A Study of Binimetinib and Encorafenib in Advanced BRAF Mutant Cancers

A Phase I/II Study of Binimetinib With Encorafenib in Patients With Non-V600 Activating BRAF Mutant Advanced Malignancies

The goal of this trial is to test the safety and efficacy of an innovative combination aimed to more profoundly inhibit ERK signaling in tumors.

Study Overview

• Status: Completed
• Conditions: Advanced BRAF Mutant Cancers
• Intervention / Treatment: Drug: Binimetinib; Drug: Encorafenib

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • New Jersey
    • Middletown, New Jersey, United States, 07748
      • Memorial Sloan Kettering Monmouth (Limited Protocol Activities)
  • New York
    • Commack, New York, United States, 11725
      • Memorial Sloan Kettering Cancer Center @ Suffolk (Limited protocol activity)
    • Harrison, New York, United States, 10604
      • Memorial Sloan Kettering Westchester (Limited Protocol Activities)
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patient has signed the Informed Consent (ICF) prior to any screening procedures being performed and is able to comply with protocol requirements
• Age ≥ 18 years at the time of informed consent
• Metastatic or advanced-stage malignant tumors confirmed histologically for whom no standard therapy is considered to be appropriate by the investigator
• Patients must have at least one other lesion that is measurable by RECIST criteria.
• Patient's tumor must harbor an activating BRAF mutation (listed in Table 4 or approved by the study Principal Investigator) or a fusion involving the kinase domain of BRAF

• Mechanistically validated activating non-V600 BRAF mutants

  • P367L/S
  • G464V/E
  • G469A/V/R
  • L485W
  • N486_A489delinsK
  • N486_P490del
  • E586K
  • L597Q/V/S
  • T599TT/TS
  • T599I/K
  • V600_K601delinsE
  • K601E/N/T
  • K601_S602delinsNT
  • BRAF kinase duplication
  • Fusions involving BRAF kinase domain
• Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2

• Adequate bone marrow, organ function and laboratory parameters:

  • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
  • Hemoglobin (Hgb) ≥ 8 g/dL with or without transfusions
  • Platelets (PLT) ≥ 75 x 109/L without transfusions
  • AST and/or ALT ≤ 2.5 × upper limit of normal (ULN); patient with liver metastases ≤ 5 ×ULN
  • Total bilirubin ≤ 1.5 × ULN and < 2 mg/dL (Note: Patients who have a total bilirubin level > 1.5 x ULN will be allowed if their indirect bilirubin level is ≤ 1.5 x ULN)
  • Serum Creatinine ≤ 1.5 x ULN, or calculated creatinine clearance (determined as per Cockcroft-Gault) ≥ 50 mL/min at screening

• Adequate cardiac function:

  • left ventricular ejection fraction (LVEF) ≥ 50% as determined by a multigated acquisition (MUGA) scan or echocardiogram
  • QTc interval ≤ 480 ms (preferably the mean from triplicate ECGs)
• Able to take oral medications
• Patient is deemed by the Investigator to have the initiative and means to be compliant with the protocol (treatment and follow-up)
• Female patients are either postmenopausal for at least 1 year, are surgically sterile for at least 6 weeks, or must agree to take appropriate precautions to avoid pregnancy from screening through 30 days after the last dose of study drug/treatmentif of childbearing potential (Note: Permitted contraception methods listed in Section 9.3 should be communicated to the patients and their understanding confirmed. For females of childbearing potential, the pregnancy test result must be negative at screening.)
• Males must agree to take appropriate precautions to avoid fathering a child from screening through 90 days following the end of therapy. (Note: Permitted contraception methods listed in Section 9.3 should be communicated to the patients and their understanding confirmed.)

