Molecular and Clinical Risk-Directed Therapy for Infants and Young Children With Newly Diagnosed Medulloblastoma

Inclusion Criteria - Screening Phase (All Patients)

* Participants with presumptive/suspected newly diagnosed medulloblastoma.
* Participant meets one of the following criteria at the time of screening:

  * Age \< 36 months OR Age ≥ 36 months and \< 60 months with presumptive/suspected non-metastatic disease
* Participant must have adequate tumor tissue from primary tumor for central review of pathology and molecular classification by methylation and IHC
* Participant must be able to begin treatment as outlined in the protocol within 36 days of definitive surgery (day of surgery is Day 0). In case a second surgery is clinically indicated to remove the residual tumor prior to starting treatment, the second surgery will be considered as the definitive surgery (Day 0).
* Parent or legal guardian can understand and is willing to sign a written informed consent document according to institutional guidelines.

Exclusion Criteria - Screening Phase

* Participants with other clinically significant medical disorders (i.e., serious infections or significant cardiac, pulmonary, hepatic, psychiatric, or other organ dysfunction) that could compromise their ability to tolerate protocol therapy or would interfere with the study procedure.

Inclusion Criteria - Study Enrollment (All Patients)

* Participant must be \< 60 months of age at time of enrollment.

  * Note: Each treatment stratum has additional specific age requirements
* Participant must have confirmation of newly diagnosed medulloblastoma per Central Review:

  * Central review includes histopathology, IHC and St. Jude Clinical Genomic Methylation Profiling conducted on MLPNet. If tissue or the extracted DNA does not meet quality control criteria for methylation analysis or if methylation classifier is unable assign molecular group/subgroup within the assigned classifier (MLPNet) parameters, then IHC will be used to define molecular group of these cases. IHC cannot be used to determine molecular subgroup. Therefore, IHC defined SHH patients will be enrolled on Stratum S-1 under "SHH-NOS", and all NWNS and indeterminate molecular group will be enrolled on stratum N.
  * Note: Diagnosis of medulloblastoma, as well as group and subgroup assignment, will be done by central pathology review at St. Jude only. No outside testing is allowed for trial enrollment.
* Participant must have disease staged by MRI of the brain and spine and by cytologic examination of CSF\* and be placed into the following categories:

  * M0: no evidence of metastatic disease.

    * must include a negative CSF cytology result
  * M1: Tumor cells found in the CSF but no other evidence of metastasis
  * M2: Intracranial tumor beyond the primary tumor site
  * M3: Metastatic disease in the spine
  * M4: Extraneural metastatic disease
  * \*All participants are to undergo CSF cytologic examination regardless of presence or absence of gross metastatic disease unless procedure is medically contraindicated. CSF is to be obtained by lumbar puncture (LP) performed at least 10 days after surgery. If LP is medically contraindicated, ventricular CSF from a shunt or Ommaya reservoir may be used for staging but this is not the preferred option due to lower sensitivity. If LP is medically contraindicated and the patient doesn't have a shunt or reservoir for CSF sampling, the treating physician should reach out to PI or Co-PI regarding decision on enrollment to SJiMB21. The decision to enroll without CSF cytology will be made on case-by-case basis.
  * Note: Participants who have M2 disease and positive CSF will be assigned to M3.
  * Note: Participants will be assigned to the highest stage number for which they meet eligibility.
  * Note: Treatment stratums may have additional stage requirements.
* Patient must have received no previous radiotherapy, chemotherapy, or other brain tumor-directed therapy other than corticosteroid therapy and surgery.
* Participant must have a Lansky performance score of \> 30 (except for patients with posterior fossa syndrome.
* Participant must have adequate organ function prior to study entry, as defined by:

  * Absolute neutrophil counts (ANC) \>750/mm\^3
  * Platelet count ≥ 50,000/mm\^3 without support of a platelet transfusion within 7 days
  * Hemoglobin ≥8.0 g/dL (with or without support of a blood transfusion).
  * Normal liver function as defined by Alanine aminotransferase (ALT) concentration ≤ 3 x 45 U/L and total bilirubin ≤ 3 x 1.0.
* Adequate renal function as defined by a serum creatinine concentration:

  * Age - 0 to \<1year; Maximum Serum Creatinine (mg/dl) - Male 0.5; Female 0.5
  * Age - 1 to \< 2years; Maximum Serum Creatinine (mg/dl) - Male 0.6; Female 0.6
  * Age - 1 to \< 2yearsr; Maximum Serum Creatinine (mg/dl) - Male 0.8; Female 0.8
* Participant's parent or legal guardian has the ability to understand and the willingness to sign a written informed consent document according to institutional guidelines.

Inclusion Criteria - Stratum S-2

* Participant must have confirmed diagnosis of the following medulloblastoma molecular group and subgroup per Central Review.

  * Medulloblastoma SHH-2
* Participant must meet one of the following criteria at time of enrollment:

  * Age \<36 months OR Age ≥ 36 months and \< 60 months with non-metastatic disease (M0) Inclusion Criteria - Stratum S-1
* Participant must have confirmed diagnosis of one of the following medulloblastoma molecular subgroups per Central Review.

  * Medulloblastoma SHH-1
  * Medulloblastoma SHH-3
  * Medulloblastoma SHH-4
  * Medulloblastoma SHH-NOS

    * Includes medulloblastoma cases that could not be assigned to a molecular subgroup using the DNA methylation classifier, but which are in the SHH group and/or cases defined as SHH by IHC.
* Participant must be \< 36 months of age at time of enrollment

  * Note: Patients who are \< 36 months of age, regardless of metastatic status (M0/M+), are eligible for enrollment on stratum S-1.

Inclusion Criteria - Stratum N

* Participant must have confirmed diagnosis of one of the following medulloblastoma molecular subgroups per Central Review.

  * Medulloblastoma G3
  * Medulloblastoma G4
  * Medulloblastoma - Not classified into SHH (i.e., NWNS or indeterminate)

    * Includes medulloblastoma cases that could not be assigned to a molecular group using the DNA methylation classifier but which are in the NWNS class and/or defined as NWNS by IHC.
* Participant must be \<36 months of age at time of enrollment
* All NWNS patients (M+ and M0) are eligible for enrollment in stratum N

Exclusion Criteria - All Patients

* CNS embryonal tumor other than medulloblastoma, for example, patients with diagnosis of Atypical Teratoid/Rhabdoid Tumor (ATRT), PNET, Pineoblastoma, Ependymoma, and ETMR are excluded.
* Participant with prior treatment for medulloblastoma, including:

  * Radiotherapy
  * Chemotherapy
  * Cancer directed immunotherapy
  * Targeted agents
  * NOTE: Corticosteroid therapy is acceptable; prior treatment with chemotherapy, immunotherapy or targeted agents for non-cancer directed indications are acceptable as long as these have been stopped at least 14 days prior to start of therapy or 2 half-lives from last dose. (i.e., methotrexate for juvenile rheumatoid arthritis, JAK inhibitor therapy for eczema, etc.)
* Participant who is actively receiving any other investigational agents.
* Participant with other clinically significant medical disorders (i.e., serious infections or significant cardiac, pulmonary, hepatic, psychiatric, or other organ dysfunction) that could compromise their ability to tolerate protocol therapy or would interfere with the study procedures or results.