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

NCT06831526 | Recruiting Early Phase 1 FDA Drug

• 1 other identifier: 202504190
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Glioblastoma

Keywords

GBM; Neoadjuvant chemoradiotherapy; Azeliragon; RAGE inhibitor; Window of opportunity study

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (5)

• 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)

• Number of participants with intolerable toxicities

  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)

• Feasibility of the regimen as measured by the number of participants who proceed with post-chemoradiotherapy surgery or LITT

  Through surgery or LITT (estimated to be 60 days)

Study Arms (2)

Arm 1: Neoadjuvant RT and Temozolomide (TMZ) + Surgery or LITT + Adjuvant TMZ & Azeliragon

ACTIVE COMPARATOR

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; Drug: Temozolomide; Radiation: Radiation therapy; Procedure: Surgery or LITT

Arm 2: Neoadjuvant RT, Temozolomide (TMZ) & Azeliragon + Surgery or LITT + Adjuvant TMZ & Azeliragon

EXPERIMENTAL

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; Drug: Temozolomide; Radiation: Radiation therapy; Procedure: Surgery or LITT

Interventions

Azeliragon DRUG

Provided by Cantex Pharmaceuticals

Arm 1: Neoadjuvant RT and Temozolomide (TMZ) + Surgery or LITT + Adjuvant TMZ & Azeliragon; Arm 2: Neoadjuvant RT, Temozolomide (TMZ) & Azeliragon + Surgery or LITT + Adjuvant TMZ & Azeliragon

Temozolomide DRUG

Standard of care.

Also known as: TMZ

Arm 1: Neoadjuvant RT and Temozolomide (TMZ) + Surgery or LITT + Adjuvant TMZ & Azeliragon; Arm 2: Neoadjuvant RT, Temozolomide (TMZ) & Azeliragon + Surgery or LITT + Adjuvant TMZ & Azeliragon

Radiation therapy RADIATION

Standard of care.

Arm 1: Neoadjuvant RT and Temozolomide (TMZ) + Surgery or LITT + Adjuvant TMZ & Azeliragon; Arm 2: Neoadjuvant RT, Temozolomide (TMZ) & Azeliragon + Surgery or LITT + Adjuvant TMZ & Azeliragon

Surgery or LITT PROCEDURE

Standard of care surgical resection or laser interstitial thermal therapy (LITT).

Arm 1: Neoadjuvant RT and Temozolomide (TMZ) + Surgery or LITT + Adjuvant TMZ & Azeliragon; Arm 2: Neoadjuvant RT, Temozolomide (TMZ) & Azeliragon + Surgery or LITT + Adjuvant TMZ & Azeliragon

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Washington University School of Medicine: lead
• Cantex Pharmaceuticals: collaborator

Study Sites (1)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

RECRUITING

Related Links

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

MeSH Terms

Conditions

Glioblastoma

Interventions

azeliragon; Temozolomide; Radiotherapy; Surgical Procedures, Operative

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Therapeutics

Study Officials

• Jiayi Huang, M.D.

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jiayi Huang, M.D.

CONTACT

314-362-8567; jiayi.huang@wustl.edu

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 12, 2025
• First Posted: February 18, 2025
• Study Start: November 6, 2025
• Primary Completion (Estimated): February 28, 2029
• Study Completion (Estimated): August 31, 2030
• Last Updated: November 12, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)