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 Act (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, an MRI of the brain (with orbital cuts for optic pathway tumors)and/or spine (depending on the site(s) of primary disease) with and without contrastmust 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 and/or their parents or legal guardians must sign a written informedconsent

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

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

• All patients have been consented and enrolled on APEC14B1 (NCT02402244) Part A forPre-Enrollment Eligibility Screening for ACNS1833

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 1 week after stopping study therapy are not eligible.

• Note: Women study participants of child-bearing potential must use acceptablecontraception during the study and for 1 week (7 days) after the last dose ofselumetinib. Men study participants with sexual partners who are pregnant orwho are of child-bearing potential must use acceptable contraception during thestudy and for 1 week (7 days) after the last dose of study agent. Acceptablecontraception includes implants, injectables, or oral contraceptives (allcombined with barrier methods), some intrauterine devices (IUDs), vasectomy orabstinence

• 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