• PRE ENROLLMENT: Patients must be =\< 25 years of age at the time of enrollment on APEC14B1 part A cnetral nervous system (CNS)/high grade glioma (HGG) pre-enrollment eligibility screening

‣ Please note:

• This required age range applies to pre-enrollment eligibility for all HGG patients. Individual treatment protocols may have different age criteria.

∙ Non-DIPG patients with tumors that do not harbor an H3K27M-mutation and are \>= 18 years of age will not be eligible to enroll on ACNS1821 (Step 1).

• PRE ENROLLMENT: Patient is suspected of having localized, newly diagnosed HGG, excluding metastatic disease, OR patient has an institutional diagnosis of DIPG

‣ Please note: there are specific radiographic criteria for DIPG patient enrollment on ACNS1821 (Step 1)

• PRE ENROLLMENT:

‣ For patients with non-pontine tumors: Patients and/or their parents or legal guardians must have signed informed consent for eligibility screening on APEC14B1 Part A.

⁃ For patients with DIPG: Patients and/or their parents or legal guardians must have signed informed consent for ACNS1821.

• PRE ENROLLMENT:

‣ For patients with non-pontine tumors only, the specimens obtained at the time of diagnostic biopsy or surgery must be submitted through APEC14B1 ASAP, preferably within 5 calendar days of definitive surgery

• STEP 1: Patients must be \>= 12 months and =\< 21 years of age at the time of enrollment

• STEP 1: Patients must have newly-diagnosed DIPG or HGG (including DMG).

• STEP 1: Stratum DIPG

‣ Patients with newly-diagnosed typical DIPG, defined as tumors with a pontine epicenter and diffuse involvement of at least 2/3 of the pons on at least 1 axial T2 weighted image, are eligible. No histologic confirmation is required.

⁃ Patients with pontine tumors that do not meet radiographic criteria for typical DIPG (e.g., focal tumors or those involving less than 2/3 of the pontine cross-sectional area with or without extrapontine extension) are eligible if the tumors are biopsied and proven to be high-grade gliomas (such as anaplastic astrocytoma, glioblastoma, high-grade glioma not otherwise specified \[NOS\], and/or H3 K27M-mutant) by institutional diagnosis.

• STEP 1: Stratum DMG (with H3 K27M mutation)

‣ Patients must have newly-diagnosed non-pontine H3 K27M-mutant HGG without BRAF V600 or IDH1 mutations as confirmed by Rapid Central Pathology and Molecular Screening Reviews performed on APEC14B1

⁃ Note: Patients need not have either measurable or evaluable disease, i.e., DMG patients may have complete resection of their tumor prior to enrollment. Primary spinal tumors are eligible for enrollment. For rare H3 K27M-mutant HGG in non-midline structures (e.g., cerebral hemispheres), these patients will be considered part of Stratum DMG.

• STEP 1: Stratum HGG (without H3 K27M mutation)

‣ Patients must have newly-diagnosed non-pontine H3 K27M-wild type HGG without BRAF V600 or IDH1 mutations as confirmed by Rapid Central Pathology and Molecular Screening Reviews performed on APEC14B1

⁃ Please note:

• Patients who fall in this category and who are \>= 18 years of age are not eligible due to another standard-of-care regimen (radiation/temozolomide) that is available

∙ Patients need not have either measurable or evaluable disease, i.e., HGG patients may have complete resection of their tumor prior to enrollment. Primary spinal tumors are eligible for enrollment

• STEP 1: 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 who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.

• STEP 1: Peripheral absolute neutrophil count (ANC) \>= 1000/uL (within 7 days prior to step 1 enrollment)

• STEP 1: Platelet count \>= 100,000/uL (transfusion independent) (within 7 days prior to step 1 enrollment)

• STEP 1: Hemoglobin \>= 8.0 g/dL (may receive red blood cell \[RBC\] transfusions) (within 7 days prior to step 1 enrollment)

• STEP 1: Creatinine clearance or radioisotope glomerular filtration rate (GFR) \>= 70 mL/min/1.73 m\^2 (within 7 days prior to step 1 enrollment) or

⁃ A serum creatinine based on age/gender as follows (within 7 days prior to step 1 enrollment):

• Age / Maximum Serum Creatinine (mg/dL)

‣ 1 to \< 2 years / male: 0.6; female: 0.6

⁃ \>= 16 years / male: 1.7; female: 1.4

• STEP 1: Total bilirubin =\< 1.5 x upper limit of normal (ULN) for age

∙ STEP 1: Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase \[ALT\]) =\< 135 U/L. For the purpose of this study, the ULN for SGPT is 45 U/L.

∙ STEP 1: Serum amylase =\< 1.5 x ULN

∙ STEP 1: Serum lipase =\< 1.5 x ULN

∙ STEP 1: No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry \> 94% if there is clinical indication for determination.

∙ STEP 1: Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled.

∙ STEP 1: Patients must be enrolled and protocol therapy must begin no later than 31 days after the date of radiographic diagnosis (in the case of non-biopsied DIPG patients only) or definitive surgery, whichever is the later date (Day 0).

⁃ For patients who have a biopsy followed by resection, the date of resection will be considered the date of definitive diagnostic surgery. If a biopsy only was performed, the biopsy date will be considered the date of definitive diagnostic surgery.