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

NCT03878719 | Terminated Phase 1 DMC FDA Drug

• 3 other identifiers: ARRAY-162-115C42210112018-001946-32
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 1

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.

Conditions

Melanoma

Keywords

Adolescent; BRAF V600K; BRAF V600E

Outcome Measures

Primary Outcomes (28)

• 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 Outcomes (12)

• 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

• 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

• 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

Study Arms (2)

Safety Run-in Phase

EXPERIMENTAL

* 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; Drug: encorafenib

Expansion Phase

EXPERIMENTAL

* 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; Drug: encorafenib

Interventions

binimetinib DRUG

taken orally

Expansion Phase; Safety Run-in Phase

encorafenib DRUG

taken orally

Expansion Phase; Safety Run-in Phase

Eligibility Criteria

• Age: 12 Years - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Pfizer: lead
• Pierre Fabre Laboratories: collaborator

Study Sites (1)

Fondazione IRCCS Istituto Nazionale Dei Tumori

Milan, Lombardy, 20133, Italy

Location

Related Links

• To obtain contact information for a study center near you, click here.

MeSH Terms

Conditions

Melanoma

Interventions

binimetinib; encorafenib

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Study Officials

• Pfizer Pfizer CT.gov Call Center

  Pfizer

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 20, 2019
• First Posted: March 18, 2019
• Study Start: August 3, 2020
• Primary Completion: August 19, 2022
• Study Completion: August 19, 2022
• Last Updated: April 3, 2023

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)