A Study of the Drugs Selumetinib vs. Carboplatin and Vincristine in Patients With Low-Grade Glioma

Inclusion Criteria:

• Patients must be >= 2 years and =< 21 years at the time of enrollment

• Patients must have a body surface area (BSA) of >= 0.5 m^2 at enrollment

• Patients must have non-neurofibromatosis type 1 (non-NF1) low-grade glioma (LGG)without a BRAFV600E mutation as confirmed by Rapid Central Pathology and MolecularScreening Reviews performed on APEC14B1 (NCT02402244) Childhood Cancer DataInitiative (CCDI)-MCI, or accepted Clinical Laboratory Improvement Amendments (CLIA)-certified test and that has not been treated with any modality besidessurgery. Note: Patients may be newly-diagnosed OR previously diagnosed, and there isno required time frame between biopsy/surgery and treatment initiation.

• Patients with residual tumor after resection or progressive tumor after initialdiagnosis (with or without surgery) who have not received treatment (chemotherapy and/or radiation) are eligible

• Patients must have two-dimensional measurable tumor >= 1 cm^2 to be eligible

• Patients with ependymoma are not eligible

• Eligible histologies will include all tumors considered low-grade glioma orlow-grade astrocytoma (World Health Organization [WHO] grade I and II) by 5thedition WHO classification of central nervous system (CNS) tumors with the exceptionof subependymal giant cell astrocytoma

• Patients with metastatic disease or multiple independent primary LGG are eligible

• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70mL/min/1.73 m^2 OR a serum creatinine based on age/sex as follows (performed within 7 days prior to enrollment):

• Age: Maximum Serum Creatinine (mg/dL)

• 2 to < 6 years: 0.8 mg/dL (male); 0.8 mg/dL (female)

• 6 to < 10 years: 1 mg/dL (male); 1 mg/dL (female)

• 10 to < 13 years: 1.2 mg/dL (male); 1.2 mg/dL (female)

• 13 to < 16 years: 1.5 mg/dL (male); 1.4 mg/dL (female)

• >= 16 years: 1.7 mg/dL (male); 1.4 mg/dL (female)

• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (performed within 7days prior to enrollment) (children with a diagnosis of Gilbert's syndrome will beallowed on study regardless of their total and indirect [unconjugated] bilirubinlevels as long as their direct [conjugated] bilirubin is < 3.1 mg/dL)

• Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135U/L (performed within 7 days prior to enrollment). For the purpose of this study,the ULN for SGPT is 45 U/L

• Albumin >= 2 g/dL (performed within 7 days prior to enrollment)

• Left ventricular ejection fraction (LVEF) >= 53% (or institutional normal; if theLVEF result is given as a range of values, then the upper value of the range will beused) by echocardiogram (performed within 4 weeks prior to enrollment)

• Corrected QT (QTc) interval =< 450 msec by electrocardiography (EKG) (performedwithin 4 weeks prior to enrollment)

• Absolute neutrophil count >= 1,000/uL (unsupported) (performed within 7 days priorto enrollment)

• Platelets >= 100,000/uL (unsupported) (performed within 7 days prior to enrollment)

• Hemoglobin >= 8 g/dL (may be supported) (performed within 7 days prior toenrollment)

• Patients with a known seizure disorder must be stable and must not have experienceda significant increase in seizure frequency within 2 weeks prior to enrollment

• Patients 2-17 years of age must have a blood pressure that is =< 95th percentile forage, height, and sex at the time of enrollment (with or without the use ofanti-hypertensive medications)

• Patients >= 18 years of age must have a blood pressure =< 130/80 mmHg at the time ofenrollment (with or without the use of anti-hypertensive medications)

• Note for patients of all ages: Adequate blood pressure can be achieved usingmedication for the treatment of hypertension

• All patients must have ophthalmology toxicity assessments performed within 8 weeksprior to enrollment

• For all patients, a magnetic resonance imaging (MRI) of the brain (with orbital cutsfor optic pathway tumors) and/or spine (depending on the site(s) of primary disease)with and without contrast must be performed within 8 weeks prior to enrollment

• Patients must have a performance status corresponding to Eastern CooperativeOncology Group (ECOG) scores of 0, 1, or 2. Use Karnofsky for patients > 16 years ofage and Lansky for patients =< 16 years of age

• Patients must have the ability to swallow whole capsules

• All patients have signed an appropriate consent form and Health InsurancePortability and Accountability Act (HIPAA) authorization form (if applicable)

• All patients and/or their parents or legal guardians must sign a written informedconsent

• All patients have been consented and enrolled on APEC14B1 (NCT02402244) followed byenrollment on the ACNS1833 Pre-Enrollment Eligibility Screening (Step 0) on the sameday to complete the Rapid Central Review

• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Exclusion Criteria:

• Patients must not have received any prior tumor-directed therapy includingchemotherapy, radiation therapy, immunotherapy, or bone marrow transplant. Priorsurgical intervention (with the exclusion of laser interstitial thermal therapy [LITT]) is permitted

• Patients with a concurrent malignancy or history of treatment (other than surgery)for another tumor within the last year are ineligible

• Patients with diffuse intrinsic pontine tumors as seen on MRI (> 2/3 of ponsinvolvement on imaging) are not eligible even if biopsy reveals grade I/II histology

• Patients may not be receiving any other investigational agents

• Patients with any serious medical or psychiatric illness/condition, includingsubstance use disorders or ophthalmological conditions, likely in the judgment ofthe investigator to interfere or limit compliance with study requirements/treatment

• Patients who, in the opinion of the investigator, are not able to comply with thestudy procedures are not eligible

• Female patients who are pregnant are not eligible since fetal toxicities andteratogenic effects have been noted for several of the study drugs. A pregnancy testis required for female patients of childbearing potential

• Lactating females who plan to breastfeed their infants are not eligible

• Sexually active patients of reproductive potential who have not agreed to use aneffective contraceptive method for the duration of their study participation and for 12 weeks after stopping study therapy are not eligible.

• Note: Women of child-bearing potential and males with sexual partners who arepregnant or who could become pregnant (i.e., women of child-bearing potential)should use effective methods of contraception for the duration of the study andfor 12 weeks after stopping study therapy to avoid pregnancy and/or potentialadverse effects on the developing embryo

• Known genetic disorder that increases risk for coronary artery disease. Note: Thepresence of dyslipidemia in a family with a history of myocardial infarction is notin itself an exclusion unless there is a known genetic disorder documented

• Symptomatic heart failure

• New York Health Association (NYHA) class II-IV prior or current cardiomyopathy

• Severe valvular heart disease

• History of atrial fibrillation

• Current or past history of central serous retinopathy

• Current or past history of retinal vein occlusion or retinal detachment

• Patients with uncontrolled glaucoma

• If checking pressure is clinically indicated, patients with intraocularpressure (IOP) > 22 mmHg or ULN adjusted by age are not eligible

• Supplementation with vitamin E greater than 100% of the daily recommended dose. Anymultivitamin containing vitamin E must be stopped prior to study enrollment even ifless than 100% of the daily recommended dosing for vitamin E

• Surgery within 2 weeks prior to enrollment, with the exception of surgical biopsy,placement of a vascular access device or cerebral spinal fluid (CSF) divertingprocedure such as endoscopic third ventriculostomy (ETV) and ventriculoperitoneal (VP) shunt.

• Note: Patients must have healed from any prior surgery

• Patients who have an uncontrolled infection are not eligible