Azeliragon in MGMT Unmethylated Glioblastoma

Inclusion Criteria:

1. Histopathologically proven diagnosis of IDH-wildtype glioblastoma (GBM, WHOgrade 4) according to the 2021 WHO classification (including subtypes such asgliosarcoma).

2. Diagnosis must be established by open biopsy or tumor resection. Patients whohave only had a stereotactic biopsy are not eligible.

3. Supratentorial location. 4. MGMT promoter methylation is negative based onlocal CLIA-certified commercial laboratory tests.

4. Must have recovered from the effects of surgery, postoperative infection, andother complications at the time the patient signs the informed consent and isdetermined to be eligible to participate in the study, as deemed eligible toparticipate per PI and sub-investigator.

5. ≥ 18 years old. 7. Karnofsky performance status ≥ 60. 8. A diagnosticcontrast-enhanced MRI or CT scan (if MRI is not available) of the brain must beperformed preoperatively and postoperatively. The postoperative scan must bedone within 21 days of the signing of informed consent prior to the initiationof radiotherapy. Preoperative and postoperative scans must be the same type. IfCT scans were performed perioperatively, a CT should be performed before thesigning of the informed consent.

6. Study therapy must begin ≤ 7 weeks after the most recent brain tumor surgery.

7. Adequate organ and bone marrow function as defined below:

• Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3;

• Untransfused platelet count ≥ 75,000 cells/mm3;

• Hemoglobin > 9.0 g/dL (Note: the use of transfusion or other intervention toachieve Hgb >9.0 g/dL is acceptable);

• Total bilirubin ≤ 1.5 ULN

• AST (SGOT) and ALT (SGPT) ≤ 3x ULN 11. • Creatinine ≤ 1.5 ULN or creatinineclearance ≥ 60 mL/min using the CKD- EPI Creatinine Equation

• If there is history of human immunodeficiency virus (HIV) infection, patientsmust be on effective antiretroviral therapy, and HIV viral load must beundetectable within 6 months of study enrollment.

• If there is history of chronic hepatitis B virus (HBV) infection, patients musthave either been treated or are on suppressive therapy (as indicated), and HBVviral load must be undetectable.

• If there is history of hepatitis C virus (HCV) infection, patients must havebeen treated, and HCV viral load must be undetectable.

12. Females of childbearing potential (defined as a female who isnon-menopausal or surgically sterilized) must be willing to use anacceptable method of birth control (i.e., hormonal contraceptive,intra-uterine device, diaphragm with spermicide, condom with spermicide,or abstinence) for the duration of the study. Should a woman becomepregnant or suspect she is pregnant while participating in this study, shemust inform her treating physician immediately 13. Patient has beeninformed about the nature of the study, and has agreed to participate inthe study, and signed the Informed Consent Form (ICF) prior toparticipation in any study-related activities (legally authorizedrepresentative permitted).

Exclusion Criteria:

1. Prior invasive malignancy (except for non-melanomatous skin cancer) unless diseasefree or not requiring active therapy for ≥ 3 years. (For example, carcinoma in situof the breast, oral cavity, and cervix are all permissible).

2. Prior cranial RT or RT to the head and neck where potential field overlap may exist.

3. Prior use of carmustine (Gliadel) wafers or any other intratumoral or intracavitarytreatment.

4. Recurrent or multicentric disease. Multicentric disease is defined as multiplediscrete areas of tumor without connecting T2 signal abnormality.

5. Infratentorial disease or metastatic disease beyond the brain.

6. Known IDH mutation. IDH status could be determined by either immunohistochemistry orsequencing as evaluated per routine clinical care.

7. Patients with a serious active infection (such as a wound infection requiringparenteral antibiotics) at the time of study entry or other serious underlyingmedical conditions that would impair the ability of the patient to receive protocoltreatment

8. Patients with any condition (e.g., psychological, geographical, etc.) that does notpermit compliance with the protocol.

9. Patients receiving CYP 2C8 inhibitors noted in Section 6.3

10. Patient is unwilling or unable to comply with study procedures, including, but notlimited to self-administration of oral medication

11. Patients with a gastrointestinal condition that could interfere with swallowing orabsorption

12. Pregnant or breast feeding. Women of childbearing potential must a negativepregnancy test within 14 days of study entry. Females of childbearing potential whoare sexually active or males with female partners of childbearing potential, whereeither the female or the male is unwilling to use a highly effective method ofcontraception during the trial and for 6 months after the last administration ofazeliragon

13. Patients with concurrent participation in another interventional clinical trial oruse of another investigational agent within 30 days prior to study entry. Patientswho are participating in non-interventional clinical trials (e.g., QOL, imaging,observational, follow-up studies, etc.) are eligible, regardless of the timing ofparticipation