Inclusion Criteria:
* Willing and able to provide written informed consent.
* ≥18 years of age.
* For Cohorts A and B, radiographic diagnosis of high-grade glioma that is then confirmed with biopsy. Patients with established histologic diagnosis of high-grade glioma is able to enroll on the study without repeating biopsy.
* For Cohort C, histologic diagnosis of high-grade glioma is required to enroll on the study.
* Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.
* Subjects must have adequate liver and kidney function, defined as: Liver transaminase levels ≤2.5 × the upper limit of normal (ULN); total bilirubin ≤1.5 × ULN, except in subjects with Gilbert's Disease in whom total bilirubin ≤5 × ULN is allowed; OR Creatinine clearance ≥60 mL/min measured from a 24-hour urine collection or calculated based on the Cockcroft-Gault formula.
* Female subjects of childbearing potential and male subjects with female partners of childbearing potential must be willing to avoid pregnancy. Female subjects of childbearing potential who are undergoing RT or who are partners to male subjects in the study should avoid sexual activity or use a highly effective method of birth control during sexual intercourse. Acceptable, highly effective methods of birth control include intrauterine device (IUD)/intrauterine hormone releasing system (IUS), bilateral tube occlusion, vasectomized partner, combined (estrogen and progesterone containing) or progesterone-only hormonal contraceptives (oral, intravaginal, transdermal, injectable).
* Subjects receiving anti-glioma therapy are eligible if treatment can be held 14 days before the first XRD-0394 dose and resume a minimum of 5 days after completion of XRD-0394 (Cohort C only).
* Patient with recurrent tumor amendable to reirradiation and is at least 3 months from end of prior brain radiation therapy (Cohort C only)
* Subjects taking glucocorticoids before and during protocol treatment period will be included per the discretion of the investigator. Intake should be minimized before and during treatment.
Exclusion Criteria:
* Prior radiotherapy to the same region or prior anti-glioma systemic therapy in patients with newly diagnosed HGG (Cohorts A and B, not applicable for Cohort C)
* Subjects with bone marrow impairment as evidenced by hemoglobin \<8.0 g/dL, neutrophil count \<1.5 × 109/L, or platelets \<100 × 109/L.
* History of difficulty swallowing, malabsorption or other chronic gastrointestinal disease or condition that may hamper compliance and/or absorption of XRD-0394, use of percutaneous endoscopic gastrostomy (PEG) tubes.
* Significant cardiac conduction abnormalities, including a history of long corrected QT (QTc) interval syndrome (\>450 msec per Fridericia's formula) and/or pacemaker, or impaired cardiovascular function such as New York Heart Association classification \>2 at screening.
* Participation in another investigational study of an unapproved drug or device or treatment with another ATM, deoxyribonucleic acid (DNA)-dependent protein kinase (DNA-PK), or ataxia-telangiectasia and Rad3-related (ATR) inhibitor within 28 days of the first dose of XRD-0394.
* Subjects who are pregnant or breast-feeding.
* Subjects with a QTc interval \>450 msec (calculated using Fridericia's QT correction formula) at screening.
* Contraindication to temozolomide (Cohort A only)
* Severe headache, rapidly progressive neurologic decline, objective neurologic manifestations of uncal herniation, depressed level of consciousness
* Subjects receiving treatment with any drug that is a strong inhibitor or inducer of CYP3A4 enzyme activity or an inhibitor of BCRP within a minimum of 5 half- lives or 14 days prior to screening or during study participation.
