• COHORT A and COHORT B: For the dose escalation phase, patients must be ≥ 12 months and \< 18 years of age at the time of study enrollment

• COHORT C and COHORT D: For the disease expansion phase, patients must be ≥ 12 months and \< 22 years of age at the time of study enrollment

• Patients with newly diagnosed primary high-grade glioma (HGG), diffuse midline glioma (DMG) (excluding primary spinal tumors), or diffuse intrinsic pontine glioma (DIPG) who are eligible to receive 54-59.4 grey (Gy) fractionated radiation at 1.8 Gy/day. Patients must have had histologic verification of malignancy at original diagnosis except in patients with DIPG as defined below.

‣ COHORTS A AND C (SUPRATENTORIAL TUMORS):

• HGG and non-pontine DMG:

‣ Patients with newly diagnosed HGG (including diffuse hemispheric glioma, H3 G34-mutant; diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype; astrocytoma; IDH-mutant; or glioblastoma, IDH-wildtype): or non-pontine DMG (including diffuse midline glioma, H3 K27-altered; diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype; astrocytoma; IDH-mutant; or glioblastoma, IDH-wildtype) require histologic diagnosis.

⁃ COHORT B AND D (INFRATENTORIAL TUMORS):

• DIPG/pontine DMG or infratentorial HGG or DMG:

‣ 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 infratentorial 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 (including diffuse midline glioma H3 K27-altered; diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype; astrocytoma; IDH-mutant; or glioblastoma, IDH-wildtype) by institutional diagnosis.

⁃ Protocol Definitions

• Supratentorial tumors are defined as tumors with an epicenter in the cerebral hemispheres, basal ganglia, thalamus, hypothalamus, or pituitary gland.

∙ Infratentorial tumors are defined as tumors with an epicenter in the brainstem, cerebellum

• Patients with measurable or non-measurable (following a gross total resection) disease

• Karnofsky ≥ 50% for patients \> 16 year of age and Lansky ≥ 50% for patients ≤ 16 years of age.

‣ Note: Patients who are unable to walk because of paralysis, but who are in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score

• Prior therapy for any cancer diagnosis (including radiation) is not allowed with the exception of surgery and/or corticosteroids. If receiving corticosteroids, dose must remain stable or decrease after enrollment

• Peripheral absolute neutrophil count (ANC) ≥ 1000/uL (must be performed within 7 days prior to enrollment unless otherwise indicated)

• Platelet count ≥ 100,000/uL (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment) (must be performed within 7 days prior to enrollment unless otherwise indicated)

• Hemoglobin ≥ 8.0 g/dL at baseline (may receive red blood cell \[RBC\] transfusions) (must be performed within 7 days prior to enrollment unless otherwise indicated)

• A creatinine based on age/sex as follows (must be performed within 7 days prior to enrollment unless otherwise indicated):

‣ 1 to \< 2 years: Maximum serum creatinine 0.6 mg/dL (male), 0.6 mg/dL (female)

⁃ \>= 16 years: Maximum serum creatinine 1.7 mg/dL (male),1.4 mg/dL (female) OR a 24 hour urine creatinine clearance ≥ 70 mL/min/1.73 m\^2 OR a glomerular filtration rate (GFR) ≥ 70 mL/min/1.73 m\^2. GFR must be performed using direct measurement with a nuclear blood sampling method OR direct small molecule clearance method (iothalamate or other molecule per institutional standard).

∙ Note: Estimated GFR (eGFR) from serum creatinine, cystatin C or other estimates are not acceptable for determining eligibility

• Note: The threshold creatinine values in this Table were derived from the Schwartz formula for estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and stature data published by the CDC.

‣ Bilirubin (sum of conjugated + unconjugated or total) ≤ 1.5 x upper limit of normal (ULN) for age except in patients diagnosed with Gilbert's disease for which bilirubin must be ≤ 3.0 × ULN (must be performed within 7 days prior to enrollment unless otherwise indicated)

⁃ Alanine aminotransferase (ALT) ≤ 3 x ULN, unless attributed to tumor involvement then ALT ≤ 5 x ULN (must be performed within 7 days prior to enrollment unless otherwise indicated)

⁃ Aspartate aminotransferase (AST) ≤ 3 x ULN, unless attributed to tumor involvement then AST ≤ 5 x ULN (must be performed within 7 days prior to enrollment unless otherwise indicated)

⁃ Albumin ≥ 2 g/dL (must be performed within 7 days prior to enrollment unless otherwise indicated)

⁃ No evidence of dyspnea at rest, no exercise intolerance and a pulse oximetry \> 93%

⁃ Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled as evidenced by no increase in seizure frequency in the prior 7 days. If needed, evaluate use of enzyme-inducing anticonvulsants

⁃ Serum lipase ≤ 1.5 ULN (must be performed within 7 days prior to enrollment unless otherwise indicated)

⁃ Prothrombin time (PT)/international normalization rate (INR) \< 1.5 x ULN (must be performed within 7 days prior to enrollment unless otherwise indicated)

⁃ Patients must have the ability to swallow whole tablets (AZD1390 may not be administered via nasogastric \[NG\]/gastric \[G\]-tubes)