A Study of the Drugs Selumetinib Versus Carboplatin/Vincristine in Patients With Neurofibromatosis and 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 neurofibromatosis type 1 (NF1) based on clinical criteria and/orgermline genetic testing

• Patients must be newly diagnosed or have previously diagnosed NF-1 associated LGGthat has not been treated with any modality other than surgery

• For patients with optic pathway gliomas (OPGs):

• Newly-diagnosed patients with OPG are eligible if there are neurologic symptoms (including visual dysfunction, as defined below) or other exam findingsassociated with the tumor

• Previously-diagnosed patients with OPG are eligible if they have new orworsening neurologic symptoms (including visual dysfunction, as defined below)or have tumor growth

• For both newly-diagnosed and previously-diagnosed OPG, the patient may beeligible, irrespective of whether there has been tumor growth or otherneurological symptoms or worsening, if they meet at least one of the followingvisual criteria:

• Visual worsening, defined as worsening of visual acuity (VA) or visualfields (VF) documented within the past year (by examination or history);OR

• Significant visual dysfunction (defined as VA worse than normal for age by 0.6 logMAR [20/80, 6/24, or 2.5/10] or more in one or both eyes)

• For patients with LGG in other locations (i.e., not OPGs):

• Newly-diagnosed patients with LGG are eligible if there are neurologic symptomsor other exam findings associated with the tumor

• NOTE: Newly-diagnosed patients with LGG without associated neurologicsymptoms or exam findings are not eligible

• Previously-diagnosed patients with LGG are eligible if they have new orworsening neurologic symptoms or have tumor growth

• Although not required, if a biopsy/tumor resection is performed, eligiblehistologies will include all tumors considered LGG or low-grade astrocytoma (WorldHealth Organization [WHO] grade I and II) by 5th edition WHO classification ofcentral nervous system (CNS) tumors with the exception of subependymal giant cellastrocytoma

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

• Patients with metastatic disease or multiple independent primary LGGs are allowed onstudy

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

• Age; maximum serum creatinine (mg/dL)

• 2 to < 6 years; 0.8 (male) and 0.8 (female)

• 6 to < 10 years; 1 (male) and 1 (female)

• 10 to < 13 years; 1.2 (male) and 1.2 (female)

• 13 to < 16 years; 1.5 (male) and 1.4 (female)

• >= 16 years; 1.7 (male) and 1.4 (female)

• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior toenrollment) (children with a diagnosis of Gilbert's syndrome will be allowed onstudy regardless of their total and indirect [unconjugated] bilirubin levels as longas their direct [conjugated] bilirubin is < 3.1 mg/dL)

• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3 xupper limit of normal (ULN) = 135 U/L (within 7 days prior to enrollment). For thepurpose of this study, the ULN for SGPT is 45 U/L

• Albumin >= 2 g/dL (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 (within 4 weeks prior to enrollment)

• Corrected QT (QTc) interval =< 450 msec by electrocardiography (EKG) (within 4 weeksprior to enrollment)

• Absolute neutrophil count >= 1,000/uL (unsupported) (within 7 days prior toenrollment)

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

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

• Patients with a known seizure disorder should be stable and should have notexperienced a significant increase in seizure frequency within 2 weeks prior toenrollment

• Patients 2-17 years of age must have a blood pressure that is =< 95th percentile forage, height, and sex at the time of enrollment. Patients >= 18 years of age musthave a blood pressure =< 130/80 mmHg at the time of enrollment (with or without theuse of antihypertensive medications).

• Note: Adequate blood pressure can be achieved using medication for thetreatment 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

• For patients who undergo a surgery on the target tumor (not required), a pre- andpost-operative* MRI of the brain (with orbital cuts for optic pathway tumors) orspine (depending on the site(s) of primary disease) with and without contrast mustalso be performed. The post-operative MRI must be performed within 4 weeks prior toenrollment. If only a biopsy is performed, a post-operative MRI is not required andthe pre-operative (op) MRI within 8 weeks of enrollment will be used as the baselinescan

• The post-operative MRIs should be performed ideally within 48 hours aftersurgery if possible

• 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

• Patients must have receptive and expressive language skills in English, Spanish orFrench to complete the quality of life (QOL) and neurocognitive assessments

• 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.

Exclusion Criteria:

• Patients must not have received any prior tumor-directed therapy includingchemotherapy, radiation therapy, immunotherapy, or bone marrow transplant. Priorsurgical intervention is permitted

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

• Patients may not be receiving any other investigational agents

• Patients with any serious medical or psychiatric illness/ condition, includingsubstance use disorders likely in the judgement of the investigator to interfere orlimit compliance with study requirements/treatment are not eligible

• 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

• Cardiac conditions:

• Known genetic disorder that increases risk for coronary artery disease. Note:The presence of dyslipidemia in a family with a history of myocardialinfarction is not in itself an exclusion unless there is a known geneticdisorder documented

• Symptomatic heart failure

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

• Severe valvular heart disease

• History of atrial fibrillation

• Ophthalmologic conditions:

• 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

• Ophthalmological findings secondary to long-standing optic pathway glioma (suchas visual loss, optic nerve pallor, or strabismus) or longstandingorbito-temporal plexiform neurofibroma (PN), such as visual loss, strabismus)will NOT be considered a significant abnormality for the purposes of the study

• Treatments and/or medications patient is receiving that would make her/himineligible, such as:

• Supplementation with vitamin E greater than 100% of the daily recommended dose.Any multivitamin containing vitamin E must be stopped prior to study enrollmenteven if less than 100% of the daily recommended dosing for vitamin E

• Surgery within 2 weeks prior to enrollment, with the exception of surgicalplacement for vascular access or cerebrospinal fluid (CSF) diverting proceduressuch as endoscopic third ventriculostomy (ETV) and ventriculo-peritoneal (VP)shunt.

• Note: Patients must have healed from any prior surgery prior to enrollment

• Patients who have an uncontrolled infection are not eligible