Inclusion Criteria:

• Patients must be greater than or equal to 3 years and less than 22 years of age at the time of enrollment.
• Patients must be newly diagnosed and have:
  • Eligibility confirmed by rapid central pathology and molecular screening review on APEC14B1:
    • classical histologic type (non LC/A) WNT medulloblastoma;
    • positive nuclear β-catenin by IHC;
    • positive for CTNNB1 mutation;
    • negative for MYC and MYCN by FISH.
• Patient must have negative lumbar CSF cytology.
  • Note: CSF cytology for staging should be performed no sooner than 14 days post operatively to avoid false positive CSF. Ideally, CSF should be obtained between Day 14 and Day 21 to allow for final staging status before enrollment onto the study. Patients with positive CSF cytology obtained 0 to 14 days after surgery should have cytology repeated to determine eligibility and final CSF status.  Patients with negative CSF cytology from lumbar puncture obtained 0 to 14 days after surgery do not need cytology repeated. Patients with negative CSF cytology from lumbar puncture obtained prior to surgery do not need cytology repeated post-operatively.
• Patients must have eligibility confirmed by Rapid Central Imaging Review on APEC14B1. Patients must have ≤ 1.5 cm2 maximal cross-sectional area of residual tumor (see Section 3.1.4). Whole brain MRI with and without gadolinium and spine MRI with gadolinium must be performed.
• Patients must be enrolled, and protocol therapy must be projected to begin, no later than 36 days after definitive diagnostic surgery (Day 0). 
• Adequate Bone Marrow Function Defined As:
  • Peripheral absolute neutrophil count (ANC) ≥ 1000/μL;
  • Platelet count ≥ 100,000/μL (transfusion independent);
  • Hemoglobin ≥ 8.0 g/dL (may receive RBC transfusions).
• Adequate Renal Function Defined As:
  • Creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.73 m^2; or
  • A serum creatinine based on age/gender as follows:
    • Age | Maximum Serum Creatinine (mg/dL) | Male | Female
    • 3 to < 6 years | 0.8 | 0.8
    • 6 to < 10 years | 1.0 | 1.0
    • 10 to < 13 years | 1.2 | 1.2
    • 13 to < 16 years | 1.5 | 1.4
    • ≥ 16 years | 1.7 | 1.4
  • The threshold creatinine values in this Table were derived from the Schwartz formula for estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and stature data published by the CDC.
• Adequate Liver Function Defined As:
  • Total or direct bilirubin ≤ 1.5 x upper limit of normal (ULN) for age; and
  • SGPT (ALT) ≤ 135 U/L (3x ULN). For the purpose of this study, the ULN for SGPT is 45 U/L.
• Central Nervous System Function Defined As:
  • Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled.
  • Patients must not be in status epilepticus, a coma or on assisted ventilation at the time of study enrollment.
• Patients must have receptive and expressive language skills in English, French, or Spanish to complete the QoL and Neurocognitive assessments. If a patient meets these criteria but the parent/guardian speaks a language other than English, French, or Spanish, the patient may still be enrolled and tested, and the parent-report measures should be omitted.

Exclusion Criteria:

• Patients with metastatic disease by either MRI evaluation (brain and spine) or lumbar CSF cytology are not eligible. Patients who are unable to undergo a lumbar puncture for assessment of CSF cytology are ineligible.
• Patients must not have received any prior radiation therapy or chemotherapy (tumor-directed therapy) other than surgical intervention and/or corticosteroids.
• Female patients who are pregnant are ineligible due to risks of fetal and teratogenic adverse events as seen in animal/human studies.
• Lactating females are not eligible unless they have agreed not to breastfeed their infants.
• Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained.
• Sexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation.
• Patients with a history of moderate to profound intellectual disability (i.e., IQ < 55) are not eligible for enrollment.
  • PLEASE NOTE: Children with a prior history of attention deficit hyperactivity disorder (ADHD) or a specific learning disability (e.g., dyslexia) are eligible for this study.
• All patients and/or their parents or legal guardians must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.
• All institutional, FDA, and NCI requirements for human studies must be met.