Patient case: 14-year-old female with Li-Fraumeni syndrome; genetic feature: TP53

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

Summary: 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.


Eligibility: 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 and < 2 mg/dL; OR total bilirubin >1.5 × ULN with indirect 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
  -  History of Gilbert's syndrome.

Relevance to patient case: not relevant