Study of the Combination of Binimetinib and Encorafenib in Adolescent Patients With Unresectable or Metastatic BRAF V600-mutant Melanoma

• Drug: binimetinib
  taken orally
• Drug: encorafenib
  taken orally

• Experimental: Safety Run-in Phase
  • binimetinib taken twice daily (BID) and
  • encorafenib taken once daily (QD)

  Dose levels by patient body surface area (BSA) for binimetinib and encorafenib tablets/capsules are specified in the protocol.

  Interventions:

  • Drug: binimetinib
  • Drug: encorafenib
• Experimental: Expansion Phase
  • binimetinib taken twice daily (BID) and
  • encorafenib taken once daily (QD)

  Dose levels by patient body surface area (BSA) for binimetinib and encorafenib tablets/capsules and pediatric formulations are specified in the protocol.

  Interventions:

  • Drug: binimetinib
  • Drug: encorafenib

Key Inclusion Criteria:

Patients must meet all of the following criteria to be eligible for enrollment in the study.

• Histologically confirmed diagnosis of locally advanced, unresectable or metastatic cutaneous melanoma or unknown primary melanoma American Joint Committee on Cancer Stage IIIB, IIIC, or IV.
• Presence of BRAF V600E or V600K mutation in tumor tissue as determined by a local or central laboratory

• Adequate cardiac function:

  • Left ventricular ejection fraction (LVEF) ? 50% as determined by ECHO or multi-gated acquisition (MUGA) scan and above the institutional lower limit of normal (LLN);
  • Triplicate average baseline QTcF value ? 450 ms.

• Adequate bone marrow, organ function, and laboratory parameters:

  • Absolute neutrophil count (ANC) ? 1.5 × 10?/L;
  • Hemoglobin ? 9 g/dL with or without transfusions;
  • Platelets ? 75 × 10?/L without transfusions;
  • Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ? 2.5 × upper limit of normal (ULN); in patients with liver metastases ? 5 × ULN;
  • Total bilirubin ? 1.5 × ULN;
  • Creatinine ? 1.5 × institutional ULN for age, or calculated creatinine clearance ? 70 mL/min/1.73 m² (following Schwartz formula).

• Adequate performance status at Screening:

  • Patients < 16 years old: Lansky Performance Scale score ? 80
  • Patients 16 to 17 years old: Karnofsky Performance Scale score ? 80

Key Exclusion Criteria:

Patients meeting any of the following criteria are not eligible for enrollment in the study.

• Uveal or mucosal melanoma.
• Brain metastases that are uncontrolled or symptomatic, require steroids, are potentially life-threatening or have required radiation within 28 days prior to starting study drug.
• History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO
• Prior therapy with a BRAF inhibitor (e.g., dabrafenib, vemurafenib) and/or a MEK inhibitor (e.g., trametinib, cobimetinib).

• Impaired cardiovascular function or clinically significant cardiovascular disease, 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, 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.
• Concurrent neuromuscular disorder associated with elevated creatine kinase (CK)
• Uncontrolled arterial hypertension despite medical treatment
• Presence of BRAF?? or indeterminate melanoma in tumor tissue.