Binimetinib in Treating Younger Patients with Progressive or Recurrent Solid Tumors or Low-Grade Gliomas

Inclusion Criteria

• PHASE I: Patients with recurrent, refractory, or progressive non-hematologic malignancies (central nervous system [CNS] or solid tumors) associated with activation of the RAS/RAF/ERK pathway, including any LGG, any tumor in a patient with NF1, or any tumor with a documented activating BRAF, NRAS, or KRAS mutation, will be eligible; LGG is defined as any World Health Organization (WHO) grade I or II (or equivalent) astrocytic, oligodendroglial, and/or glioneuronal tumor
• PHASE II: Patients with recurrent or progressive disease, as defined in the following three strata below, will be eligible; for eligibility determination, tumor imaging from at least two time-points must be available to document radiographic progression or recurrence; patients with non-progressive refractory tumors will not be eligible * Stratum 1: patients with LGG with a BRAF truncated fusion that is measurable in at least two dimensions on imaging * Stratum 2: patients with NF1 and LGG that is measurable in at least two dimensions on imaging * Stratum 3: pediatric patients with a recurrent or progressive tumor thought to involve the Ras/Raf/ERK pathway but not included in strata 1 or 2 that is measurable in at least two dimensions on imaging; this includes any LGG not included in strata 1 or 2 (i.e., any LGG without a BRAF truncated fusion in a patient without NF1), any tumor other than LGG in a patient with NF1, and any other tumor with a documented activating BRAF, NRAS, or KRAS mutation * Stratum 4 (surgical arm, target validation): patients who meet criteria for stratum 1, 2, or 3 for whom tumor biopsy and/or resection is clinically indicated
• PHASE II: Tumor tissue for correlative studies is required for all patients except those with NF1 and LGG (stratum 2) or any patient with optic pathway glioma (stratum 2 or 3), for whom tumor tissue is optional
• PHASE II: Patients must have received at least one prior chemotherapy or radiation regimen prior to progression
• PHASE II: At the time of enrollment, at least 6 weeks must have elapsed since the last dose of any nitrosourea, and the longer of 2 weeks or 3 half-lives must have elapsed since the last dose of any other tumor-directed medication, or biologic therapy
• PHASE II: At least 3 months must have elapsed since the last dose of irradiation to the target tumor(s) at the time of enrollment
• Performance score using the Karnofsky performance scale (patients > 12 years old) or Lansky Play - performance scale (patients =< 12 years old) must be >= 60 assessed within two weeks prior to enrollment
• Within two weeks prior to enrollment: Absolute neutrophil count >= 1,000/mcL
• Within two weeks prior to enrollment: Platelets >= 75,000/mcL and > 7 days since last platelet transfusion
• Within two weeks prior to enrollment: Hemoglobin >= 9 gm/dL and > 7 days since last red blood cell transfusion
• Within two weeks prior to enrollment: Not refractory to red cell or platelet transfusions
• Within two weeks prior to enrollment: Total bilirubin =< 1.5 times the upper limit of normal
• Within two weeks prior to enrollment: Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) and serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 3 times the institutional upper limit of normal
• Within two weeks prior to enrollment: Serum creatinine which is less than 1.5 times the upper limit of institutional normal for age or glomerular filtration rate (GFR) > 70 ml/min/1.73m^2
• Within two weeks prior to enrollment: Corrected QT (QTc) interval =< 450 ms
• Within two weeks prior to enrollment: Left ventricular ejection fraction (LVEF) >= 50% as determined an echocardiogram
• Female patients of childbearing potential must have negative serum or urine pregnancy test within 72 hours of the first dose of MEK162; patient must not be pregnant or breast-feeding; patients of childbearing or child-fathering potential must be willing to use a medically acceptable form of birth control, which includes abstinence, while being treated on this study and for 30 days following cessation of treatment
• Patient must be able to take oral/enteral medication
• Patient, parent, or legal guardian must be able to understand and willing to provide informed consent
• Patients must have recovered from the effects of prior therapy

Exclusion Criteria

• Patients for whom other curative or established standard-of-care therapeutic options with acceptable morbidity exist
• Patients with any significant medical illnesses that in the investigator’s opinion cannot be adequately controlled with appropriate therapy or would compromise the patient’s ability to tolerate this therapy
• History of Gilbert’s syndrome
• Patients receiving any other anticancer or experimental drug therapy
• Use of hematopoietic growth factors within 2 weeks prior to initiation of therapy
• Any other investigational agents within 2 weeks or =< 3 x half-lives (whichever is longer) before start of study therapy
• Patients who have undergone surgery =< 3 weeks or who have not recovered from side effects of this procedure prior to receiving study drug
• Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, impaired gastrointestinal function, or psychiatric illness/social situations that would limit compliance with study requirements
• History or current evidence of retinal vein occlusion (RVO) or predisposing factors to RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes)
• History of retinal degenerative disease
• Prior therapy with a MEK inhibitor
• Impairment of gastrointestinal function (e.g., active ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome)
• Patients who have a neuromuscular disorder that is associated with elevated creatine kinase (CK) (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy)
• Patients with uncontrolled hypertension