Inclusion Criteria:
* Histologically proven diagnosis of IDH-wildtype GBM (WHO grade 4) according to the 2021 WHO classification (including subtypes such as gliosarcoma).
* Radiographic evidence of residual tumor after initial surgery or biopsy.
* Patient is amenable for future surgery (either surgical resection or laser interstitial thermal therapy (LITT)) to sample the residual tumor after completion of chemoradiotherapy.
* At least 18 years of age.
* Eligible for and planning to receive standard fractionated RT of 60 Gy with concurrent TMZ.
* Recovered from the effects of surgery, postoperative infection, and other complications sufficiently for initiation of chemoradiotherapy, in the opinion of the treating physician.
* Karnofsky performance status ≥ 60.
* Adequate organ and bone marrow function as defined below:
* Absolute neutrophil count (ANC) ≥ 1.5 K/cumm;
* Platelets ≥ 100 K/cumm;
* Hemoglobin \> 9.0 g/dL (Note: the use of transfusion or other intervention to achieve Hgb \>9.0 g/dL is acceptable);
* Total bilirubin ≤ 1.5 ULN
* AST (SGOT) and ALT (SGPT) ≤ 3 x ULN
* Creatinine ≤ 1.5 ULN or creatinine clearance ≥ 60 mL/min
* If there is history of human immunodeficiency virus (HIV) infection, patients must be on effective antiretroviral therapy, and HIV viral load must be undetectable within 6 months of study enrollment.
* If there is history of chronic hepatitis B virus (HBV) infection, patients must have either been treated or are on suppressive therapy (as indicated), and HBV viral load must be undetectable.
* If there is history of hepatitis C virus (HCV) infection, patients must have been treated, and HCV viral load must be undetectable.
* Females of childbearing potential (defined as a female who is non-menopausal or surgically sterilized) and sexually active heterosexual males must be willing to use an acceptable method of birth control (i.e., hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) during the trial and for 6 months after the last administration of azeliragon. Should a female trial participant or female partner of a male trial participants become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.
* Able to understand and willingness to sign an IRB-approved written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.
Exclusion Criteria:
* Prior cranial RT or RT to the head and neck where potential field overlap may exist.
* Leptomeningeal or metastatic involvement.
* Known IDH mutation. IDH status could be determined by either immunohistochemistry or sequencing as evaluated per routine clinical care.
* Patients receiving CYP 2C8 inhibitors within 2 weeks or 5 half-lives prior to study entry.
* Patients with a gastrointestinal condition that could interfere with swallowing or absorption.
* Patients with concurrent participation in another interventional clinical trial or use of another investigational agent within 30 days prior to study entry. Patients who are participating in non-interventional clinical trials (e.g., QOL, imaging, observational, follow-up studies, etc.) are eligible, regardless of the timing of participation.
* Medical contraindication to MRI (e.g., unsafe foreign metallic implants, incompatible pacemaker, inability to lie still for long periods, severe to end-stage kidney disease or on hemodialysis).
* Pregnant or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of the first dose of RT (Arm 1) or azeliragon (Arm 2).
* Patients with psychiatric illness/social situations, including alcohol or drug abuse that in the investigator's opinion will prevent administration or completion of protocol therapy.
* Non-English speaking, as the cognitive assessments will only be available in English
