⁃ Inclusion criteria already met to enroll on TarGeT-SCR (central molecular and histopathologic screening) based on:

∙ 1) Age: patients must be ≥12 years and ≤39 years of age at the time of enrollment on TarGeT-SCR

∙ 2) Diagnosis:

‣ Patients with a newly-diagnosed IDH1-mutant HGG including DIPG are eligible. All patients must have tumor tissue from diagnostic biopsy or resection, without exceptions. The diagnosis of HGG, including DIPG, must have been confirmed through TarGeT-SCR.

‣ For the diagnosis of DIPG, patients must have a tumor with pontine epicenter and diffuse involvement of at least 2/3 of the pons, and histopathology consistent with diffuse WHO Grade 2-4 glioma.

‣ All other HGG must be WHO Grade 3 or 4.

∙ 3) Disease status: There are no disease status requirements for enrollment

‣ Measurable disease is not required. Patients without measurable disease are eligible.

‣ Primary spinal tumor: Patients with a primary spinal HGG are eligible.

‣ Patient must not have metastatic disease.

⁃ Inclusion criteria for assignment to TarGeT-D, for all strata:

• 1 Presence of at Least One Relevant Actionable Somatic Mutation in IDH1 Gene, Detailed Here:

• R132H, R132C, R132S, R132G or R132L.

• Patients whose tumors harbor other alterations in addition to IDH1 mutation will potentially be eligible following consensus recommendation by the international multidisciplinary molecular screening committee.

• Patients with IDH2 mutations are not eligible.

• Patients with oligodendroglioma, IDH-mutant and 1p/19q-codeleted are not eligible.

• 2 Performance Level: Karnofsky ≥ 50% for patients \> 16 years of age and Lansky ≥ 50 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.

• 3 Prior Therapy

• 3.1 Surgery, radiation, and/or dexamethasone are permissible. Temozolomide administered concurrently with radiotherapy is permissible. No other prior anticancer therapy for HGG will be allowed.

• 3.2 Radiation therapy requirements: RT, delivered via photon or proton beam, must have been administered at a standard dose including 54 Gy in 30 fractions for DIPG, 59.4 Gy in 33 fractions or 54-60 Gy in 30 fractions for other HGG or 45-50.4 Gy for primary spinal disease. Any variances in the radiotherapy dose within 10% of the standard doses outlined above will be discussed with the Study Chair to confirm eligibility prior to study enrollment.

• 3.3 Timing between diagnosis and start of RT: Patients must have started RT within 31 calendar days of initial diagnosis defined as the date of diagnostic biopsy or resection; if a patient underwent two upfront surgeries (e.g., biopsy then resection or debulking), this is the date of the second surgery.

• 3.4 Timing post-RT

• Patients in pre-maintenance phase must enroll and start treatment no later than 21 calendar days post-completion of RT.

• Patients not in pre-maintenance phase must enroll and start treatment no later than 35 calendar days post-completion of RT.

• 4 Organ Function Requirements

• 4.1 Adequate Bone Marrow Function Defined as:

• Peripheral absolute neutrophil count (ANC) ≥ 1000/mm3.

• Platelet count ≥ 100,000/mm3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment).

• Hemoglobin \> 8 g/dL (may be transfused).

• 4.2 Adequate Renal Function Defined as

• Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73 m2 OR

• Maximum serum creatinine based on age/gender as follows: 10 to \< 13 yrs=1.2 mg/dL for males and females. 13 to \< 16 yrs=1.5 mg/dL for males and 1.4 mg/dL for females.

• 4.3 Adequate Liver Function Defined as:

• Total bilirubin must be ≤ 1.5 × institutional ULN.

• AST(SGOT)/ALT(SGPT) \< 3 × institutional ULN.

• Alkaline Phosphatase \< 3 × institutional ULN. 2.4.4 Informed consent: All patients and/or their parents or legally authorized representatives must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.