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

The objectives of this study are: Primary Objectives * To estimate the progression free survival of SHH-2 infant (0-2.99 years) and young child (3-4.99 years) medulloblastoma patients treated with systemic HD-MTX- based chemotherapy only. * To estimate the progression free survival of SHH-1 infant (0-2.99 years) medulloblastoma patients treated with systemic HD-MTX-based chemotherapy augmented with IVT-MTX. * To estimate the progression free survival of G3/G4 infant (0-2.99 years) medulloblastoma patients treated with systemic chemotherapy and delayed risk- adapted CSI augmented with carboplatin. * To compare cognitive outcomes among infants (0-2.99 years) and young children (3-4.99 years) treated with systemic chemotherapy only to patients treated with systemic chemotherapy and intra-ventricular chemotherapy or delayed risk- adapted craniospinal irradiation. Secondary Objectives * To investigate change in neurocognitive performance among infants (0-2.99 years) and young children (3-4.99 years) treated for medulloblastoma, and examine the impact of demographic factors (e.g., age at treatment, gender, and socioeconomic status), disease-related factors (e.g., presence of hydrocephalus, posterior fossa syndrome) and variants of proposed treatment regimen (e.g., systemic chemotherapy with or without IVT-MTX, radiation dosimetry to key brain structures, treatment-related ototoxicity) on cognitive late effects. * To investigate which familial factors (e.g., family cohesion, family coping with medical management, parent-child interaction style) and environmental factors (e.g., parental verbal abilities, home literacy, adherence with rehabilitative therapies, participation in early intervention, school advocacy) associate with socioeconomic status and examine the impact of these factors on cognitive late effects. * To evaluate the feasibility and acceptability of a caregiver education program paired with interactive neurodevelopmental games used to improve parent-child interactions, cognitive and social-emotional functioning in infants undergoing treatment for medulloblastoma. (funded by NCI via the R21CA280187) * To estimate the magnitude of change in parent-child interactions following participation in a caregiver education paired with interactive neurodevelopmental games. (funded by NCI via the R21CA280187) * To estimate the magnitude of change in cognition and social-emotional development associated with a caregiver education program combined with interactive neurodevelopmental games. (funded by NCI via the R21CA280187) * To determine the extent of inter- and intra-patient variability in the plasma pharmacokinetics of high-dose systemic methotrexate, cyclophosphamide, vincristine, and topotecan in infants and young children with medulloblastoma, to assess potential covariates to explain this variability, and to explore associations between clinical effects and methotrexate, cyclophosphamide, vincristine, and topotecan pharmacokinetics. * To determine the extent of inter- and intra-patient pharmacokinetic variability of methotrexate in ventricular CSF after intraventricular methotrexate dose administration in infants with medulloblastoma, and to explore associations between methotrexate CSF pharmacokinetics and clinical effects. All participants enrolled will be treated with systemic chemotherapy post-surgical resection of the tumor. Participants will be assigned to treatment strata based first on tumor molecular group and subgroup assignment \[SHH (including SHH-1, SHH-2, SHH-3, SHH-4 and SHH-NOS), G3, G4, (including NWNS NOS, or indeterminate cases\] and then by clinical risk stratification (age and metastatic state). Infants and young children on Stratum S-2 and infants on Stratum S-1 will be treated with chemotherapy-only strategies. * Stratum S-2: Patients on S-2 will receive 8 courses of chemotherapy consisting of: * 4 Course A (A1A2A3A4) * 2 Course B (B1B2) * 2 Course C (C1C2) Courses repeat every 28 days/4 weeks. * Stratum S-1: Patients on S-1 will receive the same systemic chemotherapy regimen as S-2, with the addition of intraventricular (IVT)- MTX, administered via Ommaya reservoir, with each systemic MTX infusion. Each S-1 patient is scheduled to receive 12 doses of IVT-MTX. Each patient on S-1 will also receive 8 courses of combination chemotherapy. (4 Course A with IVT, 2 Course B with IVT and 2 Course C). Courses repeat every 28 days/4 weeks. * Stratum N: Stratum N participants will be treated with post-surgery chemotherapy until 36-months-of age followed by radiation CSI with Boost. There is no defined maximum number of systemic chemotherapy courses in stratum N. The length of chemotherapy (number of courses) will depend on the patient's age at enrollment. The chemotherapy plan for stratum N is divided into 5 sub-cohorts: * Age ≥34 months and \< 36 months: 4 cycles - 2 cycles (A1A2) prior to radiation and 2 cycles (E1, E2) post-radiation * Age: ≥32 to \<34 months-old: 4 cycles (A1A2A3A4) * Age: ≥30 to \<32 months-old: 6 cycles (A1A2A3A4 B1B2) * Age: ≥28 to \<30-months-old: 8 cycles (A1A2A3A4 B1B2 C1C2) * Age: \< 28 months-old: 8 cycles + multiple cycles of Course D until 36 months old (A1A2A3A4 B1B2 C1C2 D1D2D3D4…) Courses A, B, C and E repeat every 28 days/4 weeks and Course D repeats every 42 days. Prior to radiation therapy, around when stratum N patients achieve 36 months of age, they will be re-stratified onto substratum N-1, N-2 or N-3 based on their response to chemotherapy. Patients who receive less than or equal to 4 cycles of systemic chemotherapy prior to CSI regardless of their substratum assignment (N-1, N-2 or N-3) will have their radiation therapy augmented by IV carboplatin. Carboplatin will be given to each of these patients 1-4 hours before each radiation fraction is delivered. Patients enrolled in stratum N who have received only 2 courses of pre-radiation chemotherapy will receive 2 additional courses of adjuvant chemotherapy after completing CSI . The adjuvant chemotherapy consists of Cisplatin, Cyclophosphamide, and Vincristine. Patients who receive equal to 4 courses of systemic chemotherapy prior to CSI will have their radiation therapy augmented by IV carboplatin. The patients receiving more than 4 courses of chemotherapy prior to radiation will not receive additional adjuvant chemotherapy after completing CSI. Patients will be followed for 84 months following enrollment.