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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Multicenter, Open-label Phase 1b Study of the Combination of Binimetinib and Encorafenib in Adolescent Patients With Unresectable or Metastatic BRAF V600-mutant Melanoma

Conditions
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Melanoma

Intervention / Treatment
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* Drug: binimetinib
* Drug: encorafenib


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Safety Run-in Phase<br>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. | Drug: binimetinib<br>* taken orally<br>Drug: encorafenib<br>* taken orally<br>|
| Experimental: Expansion Phase<br>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. | Drug: binimetinib<br>* taken orally<br>Drug: encorafenib<br>* taken orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic (PK) parameter (time to reach the maximum observed plasma concentration Cmax [Tmax]) for binimetinib |  | Day 1 and Day 15 of Cycle 1, 28 day cycles | 
| PK parameter (Cmax) for binimetinib |  | Day 1 and Day 15 of Cycle 1, 28 day cycles | 
| PK parameter (time of last PK sample [Tlast]) for binimetinib |  | Day 1 and Day 15 of Cycle 1, 28 day cycles | 
| PK parameter (area under the plasma concentration-time curve from time zero to Tlast [AUClast]) for binimetinib |  | Day 1 and Day 15 of Cycle 1, 28 day cycles | 
| PK parameter (Tmax) for binimetinib's active metabolite (AR00426032) |  | Day 1 and Day 15 of Cycle 1, 28 day cycles | 
| PK parameter (Cmax) for AR00426032 |  | Day 1 and Day 15 of Cycle 1, 28 day cycles | 
| PK parameter (Tlast) for AR00426032 |  | Day 1 and Day 15 of Cycle 1, 28 day cycles | 
| PK parameter (AUClast) for AR00426032 |  | Day 1 and Day 15 of Cycle 1, 28 day cycles | 
| PK parameter (Tmax) for encorafenib |  | Day 1 and Day 15 of Cycle 1, 28 day cycles | 
| PK parameter (Cmax) for encorafenib |  | Day 1 and Day 15 of Cycle 1, 28 day cycles | 
| PK parameter (Tlast) for encorafenib |  | Day 1 and Day 15 of Cycle 1, 28 day cycles | 
| PK parameter (AUClast) for encorafenib |  | Day 1 and Day 15 of Cycle 1, 28 day cycles | 
| PK parameter (Tmax) for encorafenib's metabolite (LHY746) |  | Day 1 and Day 15 of Cycle 1, 28 day cycles | 
| PK parameter (Cmax) for LHY746 |  | Day 1 and Day 15 of Cycle 1, 28 day cycles | 
| PK parameter (Tlast) for LHY746 |  | Day 1 and Day 15 of Cycle 1, 28 day cycles | 
| PK parameter (AUClast) for LHY746 |  | Day 1 and Day 15 of Cycle 1, 28 day cycles | 
| PK parameter (trough concentration [Ctrough]) for binimetinib |  | at time zero Day 15 of Cycle 1, 28 day cycles | 
| PK parameter (trough concentration [Ctrough]) for binimetinib |  | at time zero Day 1 of Cycle 2, 28 day cycles | 
| PK parameter (trough concentration [Ctrough]) for binimetinib |  | at time zero Day 1 of Cycle 3, 28 day cycles | 
| PK parameter (Ctrough) for AR00426032 |  | at time zero Day 15 of Cycle 1, 28 day cycles | 
| PK parameter (Ctrough) for AR00426032 |  | at time zero Day 1 of Cycle 2, 28 day cycles | 
| PK parameter (Ctrough) for AR00426032 |  | at time zero Day 1 of Cycle 3, 28 day cycles | 
| PK parameter (Ctrough) for encorafenib |  | at time zero Day 15 of Cycle 1, 28 day cycles | 
| PK parameter (Ctrough) for encorafenib |  | at time zero Day 1 of Cycle 2, 28 day cycles | 
| PK parameter (Ctrough) for encorafenib |  | at time zero Day 1 of Cycle 3, 28 day cycles | 
| PK parameter (Ctrough) for LHY746 |  | at time zero Day 15 of Cycle 1, 28 day cycles | 
| PK parameter (Ctrough) for LHY746 |  | at time zero Day 1 of Cycle 2, 28 day cycles | 
| PK parameter (Ctrough) for LHY746 |  | at time zero Day 1 of Cycle 3, 28 day cycles | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of adverse events (AEs) |  | From informed consent up to 30 days following last dose of study drug | 
| Incidence of dose-limiting toxicities (DLTs) |  | Duration of treatment for safety run-in phase, approximately 6 months, 28 day cycles | 
| Palatability score for the pediatric formulations as assessed by an age-appropriate questionnaire for binimetinib | Five-point Hedonic scale from 1 to 5, 5=really good | Through Cycle 3 Day 1 in patients receiving the pediatric formulations in the Expansion Phase, 28 day cycles | 
| Palatability score for the pediatric formulations as assessed by an age-appropriate questionnaire for encorafenib | Five-point Hedonic scale from 1 to 5, 5=really good | Through Cycle 3 Day 1 in patients receiving the pediatric formulations in the Expansion Phase, 28 day cycles | 
| Objective response rate (ORR) assessed by the investigator, based on Response Criteria Evaluation in Solid Tumors (RECIST) v1.1 |  | Duration of treatment, approximately 6 months, 28 day cycles | 
| Duration of response (DOR) |  | Duration of treatment, approximately 6 months, 28 day cycles | 
| Time to response |  | Duration of treatment, approximately 6 months, 28 day cycles | 
| Progression-free survival (PFS) |  | Duration of treatment, approximately 6 months, 28 day cycles | 
| One-year survival rate |  | From first dose up to 1 year after treatment initiation | 
| Change from baseline bone age and the difference in bone age and chronological age |  | Duration of treatment, approximately 6 months, 28 day cycles | 
| Change from Baseline in bone densitometry based on dual energy X-ray absorptiometry (DEXA) scan. |  | Duration of treatment, approximately 6 months, 28 day cycles | 
| Change from Baseline in calcium-phosphorus product (Ca × P) |  | Duration of treatment, approximately 6 months, 28 day cycles | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adolescent, BRAF V600K, BRAF V600E