Clinical Trials /

A Study of Binimetinib and Encorafenib in Advanced BRAF Mutant Cancers

NCT03843775

Description:

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.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study of Binimetinib and Encorafenib in Advanced BRAF Mutant Cancers
  • Official Title: A Phase I/II Study of Binimetinib With Encorafenib in Patients With Non-V600 Activating BRAF Mutant Advanced Malignancies

Clinical Trial IDs

  • ORG STUDY ID: 18-547
  • NCT ID: NCT03843775

Conditions

  • Advanced BRAF Mutant Cancers

Interventions

DrugSynonymsArms
BinimetinibMEK162 or ARRY-438162Binimetinib and Encorafenib
EncorafenibLGX818Binimetinib and Encorafenib

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Binimetinib and EncorafenibExperimentalPatients 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.
  • Binimetinib
  • Encorafenib

Eligibility 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 a lesion that can be safely biopsied and 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)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:dose-limiting toxicities (DLTs)
Time Frame:1 year
Safety Issue:
Description:National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 5,

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Memorial Sloan Kettering Cancer Center

Trial Keywords

  • Binimetinib
  • Encorafenib
  • 18-547

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