A Study of a New Way to Treat Children and Young Adults With a Brain Tumor Called NGGCT

Inclusion Criteria:

• Patients must be >= 3 years and < 30 years at the time of study enrollment

• Patients must be newly diagnosed with localized primary CNS NGGCT of the suprasellarand/or pineal region by pathology and/or serum or cerebrospinal fluid (CSF)elevation of AFP above institutional normal or > 10 ng/mL or human chorionicgonadotropin (hCG) beta > 100 mIU/mL as confirmed by Rapid Central Marker ScreeningReview on APEC14B1-CNS. Suprasellar, pineal and bifocal tumors are included. (CSFtumor markers and cytology must be within 31 days prior to enrollment and start ofprotocol therapy [repeat if necessary]. Serum tumor markers, AFP and hCGbeta must bewithin 7 days prior to enrollment and start of protocol therapy [repeat ifnecessary]). Basal ganglia or other primary sites are excluded

• Patients with any of the following pathological elements are eligible: endodermalsinus (yolk sac), embryonal carcinoma, choriocarcinoma, malignant/immature teratomaand mixed germ cell tumor (GCT) (i.e., may include some pure germinoma) if malignantelements listed above are present. Patients with only mature teratoma are excluded.Patients with pure germinoma admixed with mature teratoma are excluded (would beeligible for pure germinoma protocols)

• Patients must have a cranial MRI with and without gadolinium at diagnosis/prior toenrollment. If surgical resection is performed, patients must have pre-operative andpost operative brain MRI with and without gadolinium. The post operative brain MRIshould be obtained within 72 hours of surgery. If patient has a biopsy only,post-operative brain MRI is recommended but not required (within 31 days prior tostudy enrollment and start of protocol therapy )

• Patients must have a spine MRI with gadolinium obtained at diagnosis/prior toenrollment. Spine MRI with and without gadolinium is recommended (within 31 daysprior to study enrollment and start of protocol therapy)

• Lumbar CSF must be obtained prior to study enrollment unless medicallycontraindicated. If a patient undergoes surgery and lumbar CSF cytology cannot beobtained at the time of surgery, then it should be performed at least 10 daysfollowing surgery and prior to study enrollment. False positive cytology can occurwithin 10 days of surgery

• Patients must have RAPID CENTRAL TUMOR MARKER REVIEW CSF tumor markers obtainedprior to enrollment unless medically contraindicated. Ventricular CSF obtained atthe time of CSF diversion procedure (if performed) is acceptable for tumor markersbut lumbar CSF is preferred. In case CSF diversion and biopsy/surgery are combined,CSF tumor markers should be collected first

• Peripheral absolute neutrophil count (ANC) >= 1000/uL (within 7 days prior toenrollment)

• Platelet count >= 100,000/uL (transfusion independent) (within 7 days prior toenrollment)

• Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions) (within 7days prior to enrollment)

• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows (within 7 daysprior to enrollment):

• Age: Maximum serum creatinine (mg/dL)

• 3 to < 6 years: 0.8 (male), 0.8 (female)

• 6 to < 10 years: 1 (male), 1 (female)

• 10 to < 13 years: 1.2 (male), 1.2 (female)

• 13 to < 16 years: 1.5 (male), 1.4 (female)

• >= 16 years: male (1.7), 1.4 (female)

• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior toenrollment)

• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135U/L (within 7 days prior to enrollment)

• Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to thevalue of 45 U/L

• Central nervous system function defined as:

• Patients with seizure disorder may be enrolled if on anticonvulsants and wellcontrolled

• Patients must not be in status epilepticus, coma or assisted ventilation priorto study enrollment

• Protocol therapy must begin within 31 calendar days of definitive surgery orclinical diagnosis, whichever is later. If a biopsy only was performed, the biopsydate will be considered the date of definitive surgery. For patients who have abiopsy or incomplete resection at diagnosis followed by additional surgery, the dateof the last resection will be considered the date of definitive surgery.

• 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

• NEUROCOGNITIVE FUNCTION AND QUALITY OF LIFE ASSESSMENT:

• English-, Spanish-, or French- speaking

• Note: Patients who speak a language other than English, Spanish, or French willbe allowed to participate in ACNS2021 but will not complete the neurocognitiveand quality of life assessments

• No known history of neurodevelopmental disorder prior to diagnosis of NGGCT (e.g.,Down syndrome, fragile X, William syndrome, intellectual disability). Patients withNF1 will be allowed to participate

• Additional eligibility criteria for the COG Standardized Neuropsychological Batteryonly: must be at a site that has a psychologist to administer the battery

• Note: If not eligible for the COG Standardized Battery, patients should stillcomplete the Behavior Rating Inventory of Executive Function, Second Edition (BRIEF-2), Pediatric Quality of Life Inventory (PedsQL), Adaptive BehaviorAssessment System Third Edition (ABAS-3), and Behavior Assessment System forChildren, Third Edition (BASC-3) questionnaires

Exclusion Criteria:

• Patients with tumors located outside the ventricles (i.e., basal ganglia, thalamus)

• Patients with only mature teratoma and non-elevated markers upon tumor sampling atdiagnosis

• Patients who have received any prior tumor-directed therapy for their diagnosis ofNGGCT other than surgical intervention and corticosteroids

• Patients with metastatic disease (i.e., MRI evaluation, lumbar CSF cytology orintraoperative evidence of dissemination)

• Female patients who are pregnant, since fetal toxicities and teratogenic effectshave been noted for several of the study drugs

• Note: Serum and urine pregnancy tests may be falsely positive due toHCGbeta-secreting germ cell tumors. Ensure the patient is not pregnant byinstitutional standards

• Lactating females who plan to breastfeed their infants

• Sexually active patients of reproductive potential who have not agreed to use aneffective contraceptive method for the duration of their study participation