Temporally-Modulated Pulsed Radiation Therapy Versus Standard Radiation Therapy for the Treatment of Newly Diagnosed, IDH Wildtype, MGMT-Unmethylated Glioblastoma

NCT07452458 | Not Yet Recruiting Phase 3 DMC

• 4 other identifiers: NRG-CC017NCI-2025-09197IVR-50415UG1CA189867
• Study Type: interventional
• Target: 398
• Locations: 0 countries
• Sites: N/A

Brief Summary

This phase III trial compares temporally-modulated pulsed radiation therapy versus standard radiation therapy in treating patients with newly diagnosed, IDH wildtype, MGMT-unmethylated glioblastoma. After completion of surgery, the standard of care for glioblastoma is radiation therapy. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. For older and frail patients, standard treatment also includes the chemotherapy drug temozolomide. Temozolomide is in a class of medications called alkylating agents. It works by damaging the cell's DNA and may kill tumor cells and slow down or stop tumor growth. Approximately 70% of glioblastoma patients have MGMT-unmethylated status. MGMT unmethylated tumors are less likely to respond to temozolomide chemotherapy, so there is more reliance on radiation therapy to kill the tumor cells. Recent clinical trials studying new therapies for MGMT-unmethylated glioblastoma have failed to improve outcomes over temozolomide. These recent studies also indicate that 80% of patients experience a decline in memory and thinking function after treatment. TMPRT differs from standard radiation therapy by delivering the same amount of radiation dose in 10-13 "pulses" with 3-minute breaks between pulses. TMPRT with temozolomide may work better than standard radiation therapy with temozolomide in increasing survival, as well as improving memory and thinking function in patients with newly diagnosed, IDH wildtype, MGMT-unmethylated glioblastoma.

Conditions

Glioblastoma, IDH-Wildtype; MGMT-Unmethylated Glioblastoma

Outcome Measures

Primary Outcomes (1)

• Neurocognitive function (NCF)

  This endpoint will be evaluated using each NCF testing interval. NCF failure is defined as a decline in NCF using the reliable change index (RCI) on at least one of the following tests: Hopkins Verbal Learning Test - Revised (HVLT-R) Total Recall, HVLT-R Delayed Recall, HVLT-R Delayed Recognition, Trail Making Test (TMT) Part A, TMT Part B, or Controlled Oral Word Association (COWA). The cumulative incidence approach will be used to estimate the time to neurocognitive failure to account for the competing risk of death. Gray's test will assess statistically significant differences in the distribution of NCF failure times (Gray 1988).

  Up to 9 months after completion of radiation therapy (RT)

Secondary Outcomes (8)

• Time to NCF failure in the subset of older patients (≤ 65 years)

  Up to 9 months after completion of RT

• NCF across time

  Up to 9 months after completion of RT

• Quality of Life (QoL)

  Up to 9 months after completion of RT

• Patient-reported cognitive outcomes (PRCO)

  Up to 9 months after completion of RT

• Frailty

  Up to 9 months after completion of RT

Study Arms (2)

Arm 1 (standard RT, temozolomide)

ACTIVE COMPARATOR

CONCURRENT TREATMENT (CYCLE 1): Patients receive standard RT over 12-15 minutes daily, 5 days a week, for 3 or 6 weeks. Patients also receive temozolomide PO QD on days 1-21 or 1-42. Cycle 1 treatment continues for 21 or 42 days in in the absence of disease progression or unacceptable toxicity. ADJUVANT TREATMENT (CYCLES 2+): Approximately 1 month after completion of standard RT, patients receive temozolomide PO QD on days 1-5 of each cycle. Cycles repeat every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI scans, as well as optional blood sample collection throughout the trial.

Procedure: Biospecimen Collection; Procedure: Computed Tomography; Procedure: Magnetic Resonance Imaging; Other: Questionnaire Administration; Radiation: Radiation Therapy; Drug: Temozolomide

Arm 2 (TMPRT, temozolomide)

EXPERIMENTAL

CONCURRENT TREATMENT (CYCLE 1): Patients receive TMPRT, delivered as 10-13 "pulses" over 30-40 minutes each with a 3 minute break in between, 5 days a week for 3 or 6 weeks. Patients also receive temozolomide PO QD on days 1-21 or 1-42. Cycle 1 treatment continues for 21 or 42 days in in the absence of disease progression or unacceptable toxicity. ADJUVANT TREATMENT (CYCLES 2+): Approximately 1 month after completion of standard RT, patients receive temozolomide PO QD on days 1-5 of each cycle. Cycles repeat every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI scans, as well as optional blood sample collection throughout the trial.

Procedure: Biospecimen Collection; Procedure: Computed Tomography; Procedure: Magnetic Resonance Imaging; Other: Questionnaire Administration; Drug: Temozolomide; Radiation: Temporally-modulated Pulsed Radiation Therapy

Interventions

Biospecimen Collection PROCEDURE

Undergo collection of blood

Also known as: Biological Sample Collection, Biospecimen Collected, Specimen Collection

Arm 1 (standard RT, temozolomide); Arm 2 (TMPRT, temozolomide)

Computed Tomography PROCEDURE

Undergo CT

Also known as: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, Diagnostic CAT Scan, Diagnostic CAT Scan Service Type, tomography

Arm 1 (standard RT, temozolomide); Arm 2 (TMPRT, temozolomide)

Magnetic Resonance Imaging PROCEDURE

Undergo MRI

Also known as: Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, MRIs, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging, sMRI, Structural MRI

Arm 1 (standard RT, temozolomide); Arm 2 (TMPRT, temozolomide)

Questionnaire Administration OTHER

Ancillary studies

Arm 1 (standard RT, temozolomide); Arm 2 (TMPRT, temozolomide)

Temozolomide DRUG

Given PO

Also known as: CCRG-81045, Gliotem, Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-, M & B 39831, M and B 39831, Methazolastone, RP-46161, SCH 52365, Temcad, Temizole, Temodal, Temodar, Temomedac, TMZ

Arm 1 (standard RT, temozolomide); Arm 2 (TMPRT, temozolomide)

Radiation Therapy RADIATION

Undergo standard RT

Also known as: Cancer Radiotherapy, Energy Type, ENERGY_TYPE, Irradiate, Irradiated, Irradiation, Radiation, Radiation Therapy, NOS, Radiotherapeutics, Radiotherapy, RT, Therapy, Radiation

Arm 1 (standard RT, temozolomide)

Temporally-modulated Pulsed Radiation Therapy RADIATION

Undergo TMPRT

Also known as: TMPRT

Arm 2 (TMPRT, temozolomide)

Eligibility Criteria

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

You may qualify if:

• PRIOR TO STEP 1 REGISTRATION:
• No known IDH mutation. (If tested before step 1 registration, patients known to have IDH mutation in the tumor on local or other testing are ineligible and should not be registered).
• Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue block and hematoxylin and eosin (H\&E) stained slide to be sent for central pathology review for confirmation of histology and MGMT promoter methylation status. Surgical resection is required; stereotactic biopsy alone is not allowed because it will not provide sufficient tissue for MGMT analysis. Note that tissue for central pathology review and central MGMT assessment must be shipped to the New York University (NYU) Center for Biospecimen Research and Development (CBRD) on or before postoperative calendar day 30. If tissue cannot be shipped by postoperative calendar day 30, then patients may NOT enroll on this trial as central pathology review will not be complete in time for the patient to start treatment no later than 8 weeks following surgery. Results of central pathology review and central MGMT analysis will generally be completed within 10 business days of receipt of tissue. Results will be entered by the central lab directly into Rave. Note: In the event of an additional tumor resection(s), tissue must be shipped within 30 days of the most recent resection and the latest resection must have been performed within 30 days after the initial resection.
• Negative urine or serum pregnancy test (in persons of childbearing potential) within 14 days prior to Step 1 registration. Childbearing potential is defined as any person who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal.
• No known leptomeningeal disease or metastatic disease outside the brain.
• Age ≥ 18
• Because neurocognitive testing is the primary goal of this study, patients must be proficient in English or French Canadian.
• Karnofsky Performance Status ≥ 70
• Hemoglobin ≥ 10 g/dl (Note: the use of transfusion or other intervention to achieve hemoglobin (Hgb) ≥ 10.0 g/dl is acceptable)
• Leukocytes ≥ 2,000/mm\^3 OR absolute neutrophil count ≥ 1,500/mm\^3
• Platelets ≥ 100,000/mm\^3
• Creatinine clearance (CrCl) ≥ 50 mL/min
• Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)
• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT)(serum glutamic pyruvate transaminase \[SGPT\]) ≤ 3 x ULN
• No prior cranial radiation therapy that would result in overlap of radiation therapy fields.

Sponsors & Collaborators

• NRG Oncology: lead

MeSH Terms

Conditions

Glioblastoma

Interventions

Specimen Handling; Magnetic Resonance Spectroscopy; Radiotherapy; Radiation; Temozolomide

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)

Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Spectrum Analysis; Chemistry Techniques, Analytical; Therapeutics; Physical Phenomena; Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Jiayi Huang

  NRG Oncology

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: As exploratory objectives of this study, T2/FLAIR sequences will be submitted for central analysis. Abnormal FLAIR volumes will be created in a semi-automated fashion by trained individuals using a consensus approach and blinded to the cognitive outcome data and treatment arm, as previously published (Bovi et al. 2019).
• Purpose: SUPPORTIVE CARE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 17, 2026
• First Posted: March 5, 2026
• Study Start (Estimated): June 8, 2026
• Primary Completion (Estimated): January 15, 2030
• Study Completion (Estimated): July 15, 2031
• Last Updated: May 4, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share