AZD1390 in Recurrent and Newly Diagnosed WHO Grade 4 Glioma Patients

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.