Melanoma
Conditions
Keywords
Adolescent, BRAF V600K, BRAF V600E
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.
Interventions
DRUGbinimetinib
taken orally
DRUGencorafenib
taken orally
Sponsors
Pierre Fabre Laboratories
Pfizer
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to 17 Years
Healthy volunteers
No
Inclusion 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| PK parameter (Ctrough) for LHY746 | at time zero 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 (Ctrough) for AR00426032 | at time zero Day 15 of Cycle 1, 28 day cycles |
| PK parameter (Ctrough) for encorafenib | at time zero Day 15 of Cycle 1, 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 (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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | — |
| 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 | 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 |
| 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 | — |
| 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 | — |
| Duration of response (DOR) | Duration of treatment, approximately 6 months, 28 day cycles | — |
Countries
Italy
Outcome results
None listed