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

This is a multicenter Phase 1b, open-label study to evaluate the pharmacokinetic, safety and efficacy of binimetinib and encorafenib co-administered to adolescent patients with BRAF V600-mutant advanced/metastatic melanoma. The study consists of a Safety Run-in Phase to determine the RDE (recommended dose in expansion), followed by an Expansion Phase.

The study did not recruit the desired number of subjects and as a result does not have sufficient data for quantitative statistical analyses. Additionally, results data cannot be reported because doing so would risk re-identification of the participant.

Eligibility Criteria:
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 × 10⁹/L;
  * Hemoglobin ≥ 9 g/dL with or without transfusions;
  * Platelets ≥ 75 × 10⁹/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 BRAFʷͭ or indeterminate melanoma in tumor tissue.