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A Study of Binimetinib and Encorafenib in Advanced BRAF Mutant Cancers

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03843775
Recruitment Status : Recruiting
First Posted : February 18, 2019
Last Update Posted : June 18, 2020
Sponsor:
Collaborator:
Array BioPharma
Information provided by (Responsible Party):
Memorial Sloan Kettering Cancer Center

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.

Condition or disease Intervention/treatment Phase
Advanced BRAF Mutant Cancers Drug: Binimetinib Drug: Encorafenib Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 38 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: 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.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Study of Binimetinib With Encorafenib in Patients With Non-V600 Activating BRAF Mutant Advanced Malignancies
Actual Study Start Date : February 14, 2019
Estimated Primary Completion Date : February 2022
Estimated Study Completion Date : February 2022

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 Name: MEK162 or ARRY-438162

Drug: Encorafenib
encorafenib 450 mg oral QD
Other Name: LGX818




Primary Outcome Measures :
  1. dose-limiting toxicities (DLTs) [ Time Frame: 1 year ]
    National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 5,

  2. objective response rate (Phase II) [ Time Frame: 1 year ]
    Per RECIST Version 1.1



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:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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)

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): NCT03843775


Contacts
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Contact: Rona Yaegar, MD 646-888-5109 yaegerr@mskcc.org
Contact: Alison Schram, MD 646-888-5388

Locations
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United States, New Jersey
Memorial Sloan Kettering Monmouth Recruiting
Middletown, New Jersey, United States, 07748
Contact: Rona Yaeger, MD    646-888-5109      
United States, New York
Memoral Sloan Kettering Westchester Recruiting
Harrison, New York, United States, 10604
Contact: Rona Yaeger, MD    646-888-5109      
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Rona Yaeger, MD    646-888-4179      
Contact: Alison Schram, MD    646-888-5388      
Principal Investigator: Rona Yaeger, MD         
Sponsors and Collaborators
Memorial Sloan Kettering Cancer Center
Array BioPharma
Investigators
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Principal Investigator: Rona Yaegar, MD Memorial Sloan Kettering Cancer Center
Additional Information:
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Responsible Party: Memorial Sloan Kettering Cancer Center
ClinicalTrials.gov Identifier: NCT03843775    
Other Study ID Numbers: 18-547
First Posted: February 18, 2019    Key Record Dates
Last Update Posted: June 18, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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.
Supporting Materials: Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)

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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 Memorial Sloan Kettering Cancer Center:
Binimetinib
Encorafenib
18-547