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/or
   germline genetic testing

   - Patients must be newly diagnosed or have previously diagnosed NF-1 associated LGG that
   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 findings
      associated with the tumor

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

      - For both newly-diagnosed and previously-diagnosed OPG, the patient may be
      eligible, irrespective of whether there has been tumor growth or other
      neurological symptoms or worsening, if they meet at least one of the following
      visual criteria:

         - Visual worsening, defined as worsening of visual acuity (VA) or visual
         fields (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 symptoms
      or other exam findings associated with the tumor

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

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

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

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

   - Patients with metastatic disease or multiple independent primary LGGs are allowed on
   study

   - Creatinine clearance or radioisotope glomerular filtration Rate (GFR) >= 70
   mL/min/1.73 m^2 OR a serum creatinine based on age/gender (within 7 days prior to
   enrollment) 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 to
   enrollment) (children with a diagnosis of Gilbert's syndrome will be allowed on study
   regardless of their total and indirect [unconjugated] bilirubin levels as long as
   their direct [conjugated] bilirubin is < 3.1 mg/dL)

   - Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3 x
   upper limit of normal (ULN) = 135 U/L (within 7 days prior to enrollment). For the
   purpose 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 the LVEF
   result is given as a range of values, then the upper value of the range will be used)
   by echocardiogram (within 4 weeks prior to enrollment)

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

   - Absolute neutrophil count >= 1,000/uL (unsupported) (within 7 days prior to
   enrollment)

   - 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 not
   experienced a 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 for
   age, height, and gender at the time of enrollment. Patients >= 18 years of age must
   have a blood pressure =< 130/80 mmHg at the time of enrollment (with or without the
   use of antihypertensive medications).

      - Note: Adequate blood pressure can be achieved using medication for the treatment
      of hypertension

   - All patients must have ophthalmology toxicity assessments performed within 4 weeks
   prior 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 contrast
   must be performed within 4 weeks prior to enrollment

   - For patients who undergo a surgery on the target tumor (not required), a pre- and
   post-operative* MRI of the brain (with orbital cuts for optic pathway tumors) or spine
   (depending on the site(s) of primary disease) with and without contrast must also be
   performed within 4 weeks prior to enrollment

      - The post-operative MRIs should be performed ideally within 48 hours after surgery
      if possible

   - Patients must have a performance status corresponding to Eastern Cooperative Oncology
   Group (ECOG) scores of 0, 1, or 2. Use Karnofsky for patients > 16 years of age 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 or Spanish to
   complete the quality of life (QOL) and neurocognitive assessments

   - All patients and/or their parents or legal guardians must sign a written informed
   consent.

   - 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 including
   chemotherapy, radiation therapy, immunotherapy, or bone marrow transplant. Prior
   surgical 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, including
   substance use disorders likely in the judgement of the investigator to interfere or
   limit compliance with study requirements/treatment are not eligible

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

   - Female patients who are pregnant are not eligible since fetal toxicities and
   teratogenic effects have been noted for several of the study drugs. A pregnancy test
   is 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 an
   effective 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 are
      pregnant or who could become pregnant (i.e., women of child-bearing potential)
      should use effective methods of contraception for the duration of the study and
      for 12 weeks after stopping study therapy to avoid pregnancy and/or potential
      adverse 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 myocardial infarction is
      not in itself an exclusion unless there is a known genetic disorder 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 intraocular
         pressure (IOP) > 22 mmHg or ULN adjusted by age are not eligible

      - Ophthalmological findings secondary to long-standing optic pathway glioma (such
      as visual loss, optic nerve pallor, or strabismus) or longstanding
      orbito-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/him ineligible,
   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 enrollment
      even if less than 100% of the daily recommended dosing for vitamin E

      - Surgery within 2 weeks prior to enrollment, with the exception of surgical
      placement for vascular access or cerebrospinal fluid (CSF) diverting procedures
      such 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