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

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ClinicalTrials.gov Identifier: NCT03878719
Recruitment Status : Recruiting
First Posted : March 18, 2019
Last Update Posted : January 7, 2021
Sponsor:
Collaborator:
Pierre Fabre Laboratories
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Melanoma Drug: binimetinib Drug: encorafenib Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : August 13, 2020
Estimated Primary Completion Date : March 20, 2023
Estimated Study Completion Date : September 5, 2025

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Melanoma
MedlinePlus related topics: Melanoma

Arm Intervention/treatment
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.

Drug: binimetinib
taken orally

Drug: encorafenib
taken orally

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.

Drug: binimetinib
taken orally

Drug: encorafenib
taken orally




Primary Outcome Measures :
  1. 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 ]
  2. PK parameter (Cmax) for binimetinib [ Time Frame: Day 1 and Day 15 of Cycle 1, 28 day cycles ]
  3. PK parameter (time of last PK sample [Tlast]) for binimetinib [ Time Frame: Day 1 and Day 15 of Cycle 1, 28 day cycles ]
  4. 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 ]
  5. PK parameter (Tmax) for binimetinib's active metabolite (AR00426032) [ Time Frame: Day 1 and Day 15 of Cycle 1, 28 day cycles ]
  6. PK parameter (Cmax) for AR00426032 [ Time Frame: Day 1 and Day 15 of Cycle 1, 28 day cycles ]
  7. PK parameter (Tlast) for AR00426032 [ Time Frame: Day 1 and Day 15 of Cycle 1, 28 day cycles ]
  8. PK parameter (AUClast) for AR00426032 [ Time Frame: Day 1 and Day 15 of Cycle 1, 28 day cycles ]
  9. PK parameter (Tmax) for encorafenib [ Time Frame: Day 1 and Day 15 of Cycle 1, 28 day cycles ]
  10. PK parameter (Cmax) for encorafenib [ Time Frame: Day 1 and Day 15 of Cycle 1, 28 day cycles ]
  11. PK parameter (Tlast) for encorafenib [ Time Frame: Day 1 and Day 15 of Cycle 1, 28 day cycles ]
  12. PK parameter (AUClast) for encorafenib [ Time Frame: Day 1 and Day 15 of Cycle 1, 28 day cycles ]
  13. PK parameter (Tmax) for encorafenib's metabolite (LHY746) [ Time Frame: Day 1 and Day 15 of Cycle 1, 28 day cycles ]
  14. PK parameter (Cmax) for LHY746 [ Time Frame: Day 1 and Day 15 of Cycle 1, 28 day cycles ]
  15. PK parameter (Tlast) for LHY746 [ Time Frame: Day 1 and Day 15 of Cycle 1, 28 day cycles ]
  16. PK parameter (AUClast) for LHY746 [ Time Frame: Day 1 and Day 15 of Cycle 1, 28 day cycles ]
  17. PK parameter (trough concentration [Ctrough]) for binimetinib [ Time Frame: at time zero Day 15 of Cycle 1, 28 day cycles ]
  18. PK parameter (trough concentration [Ctrough]) for binimetinib [ Time Frame: at time zero Day 1 of Cycle 2, 28 day cycles ]
  19. PK parameter (trough concentration [Ctrough]) for binimetinib [ Time Frame: at time zero Day 1 of Cycle 3, 28 day cycles ]
  20. PK parameter (Ctrough) for AR00426032 [ Time Frame: at time zero Day 15 of Cycle 1, 28 day cycles ]
  21. PK parameter (Ctrough) for AR00426032 [ Time Frame: at time zero Day 1 of Cycle 2, 28 day cycles ]
  22. PK parameter (Ctrough) for AR00426032 [ Time Frame: at time zero Day 1 of Cycle 3, 28 day cycles ]
  23. PK parameter (Ctrough) for encorafenib [ Time Frame: at time zero Day 15 of Cycle 1, 28 day cycles ]
  24. PK parameter (Ctrough) for encorafenib [ Time Frame: at time zero Day 1 of Cycle 2, 28 day cycles ]
  25. PK parameter (Ctrough) for encorafenib [ Time Frame: at time zero Day 1 of Cycle 3, 28 day cycles ]
  26. PK parameter (Ctrough) for LHY746 [ Time Frame: at time zero Day 15 of Cycle 1, 28 day cycles ]
  27. PK parameter (Ctrough) for LHY746 [ Time Frame: at time zero Day 1 of Cycle 2, 28 day cycles ]
  28. PK parameter (Ctrough) for LHY746 [ Time Frame: at time zero Day 1 of Cycle 3, 28 day cycles ]

Secondary Outcome Measures :
  1. Incidence and severity of adverse events (AEs) [ Time Frame: From informed consent up to 30 days following last dose of study drug ]
  2. Incidence of dose-limiting toxicities (DLTs) [ Time Frame: Duration of treatment for safety run-in phase, approximately 6 months, 28 day cycles ]
  3. 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

  4. 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

  5. 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 ]
  6. Duration of response (DOR) [ Time Frame: Duration of treatment, approximately 6 months, 28 day cycles ]
  7. Time to response [ Time Frame: Duration of treatment, approximately 6 months, 28 day cycles ]
  8. Progression-free survival (PFS) [ Time Frame: Duration of treatment, approximately 6 months, 28 day cycles ]
  9. One-year survival rate [ Time Frame: From first dose up to 1 year after treatment initiation ]
  10. 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 ]
  11. 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 ]
  12. Change from Baseline in calcium-phosphorus product (Ca × P) [ Time Frame: Duration of treatment, approximately 6 months, 28 day cycles ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   12 Years to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03878719


Contacts
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Contact: Pfizer Pfizer CT.gov Call Center 1-800-718-1021 ClinicalTrials.gov_Inquiries@pfizer.com

Locations
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United States, Pennsylvania
UPMC Children's Hospital of Pittsburgh Recruiting
Pittsburgh, Pennsylvania, United States, 15224
Czechia
Sanatorium profesora Arenbergera Recruiting
Praha 1, Czechia, 11000
Italy
Fondazione IRCCS Istituto Nazionale Dei Tumori Recruiting
Milan, Lombardy, Italy, 20133
Azienda Ospedaliera Universitaria Senese, U.O.C. Immunoterapia Oncologica Recruiting
Siena, Toscana, Italy, 53100
AOU Citta della Salute e della Scienza- Presidio Ospedaliero Infantile Regina Margherita Not yet recruiting
Torino, Turin, Italy, 10126
Istituto Nazionale per lo studio e la Cura dei tumori Fondazione Senatore Pascale Not yet recruiting
Napoli, Italy, 80131
New Zealand
Capital and Coast District Health Board Recruiting
Wellington, New Zealand, 6021
Sponsors and Collaborators
Pfizer
Pierre Fabre Laboratories
Investigators
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Study Director: Pfizer Pfizer CT.gov Call Center Pfizer
Additional Information:
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Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT03878719    
Other Study ID Numbers: ARRAY-162-115
C4221011 ( Other Identifier: Alias Study Number )
First Posted: March 18, 2019    Key Record Dates
Last Update Posted: January 7, 2021
Last Verified: January 2021
Individual Participant Data (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.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Pfizer:
Adolescent
BRAF V600K
BRAF V600E
Additional relevant MeSH terms:
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Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas