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

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.