AZD1390 in Recurrent and Newly Diagnosed WHO Grade 4 Glioma Patients

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 1contrast-enhancing lesion, with 2 perpendicular measurements of at least 1 cm.

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

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

5. Ability to swallow oral medications. 7. Participant has adequate bone marrow andorgan function as defined by the following laboratory values (as assessed by thelocal 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 toachieve this hemoglobin level at the discretion of the investigator. Initialtreatment must not begin earlier than the day after the erythrocytetransfusion.

• Adequate hepatic function: o total bilirubin ≤1.5 X ULN. Participants with Gilbert's syndrome with a totalbilirubin ≤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 withtumor-induced seizures must be well-controlled on a stable anti-epileptictreatment.

9. Participants must be willing to receive prophylaxis with levetiracetam forthe duration of study drug administration (or alternative anti-epilepticif agreed with Medical Monitor) 10. Confirmed negative serum pregnancytest (β-hCG) before starting study treatment or participant who is nolonger of childbearing potential due to surgical, chemical, or naturalmenopause.
10. For females of reproductive potential: use of highly effectivecontraception and agreement to use such a method during studyparticipation until the end of treatment administration and for 16 weeksafter the last dose of study drug.
11. For males of reproductive potential: use of condoms or other methods toensure effective contraception with partner until the end of treatmentadministration and for 16 weeks after the last dose of study drug.
12. 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 orotherwise, that cannot be discontinued prior to surgery. Therapy with heparin, lowmolecular 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, liverdisease such as cirrhosis, decompensated liver disease, and active and chronichepatitis, as determined by the investigator.

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

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

7. Any of the following cardiac criteria:

• Cardiac dysfunction defined as: Myocardial infarction within six months ofstudy entry, NYHA Class II/III/IV heart failure, unstable angina or unstablecardiac arrhythmias.

• Mean resting corrected QT interval (QTcF) > 470 msec obtained from 3electrocardiograms (ECGs) (QTc interval will be calculated using Fridericia'sformula).

• Any clinically important abnormalities in rhythm, conduction or morphology ofresting ECG, e.g., complete left bundle branch block, third degree heart block.

• Any factors that increase the risk of QTc prolongation or risk of arrhythmicevents such as heart failure, hypokalemia, congenital long QT syndrome, familyhistory of long QT syndrome or unexplained sudden death under 40 years-of-age.Patients stable on concomitant medications known to prolong the QT interval maybe allowed to participate in the study provided that their mean restingcorrected QT interval (QTcF) is < 470 msec at baseline and after discussionwith 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 ofnormal (ULN) on 2 occasions at screening.

10. Past medical history of interstitial lung disease (ILD), drug-induced ILD, radiationpneumonitis which required steroid treatment, or any evidence of clinically activeinterstitial 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 (forexample, interstitial lung disease, severe dyspnea at rest or requiring oxygentherapy, severe renal impairment [e.g. estimated creatinine clearance <30ml/min],history of major surgical resection involving the stomach or small bowel, orpreexisting Crohn's disease or ulcerative colitis or a preexisting chronic conditionresulting 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 toreceiving study drug.

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

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

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