A Study to Compare the Administration of Encorafenib + Binimetinib + Nivolumab Versus Ipilimumab + Nivolumab in BRAF-V600 Mutant Melanoma With Brain Metastases

Inclusion Criteria:

• Participants must have histologically and pathologically confirmed melanoma that hasmetastasized to the brain

• Any primary (cutaneous, acral/mucosal, etc) or unknown origin are permitted, exceptthat participants with uveal primary are not eligible

• Participants must have BRAF-V600 mutant melanoma documented by a Clinical LaboratoryImprovement Act (CLIA)-certified laboratory

• All participants must have an magnetic resonance imaging (MRI) of the brain within 28 days prior to registration and must have central nervous system metastases withat least one measurable brain metastasis >= 0.5 cm in size (per modified RECIST 1.1)that has not been irradiated, or progressed (in the opinion of the treatingphysician) after prior radiation therapy. Participating sites MUST use MRI slicethickness of =< 1.5 mm and are recommended to adhere to the 'minimum' Brain TumorImaging Protocol for Clinical Trials in Brain Metastases (BTIP-BM) compliant MRIacquisition protocol. Computed tomography (CT) of the head cannot substitute forbrain MRI. (NOTE: All central nervous system [CNS] disease must be documented onBOTH the Brain Metastases Baseline Tumor Assessment Form, using modified RECIST, andthe Baseline Tumor Assessment Form [RECIST 1.1] using RECIST 1.1.)

• Participants may have measurable or non-measurable extracranial disease. Allmeasurable disease must be assessed within 28 days prior to randomization; allnon-measurable disease must be assessed within 42 days prior to randomization.Please note, while any extracranial disease will also be assessed and followed,participants are NOT required to have extracranial disease for randomization. NOTE:All disease must be assessed and documented on the Baseline Tumor Assessment Form (RECIST 1.1). CNS disease must be documented on BOTH the Brain Metastases BaselineTumor Assessment Form, using modified RECIST, and the Baseline Tumor Assessment Form (RECIST 1.1) using RECIST 1.1

• Participants may have leptomeningeal disease

• Participants may be receiving corticosteroids for brain metastases at a dose of upto 8 mg of dexamethasone per day. The dose must not have exceeded 8 mg per day forat least 7 days prior to randomization

• Participants must have Zubrod performance status =< 2

• Participants must have complete history and physical examination within 28 daysprior to randomization

• Participants must be able to swallow and retain pills

• Hemoglobin >= 8.0 g/dL (within 28 days prior to randomization)

• Absolute neutrophil count >= 1,500/mcL (within 28 days prior to randomization)

• Platelets >= 75,000/mcL (within 28 days prior to randomization)

• Total bilirubin =< 1.5 institutional upper limit of normal (ULN) (within 28 daysprior to randomization)

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 xinstitutional ULN (in participants with liver metastases =< 5 x ULN) (within 28 daysprior to randomization)

• Creatinine =< 2.0 institutional ULN (within 28 days prior to randomization)

• Participants with known history or current symptoms of cardiac disease, or historyof treatment with cardiotoxic agents, must have a clinical risk assessment ofcardiac function using the New York Heart Association Functional Classification. Tobe eligible for this trial, participants must be class 2B or better

• Participants with a prior or concurrent malignancy whose natural history ortreatment (in the opinion of the treating physician) does not have the potential tointerfere with the safety or efficacy assessment of the investigational regimen areeligible for this trial

• Participants with known human immunodeficiency virus (HIV)-infection are eligibleproviding they are on effective anti-retroviral therapy and have undetectable viralload at their most recent viral load test and within 90 days prior to randomization

• Participants with a known history of hepatitis C virus (HCV) infection must havebeen treated and cured. Participants with HCV infection who are currently ontreatment must have an undetectable HCV viral load prior to randomization

• Participants must agree to participate in image banking. Images must be submittedvia the Triad System

• Participants must be offered the opportunity to participate in specimen and bloodcollections

• Participants must be informed of the investigational nature of this study and mustsign and give informed consent in accordance with institutional and federalguidelines

• As a part of the OPEN registration process the treating institution's identity isprovided in order to ensure that the current (within 365 days) date of institutionalreview board approval for this study has been entered in the system

Exclusion Criteria:

• Participants must not have received prior systemic therapy for metastatic disease.Prior systemic therapy received only in the neoadjuvant and/or adjuvant setting (e.g., BRAF/MEK inhibitor therapy, anti-PD-1 therapy or anti-CTLA4 therapy,alfa-interferon, etc.) is permitted. If patients received prior neoadjuvant/adjuvanttherapy, they must have had eventual disease relapse prior to randomization

• Participants must not have had prior radiation therapy within 7 days prior torandomization

• Participants must not be planning to require any additional form of systemicanti-tumor therapy for melanoma while on protocol treatment

• Participants must not be planning to use hormonal contraceptives

• Participants must not have a serious active infection requiring systemic therapy attime of randomization in the opinion of the treating physician

• Participants must not have active autoimmune disease that has required treatment inthe past 6 months with use of biologic disease modifying agents (.e.g. infliximab,adalimumab). Patients on non-biologic disease modifying agents (e.g. methotrexate)or patients on corticosteroids =< 10 mg prednisone daily or equivalent (to treatauto-immune disease), or on replacement therapy (e.g., thyroxine, insulin) areeligible if deemed in the best interest of the patient by treating physician

• Participants must not have had grade 3 or 4 immune-related adverse events onipilimumab or nivolumab that required more than 12 weeks of immune suppression withcorticosteroids

• Participants must not have had adverse events related to encorafenib and/orbinimetinib specifically, that required discontinuation of one or both drugs. (Please note this does not apply to other BRAF/MEK inhibitor drugs.)

• Participants must not be pregnant or nursing. Women/men of reproductive potentialmust have agreed to use an effective method of contraception. (NOTE: Patients mustagree to not use hormonal contraceptives, as encorafenib can result in decreasedconcentration and loss of efficacy.) A woman is considered to be of "reproductivepotential" if she has had menses at any time in the preceding 12 consecutive months.In addition to routine contraceptive methods, "effective contraception" alsoincludes heterosexual celibacy and surgery intended to prevent pregnancy (or with aside-effect of pregnancy prevention) defined as a hysterectomy, bilateraloophorectomy or bilateral tubal ligation. However, if at any point a previouslycelibate participant chooses to become heterosexually active during the time periodfor use of contraceptive measures outlined in the protocol, he/she is responsiblefor beginning contraceptive measures