This is an open-label, single-center Phase 0/1b study that will enroll at least 27 participants with recurrent WHO Grade 4 Glioma requiring re-radiation and approximately 35 participants with newly-diagnosed WHO Grade 4 glioma (nGBM). The trial will be composed of a Phase 0 component (subdivided into Arms A - C), and an expansion Phase 1b. Patients with tumors demonstrating a positive PK response in the Phase 0 component of the study will be eligible to graduate to an expansion phase that combines therapeutic dosing of AZD1390 plus standard-of-care fractionated radiotherapy (RT).

Inclusion Criteria:

1a. Arm C only: Participants undergoing resection for a suspected newly diagnosed WHO Grade 4 glioma. Participants will also need to have radiation planned as part of the post-surgical treatment plan; OR,

1b. Arms A and B only: Participants who have had a prior resection of diagnosed glioma (2021 WHO grade IV), defined as participants who have progressed on or following standard therapy, which includes maximal surgical resection, temozolomide, and fractionated radiotherapy. Participants will also need to have radiation planned as part of the post-surgical treatment plan.

2. Participants must have measurable disease preoperatively, defined as at least 1 contrast-enhancing lesion, with 2 perpendicular measurements of at least 1 cm.

3. Provision of signed and dated, written informed consent (personally or by the legally authorized representative, if applicable) prior to any study specific procedures, sampling and analyses.

4. Age ≥18 at time of consent. 5. Have a performance status (PS) of ≤2 on the Eastern Cooperative Oncology (Group (ECOG) scale1.

6. Ability to swallow oral medications. 7. Participant has adequate bone marrow and organ function as defined by the following laboratory values (as assessed by the local laboratory for eligibility):

• Adequate bone marrow function:

  • absolute neutrophil count ≥1,500/mcL
  • Platelets (at time of surgery) ≥100,000/mcL
  • hemoglobin ≥9.0 g/dL Participants may receive erythrocyte transfusions to achieve this hemoglobin level at the discretion of the investigator. Initial treatment must not begin earlier than the day after the erythrocyte transfusion.

• Adequate hepatic function:

  o total bilirubin ≤1.5 X ULN. Participants with Gilbert's syndrome with a total bilirubin ≤2.0 times ULN and direct bilirubin within normal limits are permitted.

  o AST(SGOT) ≤2.5 X institutional ULN

  o ALT(SGPT) ≤2.5 X institutional ULN

• Adequate pancreatic function:

  o Amylase within normal limits (WNL)

  o Lipase within normal limits (WNL)

• Adequate renal function:

  • Serum creatinine ≤1.5 X ULN or estimated creatinine clearance ≥ 60 mL/min (calculated using Institutional standard method) 8. Participants with tumor-induced seizures must be well-controlled on a stable anti-epileptic treatment.

    9. Participants must be willing to receive prophylaxis with levetiracetam for the duration of study drug administration (or alternative anti-epileptic if agreed with Medical Monitor) 10. Confirmed negative serum pregnancy test (β-hCG) before starting study treatment or participant who is no longer of childbearing potential due to surgical, chemical, or natural menopause.

    11. For females of reproductive potential: use of highly effective contraception and agreement to use such a method during study participation until the end of treatment administration and for 16 weeks after the last dose of study drug.

    12. For males of reproductive potential: use of condoms or other methods to ensure effective contraception with partner until the end of treatment administration and for 16 weeks after the last dose of study drug.

    13. Agreement to adhere to Lifestyle Considerations (see Section 5.3) throughout study duration.

Exclusion Criteria:

1. Current use of coumarin-derived anticoagulant for treatment, prophylaxis or otherwise, that cannot be discontinued prior to surgery. Therapy with heparin, low molecular weight heparin (LMWH) or fondaparinux is allowed.

2. Pregnancy or lactation.

3. Known allergic reactions to components of the AZD1390.

4. Known to have active (acute or chronic) or uncontrolled severe infection, liver disease such as cirrhosis, decompensated liver disease, and active and chronic hepatitis, as determined by the investigator.

5. Known active systemic bacterial infection (requiring intravenous [IV] antibiotics or fever >38.5°C at time of initiating study treatment), fungal infection, or detectable viral infection (such as known human immunodeficiency virus positivity or with known active hepatitis B or C [for example, hepatitis B surface antigen positive]. Screening of viral infection is not required for enrollment.

6. The participant has a personal history of any of the following conditions: syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest.

7. Any of the following cardiac criteria:

   • Cardiac dysfunction defined as: Myocardial infarction within six months of study entry, NYHA Class II/III/IV heart failure, unstable angina or unstable cardiac arrhythmias.
   • Mean resting corrected QT interval (QTcF) > 470 msec obtained from 3 electrocardiograms (ECGs) (QTc interval will be calculated using Fridericia's formula).
   • Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG, e.g., complete left bundle branch block, third degree heart block.
   • Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years-of-age. Patients stable on concomitant medications known to prolong the QT interval may be allowed to participate in the study provided that their mean resting corrected QT interval (QTcF) is < 470 msec at baseline and after discussion with the Medical Monitor.

8. History of epileptic disorder or any seizure history unrelated to tumor.

9. History or presence of myopathy or raised creatine kinase (CK) >5 x upper limit of normal (ULN) on 2 occasions at screening.

10. Past medical history of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease.

11. Participant has serious and/or uncontrolled preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study (for example, interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment [e.g. estimated creatinine clearance <30ml/min], history of major surgical resection involving the stomach or small bowel, or preexisting Crohn's disease or ulcerative colitis or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea).

12. Prior therapy with ATM kinase inhibitors.

13. Treatment with strong inhibitors or inducers of CYP3A4 within 2 weeks prior to receiving study drug.

14. Prior treatment with pneumotoxic drugs, e.g. busulfan, bleomycin, within the past year. If prior therapy in lifetime, then excluded if history of pulmonary toxicities from administration. Patients who have received treatment with nitrosoureas (e.g., BCNU, CCNU) in the year before study entry without experiencing lung toxicity are allowed on study.

15. Treatment with another investigational drug or other intervention within 5 half-lives of the investigational product, whichever is longer.

16. With the exception of alopecia, any unresolved toxicities from prior therapy greater than National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v5.0) Grade 1 at the time of starting study treatment and patients with chronic Grade 2 unresolved toxicities may be eligible following discussion with the Medical Monitor.