Preclinical data have demonstrated the combination of azeliragon, a RAGE inhibitor, with radiation therapy (RT) can effectively reduce immune-suppressive myeloid cells and restore T-cell activation to improve tumor control in murine glioma models. Ongoing clinical studies of azeliragon with RT alone and RT plus temozolomide (TMZ) to treat patients with newly diagnosed glioblastoma (GBM) have demonstrated safety and tolerability. The purpose of this window-of-opportunity study is to validate that the combination of azeliragon with RT and TMZ would modulate immune-suppressive myeloid and T cells in the tumor microenvironment in patients with GBM.

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