Study of the Combination of Binimetinib and Encorafenib in Adolescent Patients With Unresectable or Metastatic BRAF V600-mutant Melanoma
- Registration Number
- NCT03878719
- Lead Sponsor
- Pfizer
- Brief 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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 1
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
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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Safety Run-in Phase binimetinib * 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. Safety Run-in Phase encorafenib * 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. Expansion Phase encorafenib * 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. Expansion Phase binimetinib * 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.
- Primary Outcome Measures
Name Time Method PK parameter (Tlast) for AR00426032 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 (trough concentration [Ctrough]) for binimetinib at time zero Day 1 of Cycle 3, 28 day cycles PK parameter (Cmax) 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 (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 (AUClast) for LHY746 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 (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 encorafenib Day 1 and Day 15 of Cycle 1, 28 day cycles PK parameter (Ctrough) for LHY746 at time zero Day 1 of Cycle 3, 28 day cycles 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 (time of last PK sample [Tlast]) for binimetinib 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 (AUClast) 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 (Ctrough) for encorafenib at time zero Day 1 of Cycle 3, 28 day cycles PK parameter (Ctrough) for AR00426032 at time zero Day 1 of Cycle 3, 28 day cycles
- Secondary Outcome Measures
Name Time Method Duration of response (DOR) Duration of treatment, approximately 6 months, 28 day cycles One-year survival rate From first dose up to 1 year after treatment initiation Palatability score for the pediatric formulations as assessed by an age-appropriate questionnaire for binimetinib Through Cycle 3 Day 1 in patients receiving the pediatric formulations in the Expansion Phase, 28 day cycles Five-point Hedonic scale from 1 to 5, 5=really good
Palatability score for the pediatric formulations as assessed by an age-appropriate questionnaire for encorafenib Through Cycle 3 Day 1 in patients receiving the pediatric formulations in the Expansion Phase, 28 day cycles Five-point Hedonic scale from 1 to 5, 5=really good
Change from baseline bone age and the difference in bone age and chronological age Duration of treatment, approximately 6 months, 28 day cycles 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 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 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 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
Trial Locations
- Locations (1)
Fondazione IRCCS Istituto Nazionale Dei Tumori
🇮🇹Milan, Lombardy, Italy