion that is measurable by RECIST criteria. * Patient's tumor must harbor an activating BRAF mutation (listed in Table 4 or approved by the study Principal Investigator) or a fusion involving the kinase domain of BRAF * Mechanistically validated activating non-V600 BRAF mutants * P367L/S * G464V/E * G469A/V/R * L485W * N486\_A489delinsK * N486\_P490del * E586K * L597Q/V/S * T599TT/TS * T599I/K * V600\_K601delinsE * K601E/N/T * K601\_S602delinsNT * BRAF kinase duplication * Fusions involving BRAF kinase domain * Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2 * Adequate bone marrow, organ function and laboratory parameters: * Absolute neutrophil count (ANC) ≥ 1.5 x 109/L * Hemoglobin (Hgb) ≥ 8 g/dL with or without transfusions * Platelets (PLT) ≥ 75 x 109/L without transfusions * AST and/or ALT ≤ 2.5 × upper limit of normal (ULN); patient with liver metastases ≤ 5 ×ULN * Total bilirubin ≤ 1.5 × ULN and \< 2 mg/dL (Note: Patients who have a total bilirubin level \> 1.5 x ULN will be allowed if their indirect bilirubin level is ≤ 1.5 x ULN) * Serum Creatinine ≤ 1.5 x ULN, or calculated creatinine clearance (determined as per Cockcroft-Gault) ≥ 50 mL/min at screening * Adequate cardiac function: * left ventricular ejection fraction (LVEF) ≥ 50% as determined by a multigated acquisition (MUGA) scan or echocardiogram * QTc interval ≤ 480 ms (preferably the mean from triplicate ECGs) * Able to take oral medications * Patient is deemed by the Investigator to have the initiative and means to be compliant with the protocol (treatment and follow-up) * Female patients are either postmenopausal for at least 1 year, are surgically sterile for at least 6 weeks, or must agree to take appropriate precautions to avoid pregnancy from screening through 30 days after the last dose of study drug/treatmentif of childbearing potential (Note: Permitted contraception methods listed in Section 9.3 should be communicated to the patients and their understanding confirmed. For females of childbearing potential, the pregnancy test result must be negative at screening.) * Males must agree to take appropriate precautions to avoid fathering a child from screening through 90 days following the end of therapy. (Note: Permitted contraception methods listed in Section 9.3 should be communicated to the patients and their understanding confirmed.) Exclusion Criteria: * Any symptomatic brain metastasis (Note: Patients previously treated or untreated for this condition who are asymptomatic in the absence of corticosteroid and antiepileptic therapy are allowed. Brain metastases must be stable for ≥ 4 weeks, with imaging (e.g., magnetic resonance imaging \[MRI\] or computed tomography \[CT\]) demonstrating no current evidence of progressive brain metastases at screening.) * History or current evidence of retinal vein occlusion (RVO) or current risk factors to RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes); history of retinal degenerative disease * Leptomeningeal disease * Previous or concurrent malignancy within 2 years of study entry, with the following exceptions: adequately treated basal or squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in-situ of the cervix, early stage breast cancer, or other noninvasive or indolent malignancy * Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following: * History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) \< 6 months prior to screening * Symptomatic chronic heart failure (i.e. Grade 2 or higher), history or current evidence of clinically significant cardiac arrhythmia and/or conduction abnormality \< 6 months prior to screening except atrial fibrillation and paroxysmal supraventricular tachycardia * Uncontrolled hypertension defined as persistent elevation of systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg, despite current therapy. * Known positive serology for HIV (Human Immunodeficiency Virus), active hepatitis B, and/or active hepatitis C infection * Impaired GI function or disease that may significantly alter the absorption of encorafenib or binimetinib (e.g., ulcerative diseases, uncontrolled vomiting, malabsorption syndrome, small bowel resection with decreased intestinal absorption) * History of thromboembolic or cerebrovascular events ≤ 12 weeks prior to the first dose of study treatment. Examples include transient ischemic attacks, cerebrovascular accidents, hemodynamically significant (i.e. massive or sub-massive) deep vein thrombosis or pulmonary emboli. Note: Patients with either deep vein thrombosis or pulmonary emboli that does not result in hemodynamic instability are allowed to enroll as long as they are on a stable dose of anticoagulants for at least 4 weeks. Note: Patients with thromboembolic events related to indwelling catheters or other procedures may be enrolled.Concurrent neuromuscular disorder that is associated with the potential of elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy). * Any other condition that would, in the Investigator's judgement, contraindicate the patient'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 medications, social/psychological issues, etc. * Patients who have undergone surgery ≤ 3 weeks prior to starting study drug or who have not yet recovered from side effects of such procedure * Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test * Medical, psychiatric, cognitive, or other conditions that may compromise the patient's ability to understand the patient information, give informed consent, comply with the study protocol or complete the study * Prior treatment with any RAF, MEK, or ERK inhibitors (such as vemurafenib, dabrafenib, encorafenib; trametinib, cobimetinib, binimetinib, selumetinib; or BVD-523, respectively)