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

Early Phase 1

Not yet recruiting

• Conditions: Glioblastoma
• Interventions: Drug: Azeliragon; Drug: Temozolomide; Radiation: Radiation therapy; Procedure: Surgery or LITT

• Registration Number: NCT06831526
• Lead Sponsor: Washington University School of Medicine

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.

Detailed Description

Not available

Study Timeline

• Status Verified: 2025-02
• Study First Submitted: 2025-02-12
• Study First Submitted QC: 2025-02-12
• Last Update Submitted: 2025-02-12
• Study First Posted: 2025-02-18
• Last Update Posted: 2025-02-18
• Study Start: 2025-05-31
• Primary Completion: 2027-10-31
• Study Completion: 2029-05-31

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 12

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) 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 woman 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 study entry.
• 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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm 1: Neoadjuvant RT and Temozolomide (TMZ) + Surgery or LITT + Adjuvant TMZ & Azeliragon	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. TMZ should ideally start on day 7, but may start up to day 21.
Arm 1: Neoadjuvant RT and Temozolomide (TMZ) + Surgery or LITT + Adjuvant TMZ & Azeliragon	Temozolomide	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. TMZ should ideally start on day 7, but may start up to day 21.
Arm 1: Neoadjuvant RT and Temozolomide (TMZ) + Surgery or LITT + Adjuvant TMZ & Azeliragon	Radiation therapy	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. TMZ should ideally start on day 7, but may start up to day 21.
Arm 1: Neoadjuvant RT and Temozolomide (TMZ) + Surgery or LITT + Adjuvant TMZ & Azeliragon	Surgery or LITT	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. TMZ should ideally start on day 7, but may start up to day 21.
Arm 2: Neoadjuvant RT, Temozolomide (TMZ) & Azeliragon + Surgery or LITT + Adjuvant TMZ & Azeliragon	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 (days 1-6), followed by 20 mg daily starting on the 7th day. RT should ideally start on day 7, but may start up to day 21. 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. TMZ should ideally start on day 7, but may start up to day 21.
Arm 2: Neoadjuvant RT, Temozolomide (TMZ) & Azeliragon + Surgery or LITT + Adjuvant TMZ & Azeliragon	Temozolomide	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 (days 1-6), followed by 20 mg daily starting on the 7th day. RT should ideally start on day 7, but may start up to day 21. 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. TMZ should ideally start on day 7, but may start up to day 21.
Arm 2: Neoadjuvant RT, Temozolomide (TMZ) & Azeliragon + 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. 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 (days 1-6), followed by 20 mg daily starting on the 7th day. RT should ideally start on day 7, but may start up to day 21. 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. TMZ should ideally start on day 7, but may start up to day 21.
Arm 2: Neoadjuvant RT, Temozolomide (TMZ) & Azeliragon + Surgery or LITT + Adjuvant TMZ & Azeliragon	Surgery or LITT	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 (days 1-6), followed by 20 mg daily starting on the 7th day. RT should ideally start on day 7, but may start up to day 21. 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. TMZ should ideally start on day 7, but may start up to day 21.

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
Number of participants with adverse events	From start of neoadjuvant treatment 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)	The protocol lists the specific toxicities that are considered intolerable.
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 biopsy	Through surgery or biopsy (estimated to be 60 days)	Feasibility is defined as at least 50% of patients in each arm who are able to proceed with post-chemoradiotherapy surgery or biopsy.

Trial Locations

Locations (1)

Washington University School of Medicine; 🇺🇸 Saint Louis, Missouri, United States