Inclusion Criteria:

• 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)
  • 2 to < 6 years: Maximum serum creatinine 0.8 mg/dL (male), 0.8 mg/dL (female)
  • 6 to < 10 years: Maximum serum creatinine 1 mg/dL (male), 1 mg/dL (female)
  • 10 to < 13 years: Maximum serum creatinine 1.2 mg/dL (male), 1.2 mg/dL (female)
  • 13 to < 16 years: Maximum serum creatinine 1.5 mg/dL (male), 1.4 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)

Exclusion Criteria:

• Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies, OR because there is yet no available information regarding human fetal or teratogenic toxicities. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use two effective methods of birth control, including a medically accepted barrier or contraceptive method (eg, male or female condom) for the duration of the study. Abstinence is an acceptable method of birth control. Women of childbearing potential should use adequate contraception during study participation and for 6 months after the last dose of AZD1390. Male patients with female partners of childbearing potential should use adequate contraception during study participation and for 16 weeks after the last dose of AZD1390
• Investigational Drugs: Patients who are currently receiving another investigational drug are not eligible
• Anti-cancer Agents: Patients who are currently receiving other anti-cancer agents are not eligible with the exception of corticosteroids
• Anti-graft versus host disease (GVHD) agents post-transplant: Patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant are not eligible for this trial
• CYP-450/Transport Proteins: Patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A4/5 enzyme are ineligible. Moderate inhibitors and inducers of CYP3A4/5 are permitted but caution should be exercised, and patients monitored closely for possible drug interactions. Strong inhibitors or inducers CYP3A4 should be stopped at least 2 weeks before the first dose of AZD1390 (3 weeks for St John's Wort). As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
• Enzyme-Inducing Anticonvulsants: Patients must not have received enzyme-inducing anticonvulsants within 14 days prior to enrollment
• Patients who have an uncontrolled infection are not eligible
• Patients who have received a prior solid organ transplantation are not eligible
• Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible. This includes patients with rapidly declining neurological status
• Patients must have the ability to swallow whole tablets (AZD1390 may not be administered via NG/G-tubes). Patients with medical conditions that affect drug absorption, such as short gut syndrome are not eligible
• Patients with known macular degeneration, uncontrolled glaucoma, or cataracts are not eligible
• Patients with primary spinal cord high grade gliomas are not eligible
• Patients with metastatic disease are not eligible; Metastatic disease is defined as distant intracranial or spinal metastasis including leptomeningeal disease, or tumor cells within the CSF. MRI of the spine with and without contrast must be performed if metastatic disease is suspected by the treating physician
• Patients with gliomatosis type growth pattern (or diffuse spread) with involvement of at least 3 lobes of the brain are not eligible with the exception of H3 K27M-mutant bithalamic tumors
• Patients with infant-type hemispheric high-grade gliomas are excluded
• Patients with BRAFV600E mutations are excluded
• Patients who are not able to receive protocol specified radiation therapy
• Patients with a history of radiotherapy as part of anti-cancer therapy are excluded
• Presence of myopathy or raised CK > 5 x ULN on 2 occasions at screening will result in exclusion.
  • CK should not be measured following strenuous exercise or in the presence of a plausible alternative cause of CK increase, which may confound interpretation of the results.
  • If CK levels are significantly elevated at baseline (>5 x ULN) a confirmatory test should be carried out within 5 - 7 days.
  • If the repeat test confirms a baseline CK >5 x ULN, treatment should not be started
• HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible as long as they are NOT receiving anti-retroviral agents that are strong inhibitors or inducers of CYP3A4 or substrates of UGT1A1 and UGT1A9
• Evidence of clinically significant cardiac dysfunction or prolonged corrected QT interval (QTc) (> 450 msec) on baseline electrocardiogram (EKG)
• Patients with known hepatitis B or C with detectable viral load
• Any significant medical condition that in the medical judgement of the investigator would compromise the patient's ability to tolerate study drug or participate in the study