A Study of Binimetinib and Encorafenib in Advanced BRAF Mutant Cancers

NCT03843775 | Completed Phase 1 Results FDA Drug

• 1 other identifier: 18-547
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 4

Brief Summary

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.

Conditions

Advanced BRAF Mutant Cancers

Keywords

Binimetinib; Encorafenib; 18-547

Outcome Measures

Primary Outcomes (2)

• 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

Study Arms (1)

Binimetinib and Encorafenib

EXPERIMENTAL

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; Drug: Encorafenib

Interventions

Binimetinib DRUG

Dose level 1 binimetinib 45 mg PO BID. Dose level 2 binimetinib 60 mg oral BID

Also known as: MEK162 or ARRY-438162

Binimetinib and Encorafenib

Encorafenib DRUG

encorafenib 450 mg oral QD

Also known as: LGX818

Binimetinib and Encorafenib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Memorial Sloan Kettering Cancer Center: lead
• Array BioPharma: collaborator

Study Sites (4)

Memorial Sloan Kettering Monmouth (Limited Protocol Activities)

Middletown, New Jersey, 07748, United States

Location

Memorial Sloan Kettering Cancer Center @ Suffolk (Limited protocol activity)

Commack, New York, 11725, United States

Location

Memorial Sloan Kettering Westchester (Limited Protocol Activities)

Harrison, New York, 10604, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Related Publications (1)

• 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.

  PMID: 35385748 DERIVED

Related Links

• Memorial Sloan Kettering Cancer Center

MeSH Terms

Interventions

binimetinib; encorafenib

Results Point of Contact

• Title: Dr. Rona Yaeger MD
• Organization: Memorial Sloan Kettering Cancer Center

yaegerr@mskcc.org

646-888-5109

Study Officials

• Rona Yaegar, MD

  Memorial Sloan Kettering Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

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

Model Details: This phase I/II study consists of a Phase I part followed by an efficacy analysis (Phase II) of the dosing schedule deemed safe in patients with advanced cancer with activating non-V600 BRAF mutant tumors. As patients in the phase I part of the start will start at the lower dose level 1, they will not be included in the stage one efficacy cohort.

Study Record Dates

• First Submitted: February 15, 2019
• First Posted: February 18, 2019
• Study Start: February 14, 2019
• Primary Completion: September 2, 2023
• Study Completion: September 2, 2023
• Last Updated: October 21, 2024
• Results First Posted: October 21, 2024

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: SAP, ICF

Locations

US (4)