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

• ClinicalTrials.gov Identifier: NCT03878719
• Recruitment Status: Terminated
• First Posted: March 18, 2019
• Last Update Posted: April 3, 2023
• Sponsor: Pfizer
• Collaborator: Pierre Fabre Laboratories
• Information provided by (Responsible Party): Pfizer

Tracking Information

• First Submitted Date: February 20, 2019
• First Posted Date: March 18, 2019
• Last Update Posted Date: April 3, 2023
• Actual Study Start Date: August 3, 2020
• Actual Primary Completion Date: August 19, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 15, 2019)

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

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: August 31, 2020)

• Incidence and severity of adverse events (AEs) [ Time Frame: From informed consent up to 30 days following last dose of study drug ]
• Incidence of dose-limiting toxicities (DLTs) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Duration of treatment, approximately 6 months, 28 day cycles ]
• Duration of response (DOR) [ Time Frame: Duration of treatment, approximately 6 months, 28 day cycles ]
• Time to response [ Time Frame: Duration of treatment, approximately 6 months, 28 day cycles ]
• Progression-free survival (PFS) [ Time Frame: Duration of treatment, approximately 6 months, 28 day cycles ]
• One-year survival rate [ Time Frame: From first dose up to 1 year after treatment initiation ]
• Change from baseline bone age and the difference in bone age and chronological age [ Time Frame: Duration of treatment, approximately 6 months, 28 day cycles ]
• Change from Baseline in bone densitometry based on dual energy X-ray absorptiometry (DEXA) scan. [ Time Frame: Duration of treatment, approximately 6 months, 28 day cycles ]
• Change from Baseline in calcium-phosphorus product (Ca × P) [ Time Frame: Duration of treatment, approximately 6 months, 28 day cycles ]

Original Secondary Outcome Measures (submitted: March 15, 2019)

• Incidence and severity of adverse events (AEs) [ Time Frame: From informed consent up to 30 days following last dose of study drug ]
• Incidence of dose-limiting toxicities (DLTs) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Duration of treatment, approximately 6 months, 28 day cycles ]
• Duration of response (DOR) [ Time Frame: Duration of treatment, approximately 6 months, 28 day cycles ]
• Time to response [ Time Frame: Duration of treatment, approximately 6 months, 28 day cycles ]
• Progression-free survival (PFS) [ Time Frame: Duration of treatment, approximately 6 months, 28 day cycles ]
• One-year survival rate [ Time Frame: From first dose up to 1 year after treatment initiation ]
• Change from Baseline in bone densitometry based on dual energy X-ray absorptiometry (DEXA) scan. [ Time Frame: Duration of treatment, approximately 6 months, 28 day cycles ]
• Change from Baseline in calcium-phosphorus product (Ca × P) [ Time Frame: Duration of treatment, approximately 6 months, 28 day cycles ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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.
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Melanoma

Intervention

• Drug: binimetinib
  taken orally
• Drug: encorafenib
  taken orally

Study Arms

• Experimental: Safety Run-in Phase
  • 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.

  Interventions:

  • Drug: binimetinib
  • Drug: encorafenib
• Experimental: Expansion Phase
  • 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.

  Interventions:

  • Drug: binimetinib
  • Drug: encorafenib

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: December 29, 2022): 1
• Original Estimated Enrollment (submitted: March 15, 2019): 18
• Actual Study Completion Date: August 19, 2022
• Actual Primary Completion Date: August 19, 2022 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 12 Years to 17 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Italy
• Removed Location Countries: Australia, Czechia, New Zealand, United States

Administrative Information

• NCT Number: NCT03878719
• Other Study ID Numbers: ARRAY-162-115; C4221011 ( Other Identifier: Alias Study Number ); 2018-001946-32 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No
• Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

• Current Responsible Party: Pfizer
• Original Responsible Party: Array BioPharma
• Current Study Sponsor: Pfizer
• Original Study Sponsor: Array BioPharma
• Collaborators: Pierre Fabre Laboratories

Investigators

• Study Director: Pfizer Pfizer CT.gov Call Center; Pfizer

• PRS Account: Pfizer
• Verification Date: March 2023