The trial was terminated early on 05 October 2022 due to non-feasibility and poor recruitment and not based on safety concerns.

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.

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.

Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical\_trials/trial\_data\_and\_results/data\_requests.