Neoadjuvant Chemoradiotherapy With or Without Concurrent Azeliragon in Patients With Newly Diagnosed Glioblastoma

A Window-of-opportunity Early Phase I Randomized Study of Neoadjuvant Chemoradiotherapy With or Without Concurrent Azeliragon in Patients With Newly Diagnosed Glioblastoma

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.

Study Overview

• Status: Recruiting
• Conditions: Glioblastoma
• Intervention / Treatment: Drug: Azeliragon; Drug: Temozolomide; Radiation: Radiation therapy; Procedure: Surgery or LITT

• Study Type: Interventional
• Enrollment (Estimated): 12
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Jiayi Huang, M.D.; Phone Number: 314-362-8567; Email: jiayi.huang@wustl.edu

Study Locations

• United States
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Recruiting
      • Washington University School of Medicine
      • Contact: Jiayi Huang, M.D.; Phone Number: 314-362-8567; Email: jiayi.huang@wustl.edu
      • Principal Investigator: Jiayi Huang, M.D.
      • Sub-Investigator: Eric Leuthardt, M.D.
      • Sub-Investigator: Albert Kim, M.D., Ph.D.
      • Sub-Investigator: Joshua Dowling, M.D.
      • Sub-Investigator: Omar Butt, M.D., Ph.D.
      • Sub-Investigator: Tanner Johanns, M.D., Ph.D.
      • Sub-Investigator: Joshua Shimony, M.D.
      • Sub-Investigator: Nikhil Rammohan, M.D., Ph.D.
      • Sub-Investigator: Chun-Kan Chen, Ph.D.
      • Sub-Investigator: Dimitrios Mathios, M.D.
      • Sub-Investigator: Abraham Snyder, M.D.
      • Sub-Investigator: Chongliang Luo, Ph.D.
      • Sub-Investigator: Milan Chheda, M.D., Ph.D.
      • Sub-Investigator: Robert Fucetola, Ph.D.
      • Sub-Investigator: Timothy Mitchell, Ph.D.
      • Sub-Investigator: Zhihua Liu, Ph.D.
      • Sub-Investigator: Ananth Vellimana, M.D.
      • Sub-Investigator: Greg Zipfel, M.D.
      • Sub-Investigator: Tammie Benzinger, M.D., Ph.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm 1: Neoadjuvant RT and Temozolomide (TMZ) + Surgery or LITT + Adjuvant TMZ & Azeliragon; Radiation therapy (RT) will consist of fractionated RT to 60 Gy in 30 daily fractions administered per standard of care RTOG approach. Concurrent TMZ during RT will be self-administered by mouth (PO) as per standard of care. 1 month after completion of RT, patient will proceed with planned surgery of either resection or LITT. Patients will then receive adjuvant TMZ and azeliragon for up to 6 months. Patient should start with the loading dose 30 mg BID for 6 days before the start of adjuvant TMZ. After 6 days, azeliragon 20 mg once daily should be continued in combination with TMZ.	Drug: Azeliragon; Provided by Cantex Pharmaceuticals; Drug: Temozolomide; Standard of care.; Other Names: TMZ; Radiation: Radiation therapy; Standard of care.; Procedure: Surgery or LITT; Standard of care surgical resection or laser interstitial thermal therapy (LITT).
Experimental: Arm 2: Neoadjuvant RT, Temozolomide (TMZ) & Azeliragon + Surgery or LITT + Adjuvant TMZ & Azeliragon; RT will consist of fractionated RT to 60 Gy in 30 daily fractions administered per standard of care RTOG approach. Concurrent TMZ during RT will be self-administered by mouth (PO) as per standard of care. Patients will receive azeliragon as well. Azeliragon is self-administered PO. Azeliragon dosing will consist of 6 days of a loading dose of 30 mg twice per day starting on day -6, followed by 20 mg daily starting on the Day 1. Concurrent RT and TMZ start on Day 1. Azeliragon should continue until the day before planned surgical procedure. 1 month after completion of RT, patient will proceed with planned surgery of either resection or LITT. Patients will then receive adjuvant TMZ and azeliragon for up to 6 months. Patient should start with the loading dose 30 mg BID for 6 days before the start of adjuvant TMZ. After 6 days, azeliragon 20 mg once daily should be continued in combination with TMZ.	Drug: Azeliragon; Provided by Cantex Pharmaceuticals; Drug: Temozolomide; Standard of care.; Other Names: TMZ; Radiation: Radiation therapy; Standard of care.; Procedure: Surgery or LITT; Standard of care surgical resection or laser interstitial thermal therapy (LITT).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Percentage of immune-suppressive myeloid cells in the tumor tissue	At time of surgery or LITT (estimated to be day 60)
Percentage of immune-suppressive T cells in the tumor tissue	At time of surgery or LITT (estimated to be day 60)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with intolerable toxicities	The protocol lists the specific toxicities that are considered intolerable.	From first dose of azeliragon until 30 days after the last dose (estimated to be 6-9 months)
Progression-free survival (PFS)		Up to 12 months after completion of study treatment (estimated to be 21 months)
Overall survival (OS)		Up to 12 months after completion of study treatment (estimated to be 21 months)
Number of participants with adverse events		From day 1 (Arm 1) or Day -6 (Arm 2) through 30 days after last dose of azeliragon (estimated to be 10 months)
Feasibility of the regimen as measured by the number of participants who proceed with post-chemoradiotherapy surgery or LITT	Feasibility is defined as at least 50% of patients in each arm who are able to proceed with post-chemoradiotherapy surgery or LITT.	Through surgery or LITT (estimated to be 60 days)

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: Cantex Pharmaceuticals
• Investigators: Principal Investigator: Jiayi Huang, M.D., Washington University School of Medicine

Publications and helpful links

Helpful Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): November 6, 2025
• Primary Completion (Estimated): February 28, 2029
• Study Completion (Estimated): August 31, 2030

Study Registration Dates

• First Submitted: February 12, 2025
• First Submitted That Met QC Criteria: February 12, 2025
• First Posted (Actual): February 18, 2025

Study Record Updates

• Last Update Posted (Actual): May 29, 2026
• Last Update Submitted That Met QC Criteria: May 26, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: GBM; Azeliragon; Neoadjuvant chemoradiotherapy; RAGE inhibitor; Window of opportunity study
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Therapeutics; Azoles; Dacarbazine; Triazenes; Imidazoles; Temozolomide; Radiotherapy; Surgical Procedures, Operative; azeliragon
• Other Study ID Numbers: 202504190

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No