Exclusion Criteria:

• Any symptomatic brain metastasis (Note: Patients previously treated or untreated for this condition who are asymptomatic in the absence of corticosteroid and antiepileptic therapy are allowed. Brain metastases must be stable for ≥ 4 weeks, with imaging (e.g., magnetic resonance imaging [MRI] or computed tomography [CT]) demonstrating no current evidence of progressive brain metastases at screening.)
• History or current evidence of retinal vein occlusion (RVO) or current risk factors to RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes); history of retinal degenerative disease
• Leptomeningeal disease
• Previous or concurrent malignancy within 2 years of study entry, with the following exceptions: adequately treated basal or squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in-situ of the cervix, early stage breast cancer, or other noninvasive or indolent malignancy

• Impaired cardiovascular function or clinically significant cardiovascular diseases, 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 (i.e. Grade 2 or higher), 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
• Uncontrolled hypertension defined as persistent elevation of systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg, despite current therapy.
• Known positive serology for HIV (Human Immunodeficiency Virus), active hepatitis B, and/or active hepatitis C infection
• Impaired GI function or disease that may significantly alter the absorption of encorafenib or binimetinib (e.g., ulcerative diseases, uncontrolled vomiting, malabsorption syndrome, small bowel resection with decreased intestinal absorption)
• History of thromboembolic or cerebrovascular events ≤ 12 weeks prior to the first dose of study treatment. Examples include transient ischemic attacks, cerebrovascular accidents, hemodynamically significant (i.e. massive or sub-massive) deep vein thrombosis or pulmonary emboli.

Note: Patients with either deep vein thrombosis or pulmonary emboli that does not result in hemodynamic instability are allowed to enroll as long as they are on a stable dose of anticoagulants for at least 4 weeks. Note: Patients with thromboembolic events related to indwelling catheters or other procedures may be enrolled.Concurrent neuromuscular disorder that is associated with the potential of elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy).

• Any other condition that would, in the Investigator's judgement, contraindicate the patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures, e.g., infection/inflammation, intestinal obstruction, unable to swallow medications, social/psychological issues, etc.
• Patients who have undergone surgery ≤ 3 weeks prior to starting study drug or who have not yet recovered from side effects of such procedure
• Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test
• Medical, psychiatric, cognitive, or other conditions that may compromise the patient's ability to understand the patient information, give informed consent, comply with the study protocol or complete the study
• Prior treatment with any RAF, MEK, or ERK inhibitors (such as vemurafenib, dabrafenib, encorafenib; trametinib, cobimetinib, binimetinib, selumetinib; or BVD-523, respectively)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Binimetinib and Encorafenib; Patients will be initially enrolled to the approved dose of encorafenib 450 mg oral QD and binimetinib 45 mg PO BID, dose level 1. If confirmed this dose level is safely tolerated in the study population, we will then escalate treatment to dose level 2 with the novel dosing regimen of encorafenib 450 mg oral QD continuous and binimetinib 60 mg oral BID 21 days on/7 days off.

Drug: Binimetinib; Dose level 1 binimetinib 45 mg PO BID. Dose level 2 binimetinib 60 mg oral BID; Other Names: MEK162 or ARRY-438162; Drug: Encorafenib; encorafenib 450 mg oral QD; Other Names: LGX818

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
dose-limiting toxicities (DLTs)	National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 5,	1 year
objective response rate (Phase II)	Per RECIST Version 1.1	1 year

Collaborators and Investigators

• Sponsor: Memorial Sloan Kettering Cancer Center
• Collaborators: Array BioPharma
• Investigators: Principal Investigator: Rona Yaegar, MD, Memorial Sloan Kettering Cancer Center

Publications and helpful links

General Publications

• Rajkumar S, Berry D, Heney KA, Strong C, Ramsay L, Lajoie M, Alkallas R, Nguyen TT, Thomson C, Ahanfeshar-Adams M, Dankner M, Petrella T, Rose AAN, Siegel PM, Watson IR. Melanomas with concurrent BRAF non-p.V600 and NF1 loss-of-function mutations are targetable by BRAF/MEK inhibitor combination therapy. Cell Rep. 2022 Apr 5;39(1):110634. doi: 10.1016/j.celrep.2022.110634.

Helpful Links

• Memorial Sloan Kettering Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): February 14, 2019
• Primary Completion (Actual): September 2, 2023
• Study Completion (Actual): September 2, 2023

Study Registration Dates

• First Submitted: February 15, 2019
• First Submitted That Met QC Criteria: February 15, 2019
• First Posted (Actual): February 18, 2019

Study Record Updates

• Last Update Posted (Actual): September 6, 2023
• Last Update Submitted That Met QC Criteria: September 5, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Encorafenib; Binimetinib; 18-547
• Other Study ID Numbers: 18-547

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months post publication. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.
• IPD Sharing Supporting Information Type: SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No