Safety and Efficacy in Participants With Metastatic BRAF-mutant Melanoma Treated With Encorafenib With and Without Binimetinib in Combination With Nivolumab and Low-dose Ipilimuma

Inclusion Criteria: 1. Signed Written Informed Consent 1. Participants must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol-related procedures that are not part of normal subject care. 2. Participants must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study. 2. Age ≥18 years 3. Histologically confirmed diagnosis of unresectable or metastatic melanoma 4. Presence of BRAFV600E/K mutation in tumor tissue as determined in a CLIA certified laboratory 5. Patients are required to submit archival biopsy material, if available, and submit research blood samples prior to first dose. Ten patients in each Phase Ib cohort will undergo fresh biopsy. These will be the first 10 unless medical or societal factors (e.g. COVID19) limit the pursuit of research biopsies. 6. Patients must be greater than 6 months from completion of adjuvant therapy (if any given) and/or treatment naïve in the metastatic setting or have recently started targeted therapy within the last 6 weeks. 7. Prior radiotherapy must have been completed at least 2 weeks prior to study drug administration. 8. An ECOG Performance Status of 0 or 1. If enrolling in Group 1 of Phase II, can have Performance Status from 0-2. 9. Measurable disease by CT or MRI per RANO-BM (brain metastases) OR RECIST v1.1 criteria 10. Must have high risk features described as described in Phase II expansion cohort - EITHER brain metastases as described in Phase II Group 1 OR Elevated LDH/Bulky Visceral Disease as described in Phase II Group 2. 11. Adequate bone marrow, organ function, and laboratory parameters: 1. ANC \> 1.5 x 109 ¬ /L; 2. Hemoglobin \> 8 g/dL with or without transfusions; 3. Platelet \> 100 x 109 ¬ /L; 4. Serum creatinine ≤ 1.5 × ULN, OR calculated creatinine clearance \> 50 mL/min by Cockcroft-Gault formula, OR estimated glomerular filtration rate \> 50 mL/min/1.73 m 12. Patient IS permitted to be on corticosteroids if related to disease burden and MAY have symptomatic brain lesions as long as radiation or surgical intervention is not deemed to be urgently necessary. 1. Symptomatic intracranial metastases may be on steroids at a total daily dose of no higher than 4 mg of dexamethasone or equivalent that is stable or tapering for 10 days prior to first treatment, 2. have no immediate need for SRT or surgery (within 3 week prior to first treatment), 3. have a performance status of 0-2 and 4. have had no experience of seizure within 10 days prior to first treatment. 13. Female patients of childbearing potential must have a negative serum β-HCG test result during screening prior to first dose 14. Females of childbearing potential must agree to protocol-approved methods of contraception, and to not donate Ova from Screening until 30 days of last dose of study drug. 15. Male patients must use contraception that is highly effective or acceptable, and not donate sperm from Screening until 90 days after the last dose of study drug. 16. The patient is deemed by the Investigator to have the initiative and means to comply with scheduled visits, treatment plan and study procedures. Exclusion Criteria: 1. Known hypersensitivity or contraindication to any component of study treatment or their excipients. 2. Previous Grade 3-4 AEs, or discontinuation of PD-1 or CTLA-4 inhibitor therapy, or BRAF/MEK inhibitor therapy 3. Inability to swallow and retain study treatment 4. Impairment of gastrointestinal function or disease which may significantly alter the absorption of study treatment (e.g., active ulcerative disease; uncontrolled nausea, vomiting or diarrhea; malabsorption syndrome; small bowel resection). 5. Participants with a non-melanoma related condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids, and adrenal replacement doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. 6. Participants with active, known or suspected autoimmune disease including those who have required systemic anti-rheumatic therapies in the preceding 2 years. Participants with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll. 7. Impaired cardiovascular function or clinically significant cardiovascular disease including, but not limited to, the following: 1. History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty or stenting) \< 6 months prior to Screening 2. Congestive heart failure requiring treatment (New York Heart Association Grade ≥ 2) 3. A known LVEF \< 50% as determined by MUGA or ECHO 4. Uncontrolled hypertension defined as persistent systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg despite current therapy 5. History or presence of clinically significant cardiac arrhythmias (including resting bradycardia, uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular tachycardia) 6. Baseline QTcF interval ≥ 480 ms. 8. Second malignancy that requires active treatment or would interfere with treatment efficacy evaluation. Participants with a second malignancy treated with curative intent are eligible. 9. On-going or use of systemic antibiotics during the preceding 2 weeks prior to enrollment 10. Known acute or chronic infection with hepatitis B or hepatitis C virus. Participants treated with curative anti-viral therapy are eligible. 11. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) even if fully immunocompetent on ART-due to the unknown effects of HIV on the immune response to combined nivolumab plus ipilimumab or the unique toxicity spectrum of these drugs in patients with HIV. 12. History of a thromboembolic event \< 12 weeks prior to starting study treatment. Examples of thromboembolic events include transient ischemia attack, cerebrovascular accident, deep vein thrombosis or pulmonary embolism. Catheter-related venous thrombosis is not considered a thromboembolic event for this trial even if \< 12 weeks prior to starting study treatment. 13. Use of herbal supplements, medications or foods that are moderate or strong inhibitors or inducers of cytochrome P450 (CYP) 3A4/5 ≤ 1 week prior to the start of study treatment (Section 4.5.1). 14. History or current evidence of RVO or current risk factors for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes); history of retinal degenerative disease. Phase II Group 1 Specific Criteria 1\. For Phase II Group 1 (Brain Metastases): Patients may have an ECOG status of 0-2 and IS permitted to be on corticosteroids if related to disease burden and MAY have symptomatic brain lesions as long as radiation or surgical intervention is not deemed to be urgently necessary. 1. Symptomatic intracranial metastases may be on steroids at a total daily dose of no higher than 4 mg of dexamethasone or equivalent that is stable or tapering for 10 days prior to first treatment, 2. have no immediate need for SRT or surgery (within 3 week prior to first treatment), 3. have had no experience of seizure within 10 days prior to first treatment.