Clinical trial NCT03878719: Study of the Combination of Binimetinib and Encorafenib in Adolescent Patients With Unresectable or Metastatic BRAF V600-mutant Melanoma
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Melanoma
Keywords: Adolescent
BRAF V600K
BRAF V600E
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
Collaborators: name: Pierre Fabre Laboratories
First posted: 2019-03-18
Enrollment: 1
Sex: ALL
Minimum age (years): 12
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility 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.

Primary outcomes:
measure: Pharmacokinetic (PK) parameter (time to reach the maximum observed plasma concentration Cmax [Tmax]) for binimetinib
timeFrame: Day 1 and Day 15 of Cycle 1, 28 day cycles
measure: PK parameter (Cmax) for binimetinib
timeFrame: Day 1 and Day 15 of Cycle 1, 28 day cycles
measure: PK parameter (time of last PK sample [Tlast]) for binimetinib
timeFrame: Day 1 and Day 15 of Cycle 1, 28 day cycles
measure: PK parameter (area under the plasma concentration-time curve from time zero to Tlast [AUClast]) for binimetinib
timeFrame: Day 1 and Day 15 of Cycle 1, 28 day cycles
measure: PK parameter (Tmax) for binimetinib's active metabolite (AR00426032)
timeFrame: Day 1 and Day 15 of Cycle 1, 28 day cycles
measure: PK parameter (Cmax) for AR00426032
timeFrame: Day 1 and Day 15 of Cycle 1, 28 day cycles
measure: PK parameter (Tlast) for AR00426032
timeFrame: Day 1 and Day 15 of Cycle 1, 28 day cycles
measure: PK parameter (AUClast) for AR00426032
timeFrame: Day 1 and Day 15 of Cycle 1, 28 day cycles
measure: PK parameter (Tmax) for encorafenib
timeFrame: Day 1 and Day 15 of Cycle 1, 28 day cycles
measure: PK parameter (Cmax) for encorafenib
timeFrame: Day 1 and Day 15 of Cycle 1, 28 day cycles
measure: PK parameter (Tlast) for encorafenib
timeFrame: Day 1 and Day 15 of Cycle 1, 28 day cycles
measure: PK parameter (AUClast) for encorafenib
timeFrame: Day 1 and Day 15 of Cycle 1, 28 day cycles
measure: PK parameter (Tmax) for encorafenib's metabolite (LHY746)
timeFrame: Day 1 and Day 15 of Cycle 1, 28 day cycles
measure: PK parameter (Cmax) for LHY746
timeFrame: Day 1 and Day 15 of Cycle 1, 28 day cycles
measure: PK parameter (Tlast) for LHY746
timeFrame: Day 1 and Day 15 of Cycle 1, 28 day cycles
measure: PK parameter (AUClast) for LHY746
timeFrame: Day 1 and Day 15 of Cycle 1, 28 day cycles
measure: PK parameter (trough concentration [Ctrough]) for binimetinib
timeFrame: at time zero Day 15 of Cycle 1, 28 day cycles
measure: PK parameter (trough concentration [Ctrough]) for binimetinib
timeFrame: at time zero Day 1 of Cycle 2, 28 day cycles
measure: PK parameter (trough concentration [Ctrough]) for binimetinib
timeFrame: at time zero Day 1 of Cycle 3, 28 day cycles
measure: PK parameter (Ctrough) for AR00426032
timeFrame: at time zero Day 15 of Cycle 1, 28 day cycles
measure: PK parameter (Ctrough) for AR00426032
timeFrame: at time zero Day 1 of Cycle 2, 28 day cycles
measure: PK parameter (Ctrough) for AR00426032
timeFrame: at time zero Day 1 of Cycle 3, 28 day cycles
measure: PK parameter (Ctrough) for encorafenib
timeFrame: at time zero Day 15 of Cycle 1, 28 day cycles
measure: PK parameter (Ctrough) for encorafenib
timeFrame: at time zero Day 1 of Cycle 2, 28 day cycles
measure: PK parameter (Ctrough) for encorafenib
timeFrame: at time zero Day 1 of Cycle 3, 28 day cycles
measure: PK parameter (Ctrough) for LHY746
timeFrame: at time zero Day 15 of Cycle 1, 28 day cycles
measure: PK parameter (Ctrough) for LHY746
timeFrame: at time zero Day 1 of Cycle 2, 28 day cycles
measure: PK parameter (Ctrough) for LHY746
timeFrame: at time zero Day 1 of Cycle 3, 28 day cycles
Secondary outcomes:
measure: Incidence and severity of adverse events (AEs)
timeFrame: From informed consent up to 30 days following last dose of study drug
measure: Incidence of dose-limiting toxicities (DLTs)
timeFrame: Duration of treatment for safety run-in phase, approximately 6 months, 28 day cycles
measure: Palatability score for the pediatric formulations as assessed by an age-appropriate questionnaire for binimetinib
timeFrame: Through Cycle 3 Day 1 in patients receiving the pediatric formulations in the Expansion Phase, 28 day cycles
measure: Palatability score for the pediatric formulations as assessed by an age-appropriate questionnaire for encorafenib
timeFrame: Through Cycle 3 Day 1 in patients receiving the pediatric formulations in the Expansion Phase, 28 day cycles
measure: Objective response rate (ORR) assessed by the investigator, based on Response Criteria Evaluation in Solid Tumors (RECIST) v1.1
timeFrame: Duration of treatment, approximately 6 months, 28 day cycles
measure: Duration of response (DOR)
timeFrame: Duration of treatment, approximately 6 months, 28 day cycles
measure: Time to response
timeFrame: Duration of treatment, approximately 6 months, 28 day cycles
measure: Progression-free survival (PFS)
timeFrame: Duration of treatment, approximately 6 months, 28 day cycles
measure: One-year survival rate
timeFrame: From first dose up to 1 year after treatment initiation
measure: Change from baseline bone age and the difference in bone age and chronological age
timeFrame: Duration of treatment, approximately 6 months, 28 day cycles
measure: Change from Baseline in bone densitometry based on dual energy X-ray absorptiometry (DEXA) scan.
timeFrame: Duration of treatment, approximately 6 months, 28 day cycles
measure: Change from Baseline in calcium-phosphorus product (Ca × P)
timeFrame: Duration of treatment, approximately 6 months, 28 day cycles
Other outcomes:
Locations:
city: Milan
country: Italy
facility: Fondazione IRCCS Istituto Nazionale Dei Tumori
state: Lombardy
Study officials:
affiliation: Pfizer
name: Pfizer Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References: