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

September 9, 2026 updated by: NRG Oncology

A Randomized Phase III Study Comparing Temporally-Modulated Pulsed Radiation Therapy (TMPRT) Versus Standard Radiation Therapy With Temozolomide for Adults With Newly Diagnosed MGMT-Unmethylated Glioblastoma

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

PRIMARY OBJECTIVE:

I. To determine whether TMPRT concurrently with TMZ can significantly improve time to neurocognitive function (NCF) failure compared to standard radiation therapy (RT) with temozolomide for patients with MGMT-unmethylated GBM.

SECONDARY OBJECTIVES:

I. To determine whether TMPRT can significantly improve time to NCF failure for the subset of older patients (age ≥ 65) with MGMT-unmethylated GBM.

II. To evaluate between arm differences in NCF across time. III. To evaluate whether TMPRT prolongs overall survival (OS) compared to the control arm.

IV. To determine if progression free survival (PFS) is prolonged after TMPRT compared to the control arm.

V. To determine if TMPRT improves quality of life (QoL), compared to the control arm, as measured by the Functional Assessment of Cancer Therapy - Brain (FACT-Br) Total Score.

VI. To determine if TMPRT improves patient-reported cognitive outcome (PRCO) compared to the control arm, as measured by the Functional Assessment of Cancer Therapy - Brain Cognitive Index (FACT-Br- CI).

VII. To determine the impact of TMPRT on longitudinal changes in frailty after treatment compared to the control arm, as measured by the Deficit Accumulation Frailty Index (DAFI) derived from the Practical Geriatric Assessment (PGA).

VIII. To evaluate if TMPRT reduces toxicity compared to the control arm.

EXPLORATORY OBJECTIVES:

I. To evaluate the impact of TMPRT on functional, social, and emotional QoL compared to the control arm, as measured by the FACT-Br.

II. To evaluate the impact of TMPRT on longitudinal changes of specific geriatric assessment subscales compared to the control arm, as measured by the PGA.

III. To evaluate the impact of TMPRT on treatment burden during RT compared to the control arm, as measured by the FACT-Br Physical Wellbeing subscale (FACT-Br PWB).

IV. To investigate if TMPRT results in less white matter injury on post-treatment magnetic resonance imaging (MRI).

V. To collect blood samples for future translational studies. VI. To correlate NCF with QoL and frailty. VII. To determine if baseline NCF, QoL, and frailty are associated with OS. VIII. To correlate adverse events with baseline frailty and specific geriatric assessment subscales.

IX. To determine the concordance between institutional and central MGMT promoter status.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM 1:

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 orally (PO) once daily (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.

ARM 2:

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.

All patients also undergo computed tomography (CT) or MRI scans, as well as optional blood sample collection throughout the trial.

After completion of study treatment, patients are followed at months 1, 3, 5, 7, 9, and 12, then annually for 4 years.

Study Type

Interventional

Enrollment (Estimated)

398

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • Irvine, California, United States, 92612
        • Recruiting
        • UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care
        • Contact:
        • Principal Investigator:
          • Xiao-Tang Kong
      • Los Angeles, California, United States, 90033
        • Recruiting
        • USC / Norris Comprehensive Cancer Center
        • Principal Investigator:
          • Adam Garsa
        • Contact:
          • Site Public Contact
          • Phone Number: 323-865-0451
      • Orange, California, United States, 92868
        • Recruiting
        • UC Irvine Health/Chao Family Comprehensive Cancer Center
        • Contact:
        • Principal Investigator:
          • Xiao-Tang Kong
      • Sacramento, California, United States, 95817
        • Recruiting
        • University of California Davis Comprehensive Cancer Center
        • Principal Investigator:
          • Ruben C. Fragoso
        • Contact:
          • Site Public Contact
          • Phone Number: 916-734-3089
    • Colorado
      • Grand Junction, Colorado, United States, 81501
        • Recruiting
        • Saint Mary's Hospital and Regional Medical Center
        • Contact:
        • Principal Investigator:
          • Lucas Gilbride
    • Illinois
      • Alton, Illinois, United States, 62002
        • Recruiting
        • Alton Memorial Hospital
        • Contact:
          • Site Public Contact
          • Phone Number: 618-463-7323
        • Principal Investigator:
          • Jiayi Huang
      • DeKalb, Illinois, United States, 60115
        • Recruiting
        • Northwestern Medicine Cancer Center Kishwaukee
        • Contact:
        • Principal Investigator:
          • Vinai Gondi
      • Decatur, Illinois, United States, 62526
        • Recruiting
        • Decatur Memorial Hospital
        • Principal Investigator:
          • Bryan A. Faller
        • Contact:
      • Geneva, Illinois, United States, 60134
        • Recruiting
        • Northwestern Medicine Cancer Center Delnor
        • Contact:
        • Principal Investigator:
          • Vinai Gondi
      • O'Fallon, Illinois, United States, 62269
        • Recruiting
        • Cancer Care Center of O'Fallon
        • Principal Investigator:
          • Bryan A. Faller
        • Contact:
      • O'Fallon, Illinois, United States, 62269
        • Recruiting
        • HSHS Saint Elizabeth's Hospital
        • Principal Investigator:
          • Bryan A. Faller
        • Contact:
      • Shiloh, Illinois, United States, 62269
        • Recruiting
        • Memorial Hospital East
        • Contact:
        • Principal Investigator:
          • Jiayi Huang
      • Warrenville, Illinois, United States, 60555
        • Recruiting
        • Northwestern Medicine Cancer Center Warrenville
        • Contact:
        • Principal Investigator:
          • Vinai Gondi
    • Iowa
      • Ankeny, Iowa, United States, 50023
        • Recruiting
        • UI Health Care Mission Cancer and Blood - Ankeny Clinic
        • Contact:
          • Site Public Contact
          • Phone Number: 515-241-3305
        • Principal Investigator:
          • Seema Harichand-Herdt
      • Carroll, Iowa, United States, 51401
        • Recruiting
        • Saint Anthony Regional Hospital
        • Contact:
        • Principal Investigator:
          • Seema Harichand-Herdt
      • Clive, Iowa, United States, 50325
        • Recruiting
        • UI Health Care Mission Cancer and Blood - West Des Moines Clinic
        • Contact:
          • Site Public Contact
          • Phone Number: 515-241-3305
        • Principal Investigator:
          • Seema Harichand-Herdt
      • Des Moines, Iowa, United States, 50314
        • Recruiting
        • Broadlawns Medical Center
        • Contact:
          • Site Public Contact
          • Phone Number: 515-282-2200
        • Principal Investigator:
          • Seema Harichand-Herdt
      • Des Moines, Iowa, United States, 50309
        • Recruiting
        • Iowa Methodist Medical Center
        • Contact:
          • Site Public Contact
          • Phone Number: 515-241-6727
        • Principal Investigator:
          • Seema Harichand-Herdt
      • Des Moines, Iowa, United States, 50309
        • Recruiting
        • UI Health Care Mission Cancer and Blood - Des Moines Clinic
        • Contact:
          • Site Public Contact
          • Phone Number: 515-241-3305
        • Principal Investigator:
          • Seema Harichand-Herdt
      • Des Moines, Iowa, United States, 50314
        • Recruiting
        • UI Health Care Mission Cancer and Blood - Laurel Clinic
        • Contact:
          • Site Public Contact
          • Phone Number: 515-241-3305
        • Principal Investigator:
          • Seema Harichand-Herdt
      • Pella, Iowa, United States, 50219
        • Recruiting
        • UI Healthcare Mission Cancer and Blood - Pella
        • Principal Investigator:
          • Seema Harichand-Herdt
        • Contact:
      • Waukee, Iowa, United States, 50263
        • Recruiting
        • UI Health Care Mission Cancer and Blood - Waukee Clinic
        • Contact:
          • Site Public Contact
          • Phone Number: 515-241-3305
        • Principal Investigator:
          • Seema Harichand-Herdt
    • Kansas
      • Kansas City, Kansas, United States, 66160
        • Recruiting
        • University of Kansas Cancer Center
        • Contact:
        • Principal Investigator:
          • Danielle Cunningham
      • Overland Park, Kansas, United States, 66210
        • Recruiting
        • University of Kansas Cancer Center-Overland Park
        • Contact:
        • Principal Investigator:
          • Danielle Cunningham
      • Westwood, Kansas, United States, 66205
        • Recruiting
        • University of Kansas Hospital-Westwood Cancer Center
        • Contact:
        • Principal Investigator:
          • Danielle Cunningham
    • Maryland
      • Baltimore, Maryland, United States, 21201
        • Recruiting
        • University of Maryland/Greenebaum Cancer Center
        • Contact:
          • Site Public Contact
          • Phone Number: 800-888-8823
        • Principal Investigator:
          • Mark V. Mishra
      • Baltimore, Maryland, United States, 21201
        • Recruiting
        • Maryland Proton Treatment Center
        • Contact:
        • Principal Investigator:
          • Mark V. Mishra
      • Bel Air, Maryland, United States, 21014
        • Recruiting
        • UM Upper Chesapeake Medical Center
        • Contact:
          • Site Public Contact
          • Phone Number: 443-643-3010
        • Principal Investigator:
          • Mark V. Mishra
      • Glen Burnie, Maryland, United States, 21061
        • Recruiting
        • UM Baltimore Washington Medical Center/Tate Cancer Center
        • Contact:
          • Site Public Contact
          • Phone Number: 410-553-8100
        • Principal Investigator:
          • Mark V. Mishra
    • Missouri
      • City of Saint Peters, Missouri, United States, 63376
        • Recruiting
        • Siteman Cancer Center at Saint Peters Hospital
        • Contact:
        • Principal Investigator:
          • Jiayi Huang
      • Columbia, Missouri, United States, 65212
        • Recruiting
        • MU Health - University Hospital/Ellis Fischel Cancer Center
        • Contact:
          • Site Public Contact
          • Phone Number: 573-882-7440
        • Principal Investigator:
          • Mohamed Abdelhakiem
      • Creve Coeur, Missouri, United States, 63141
        • Recruiting
        • Siteman Cancer Center at West County Hospital
        • Contact:
        • Principal Investigator:
          • Jiayi Huang
      • Kansas City, Missouri, United States, 64154
        • Recruiting
        • University of Kansas Cancer Center - North
        • Contact:
        • Principal Investigator:
          • Danielle Cunningham
      • Kansas City, Missouri, United States, 64116
        • Recruiting
        • University of Kansas Cancer Center - Briarcliff
        • Principal Investigator:
          • Danielle Cunningham
        • Contact:
          • Site Public Contact
          • Phone Number: 913-588-3671
      • Lee's Summit, Missouri, United States, 64064
        • Recruiting
        • University of Kansas Cancer Center - Lee's Summit
        • Contact:
        • Principal Investigator:
          • Danielle Cunningham
      • St Louis, Missouri, United States, 63110
        • Recruiting
        • Washington University School of Medicine
        • Contact:
        • Principal Investigator:
          • Jiayi Huang
      • St Louis, Missouri, United States, 63129
        • Recruiting
        • Siteman Cancer Center-South County
        • Contact:
        • Principal Investigator:
          • Jiayi Huang
      • St Louis, Missouri, United States, 63136
        • Recruiting
        • Siteman Cancer Center at Christian Hospital
        • Contact:
        • Principal Investigator:
          • Jiayi Huang
    • Nevada
      • Reno, Nevada, United States, 89502
        • Recruiting
        • Renown Regional Medical Center
        • Contact:
        • Principal Investigator:
          • Suchit H. Patel
    • New York
      • New York, New York, United States, 10032
        • Recruiting
        • NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
        • Principal Investigator:
          • Tony J. Wang
        • Contact:
      • The Bronx, New York, United States, 10461
        • Recruiting
        • Montefiore Medical Center-Einstein Campus
        • Principal Investigator:
          • Justin Tang
        • Contact:
      • The Bronx, New York, United States, 10467
        • Recruiting
        • Montefiore Medical Center - Moses Campus
        • Principal Investigator:
          • Justin Tang
        • Contact:
      • The Bronx, New York, United States, 10461
        • Recruiting
        • Montefiore Medical Center-Weiler Hospital
        • Principal Investigator:
          • Justin Tang
        • Contact:
    • Ohio
      • Cleveland, Ohio, United States, 44106
        • Recruiting
        • Case Western Reserve University
        • Contact:
        • Principal Investigator:
          • Haley K. Perlow
    • Oklahoma
      • Oklahoma City, Oklahoma, United States, 73104
        • Recruiting
        • University of Oklahoma Health Sciences Center
        • Contact:
        • Principal Investigator:
          • Shearwood McClelland
    • Wisconsin
      • Appleton, Wisconsin, United States, 54911
        • Recruiting
        • ThedaCare Regional Cancer Center
        • Contact:
        • Principal Investigator:
          • Joseph A. Bovi
      • Johnson Creek, Wisconsin, United States, 53038
        • Recruiting
        • University of Wisconsin Carbone Cancer Center - Johnson Creek
        • Contact:
        • Principal Investigator:
          • Brett A. Morris
      • Madison, Wisconsin, United States, 53792
        • Recruiting
        • University of Wisconsin Carbone Cancer Center - University Hospital
        • Contact:
        • Principal Investigator:
          • Brett A. Morris
      • Madison, Wisconsin, United States, 53718
        • Recruiting
        • University of Wisconsin Carbone Cancer Center - Eastpark Medical Center
        • Contact:
        • Principal Investigator:
          • Brett A. Morris
      • Menomonee Falls, Wisconsin, United States, 53051
        • Recruiting
        • Froedtert Menomonee Falls Hospital
        • Contact:
          • Site Public Contact
          • Phone Number: 262-257-5100
        • Principal Investigator:
          • Michael W. Straza
      • Milwaukee, Wisconsin, United States, 53226
        • Recruiting
        • Medical College of Wisconsin
        • Contact:
          • Site Public Contact
          • Phone Number: 414-805-3666
        • Principal Investigator:
          • Michael W. Straza
      • New Berlin, Wisconsin, United States, 53151
        • Recruiting
        • Froedtert and MCW Moorland Reserve Health Center
        • Contact:
          • Site Public Contact
          • Phone Number: 414-805-0505
        • Principal Investigator:
          • Michael W. Straza
      • Oak Creek, Wisconsin, United States, 53154
        • Recruiting
        • Drexel Town Square Health Center
        • Contact:
          • Site Public Contact
          • Phone Number: 414-805-0505
        • Principal Investigator:
          • Michael W. Straza
      • West Bend, Wisconsin, United States, 53095
        • Recruiting
        • Froedtert West Bend Hospital/Kraemer Cancer Center
        • Contact:
          • Site Public Contact
          • Phone Number: 414-805-0505
        • Principal Investigator:
          • Michael W. Straza

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • 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.

  • No previous therapy for GBM except surgery, laser interstitial thermal therapy (LITT) or Gliadel wafer.

    • Note: 5-aminolevulinic acid (ALA)-mediated fluorescence-guided resection (FGR) photodynamic therapy (PDT) or fluorescein administered prior to/during surgery to aid resection is not exclusionary and is not considered a chemotherapy or intracerebral agent.
  • No history of unstable angina requiring hospitalization in the last 3 months
  • No history of myocardial infarction within the last 3 months
  • New York Heart Association Functional Classification II or better (NYHA Functional Classification III/IV are not eligible) (Note: Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification)
  • No active infection currently requiring IV antibiotic management
  • No chronic obstructive pulmonary disease exacerbation or other acute respiratory illness precluding study therapy
  • No movement disorder that could impede ability to lie still with an immobilization mask for approximately 40 minutes
  • No significant sensory deficits (i.e., blindness, mutism) that would prohibit participation of NCF testing
  • No history of allergic reaction attributed to compounds of similar chemical or biological composition to temozolomide
  • PRIOR TO STEP 2 REGISTRATION:

  • The following baseline neurocognitive tests must be completed within 28 days prior to Step 2 registration: (Hopkins Verbal Learning Test - Revised [HVLT-R], Trail Making Test [TMT], Controlled Oral Word Association [COWA]). The neurocognitive tests will be uploaded into RAVE for evaluation by Dr. Wefel. The following scores must be obtained for patient eligibility: HVLT-R Total Recall > 5, HVLT-R Delayed Recall > 3, HVLT-R Delayed Recognition > -10, TMT Part A . 2738, TMT Part B . 3724, COWA . 12. Central review of the Neurocognitive tests will be completed in Rave within 3 business days after the upload is completed. Users with the Rave clinical research associate (CRA) role will be able to view the results in Rave. The CRA must confirm that the results are available and meet eligibility requirements prior to proceeding with Step 2 Registration.

    • NOTE: Completed baseline neurocognitive tests can be uploaded at the time of Step 1 registration.
    • Note: Patients whose neurocognitive test scores do not meet the criteria above will not be eligible for the study and will be reported as ineligible due to "Failure to meet Neurocognitive testing criteria" on Step 2 registration.

  • Pathology proven diagnosis of IDH-wildtype glioblastoma with unmethylated MGMT promoter confirmed by central pathology review. IDH mutation testing by at least one method (such as immunohistochemistry for IDH1 R132H) must be performed as part of standard of care and no mutation must be found (i.e. IDH-wildtype). (If a mutation is identified then the patient will be ineligible and must be registered as ineligible at Step 2.)

    • Central pathology review will generally be completed within 10 business days of receipt of the tissue. Users with the Rave CRA role will be able to view the results in Rave. It must be confirmed that the results are available and meet eligibility requirements prior to proceeding with Step 2 Registration.
    • Note: Patients with tissue that is insufficient or inadequate for analysis, has failed MGMT testing, or has indeterminate or methylated MGMT promoter are excluded and will be reported as a "central pathology review failure" on step 2 registration.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Supportive Care
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Arm 1 (standard RT, temozolomide)

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.
Other: Questionnaire Administration
Ancillary studies
Procedure: Biospecimen Collection
Undergo collection of blood
Other Names:
  • Biological Sample Collection
  • Biospecimen Collected
  • Specimen Collection
Procedure: Magnetic Resonance Imaging
Undergo MRI
Other Names:
  • MRI
  • Magnetic Resonance
  • Magnetic Resonance Imaging Scan
  • Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
  • MR
  • MR Imaging
  • MRI Scan
  • NMR Imaging
  • NMRI
  • Nuclear Magnetic Resonance Imaging
  • Magnetic Resonance Imaging (MRI)
  • sMRI
  • Magnetic resonance imaging (procedure)
  • MRIs
  • Structural MRI
Procedure: Computed Tomography
Undergo CT
Other Names:
  • CT
  • CAT
  • CAT Scan
  • Computed Axial Tomography
  • Computerized Axial Tomography
  • Computerized Tomography
  • CT Scan
  • tomography
  • Computerized axial tomography (procedure)
  • Computerized Tomography (CT) scan
  • Diagnostic CAT Scan
  • Diagnostic CAT Scan Service Type
Drug: Temozolomide
Given PO
Other Names:
  • Temodar
  • SCH 52365
  • Temodal
  • Temcad
  • Methazolastone
  • RP-46161
  • Temomedac
  • TMZ
  • CCRG-81045
  • 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
  • Gliotem
  • Temizole
Radiation: Radiation Therapy
Undergo standard RT
Other Names:
  • Cancer Radiotherapy
  • ENERGY_TYPE
  • Irradiate
  • Irradiated
  • Irradiation
  • Radiation
  • Radiation Therapy, NOS
  • Radiotherapeutics
  • Radiotherapy
  • RT
  • Therapy, Radiation
  • Energy Type
Experimental: Arm 2 (TMPRT, temozolomide)

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.
Other: Questionnaire Administration
Ancillary studies
Procedure: Biospecimen Collection
Undergo collection of blood
Other Names:
  • Biological Sample Collection
  • Biospecimen Collected
  • Specimen Collection
Procedure: Magnetic Resonance Imaging
Undergo MRI
Other Names:
  • MRI
  • Magnetic Resonance
  • Magnetic Resonance Imaging Scan
  • Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
  • MR
  • MR Imaging
  • MRI Scan
  • NMR Imaging
  • NMRI
  • Nuclear Magnetic Resonance Imaging
  • Magnetic Resonance Imaging (MRI)
  • sMRI
  • Magnetic resonance imaging (procedure)
  • MRIs
  • Structural MRI
Procedure: Computed Tomography
Undergo CT
Other Names:
  • CT
  • CAT
  • CAT Scan
  • Computed Axial Tomography
  • Computerized Axial Tomography
  • Computerized Tomography
  • CT Scan
  • tomography
  • Computerized axial tomography (procedure)
  • Computerized Tomography (CT) scan
  • Diagnostic CAT Scan
  • Diagnostic CAT Scan Service Type
Drug: Temozolomide
Given PO
Other Names:
  • Temodar
  • SCH 52365
  • Temodal
  • Temcad
  • Methazolastone
  • RP-46161
  • Temomedac
  • TMZ
  • CCRG-81045
  • 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
  • Gliotem
  • Temizole
Radiation: Temporally-modulated Pulsed Radiation Therapy
Undergo TMPRT
Other Names:
  • TMPRT

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Neurocognitive function (NCF)
Time Frame: Up to 9 months after completion of radiation therapy (RT)
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Time to NCF failure in the subset of older patients (≤ 65 years)
Time Frame: Up to 9 months after completion of RT
Will be measured by the HVLT-R, COWA, and TMT. A mixed effects model will be used to assess changes of standardized neurocognitive scores across time using all available data while adjusting for stratification variables and other baseline characteristics. Fixed effects will consist of treatment arm, baseline score, Recursive Partitioning Analysis (RPA) class, fractionation, tumor treating fields therapy (TTFields), steroid use, anti-seizure medication use as well as the interaction between time and treatment arm.
Up to 9 months after completion of RT
NCF across time
Time Frame: Up to 9 months after completion of RT
Will be measured by the HVLT-R, COWA, and TMT. A mixed effects model will be used to assess changes of standardized neurocognitive scores across time using all available data while adjusting for stratification variables and other baseline characteristics. Fixed effects will consist of treatment arm, baseline score, RPA class, fractionation, TTFields, steroid use, anti-seizure medication use as well as the interaction between time and treatment arm.
Up to 9 months after completion of RT
Quality of Life (QoL)
Time Frame: Up to 9 months after completion of RT
The Functional Assessment of Cancer Therapy - Brain (FACT-Br) total score will be used to measure overall QoL. Scores will be analyzed similarly to the individual NCF tests as described above. Briefly, mixed effects models will be performed. If the time by treatment interaction is significant, then tests will be conducted at each timepoint, within the model framework. Missing data will also be assessed and sensitivity analyses performed as needed.
Up to 9 months after completion of RT
Patient-reported cognitive outcomes (PRCO)
Time Frame: Up to 9 months after completion of RT
Nine items make up the FACT-Br-Cognitive Index score that will be used to assess PRCO. Scores will be analyzed similarly to the individual NCF tests as described above. Briefly, mixed effects models will be performed. If the time by treatment interaction is significant, then tests will be conducted at each timepoint, within the model framework. Missing data will also be assessed and sensitivity analyses performed as needed.
Up to 9 months after completion of RT
Frailty
Time Frame: Up to 9 months after completion of RT
The primary frailty endpoint is the Deficit Accumulation Frailty Index (DAFI) which requires at least 30 items in the score for it to be valid (Searle 2008). Thus, the NCF score will be removed from the DAFI score calculation since the primary endpoint of the trial is NCF. At least 90% of the DAFI must be completed to be included in the analysis. The continuous DAFI score will be analyzed similarly to the individual NCF tests as described above in the section. Briefly, mixed effects models will be performed. If the time by treatment interaction is significant, then tests will be conducted at each timepoint, within the model framework. Missing data will also be assessed and sensitivity analyses performed as needed.
Up to 9 months after completion of RT
Overall survival (OS)
Time Frame: From the date of randomization to the date of death, or, otherwise, the last follow-up date on which the patient was reported alive, assessed up to 9 months after completion of RT
OS rates will be estimated using the Kaplan-Meier method, and differences between treatment arms will be tested using the log rank test.
From the date of randomization to the date of death, or, otherwise, the last follow-up date on which the patient was reported alive, assessed up to 9 months after completion of RT
Progression-free survival (PFS)
Time Frame: From the date of randomization to the date of progression or death, whichever occurs first, or the last follow-up date on which the patient was reported alive, assessed up to 9 months after completion of RT
PFS rates will be estimated using the Kaplan-Meier method, and differences between treatment arms will be tested using the log rank test.
From the date of randomization to the date of progression or death, whichever occurs first, or the last follow-up date on which the patient was reported alive, assessed up to 9 months after completion of RT
Incidence of adverse events (AEs)
Time Frame: Up to 9 months after completion of RT
AEs will be evaluated using Common Terminology Criteria for Adverse Events version 5.0. Counts of all AEs by grade will be provided by treatment arm. Counts and frequencies will be provided for the worst grade AE experienced by the patient by treatment arm. The rate of grade 3+ AEs and the rate of grade 3+ central nervous system necrosis, stroke, and intra-cranial hemorrhage will be compared between treatment arms using a Chi-square test at a two-sided significance level of 0.05.
Up to 9 months after completion of RT

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

NRG Oncology

Investigators

  • Principal Investigator: Jiayi Huang, NRG Oncology

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 16, 2026

Primary Completion (Estimated)

January 15, 2030

Study Completion (Estimated)

July 15, 2035

Study Registration Dates

First Submitted

February 17, 2026

First Submitted That Met QC Criteria

March 2, 2026

First Posted (Actual)

March 5, 2026

Study Record Updates

Last Update Posted (Actual)

September 10, 2026

Last Update Submitted That Met QC Criteria

September 9, 2026

Last Verified

September 1, 2026

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NRG-CC017 (Other Identifier: DCP)
  • UG1CA189867 (U.S. NIH Grant/Contract)
  • NCI-2025-09197 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
  • IVR-50415 (Other Identifier: CTEP)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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