Study of MEK162 for Children With Low-Grade Gliomas

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.
• Tumor tissue for correlative studies must be available 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.
• Patients must have received at least one prior chemotherapy or radiation regimen prior to progression.
• 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.
• At least 3 months must have elapsed since the last dose of irradiation to the target tumor(s) at the time of enrollment.
• Patients must be >1 year and 12 years old) or Lansky Play - Performance Scale (patients ≤ 12 years old) must be ≥ 60 assessed within two weeks prior to enrollment.
• Participants must have normal organ and marrow function as defined below within two weeks prior to enrollment:
• Absolute neutrophil count > 1,000/mcL
• Platelets > 75, 000/mcL and > 7 days since last platelet transfusion. Hemoglobin > 9 gm/dL and > 7 days since last red blood cell transfusion
• Not refractory to red cell or platelet transfusions
• Hepatic: Total bilirubin ≤ 1.5 times the upper limit of normal; SGPT (ALT) and SGOT (AST) 70 ml/min/1.73m2
• QTc interval 50% as determined by 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 with any of the following characteristics will not be eligible:

• 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 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