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

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.

Interventions

• Biospecimen Collection · PROCEDURE

  Undergo collection of blood

• Computed Tomography · PROCEDURE

  Undergo CT

• Magnetic Resonance Imaging · PROCEDURE

  Undergo MRI

• Questionnaire Administration · OTHER

  Ancillary studies

• Radiation Therapy · RADIATION

  Undergo standard RT

• Temozolomide · DRUG

  Given PO

• Temporally-modulated Pulsed Radiation Therapy · RADIATION

  Undergo TMPRT

Published eligibility criteria

Verbatim from the registry. Only the site can decide how these apply to a specific patient.

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.

Sites (54)

• UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care, Irvine, California · Recruiting
• USC / Norris Comprehensive Cancer Center, Los Angeles, California · Recruiting
• UC Irvine Health/Chao Family Comprehensive Cancer Center, Orange, California · Recruiting
• University of California Davis Comprehensive Cancer Center, Sacramento, California · Recruiting
• Saint Mary's Hospital and Regional Medical Center, Grand Junction, Colorado · Recruiting
• Alton Memorial Hospital, Alton, Illinois · Recruiting
• Decatur Memorial Hospital, Decatur, Illinois · Recruiting
• Northwestern Medicine Cancer Center Kishwaukee, DeKalb, Illinois · Recruiting
• Northwestern Medicine Cancer Center Delnor, Geneva, Illinois · Recruiting
• Cancer Care Center of O'Fallon, O'Fallon, Illinois · Recruiting
• HSHS Saint Elizabeth's Hospital, O'Fallon, Illinois · Recruiting
• Memorial Hospital East, Shiloh, Illinois · Recruiting
• Northwestern Medicine Cancer Center Warrenville, Warrenville, Illinois · Recruiting
• UI Health Care Mission Cancer and Blood - Ankeny Clinic, Ankeny, Iowa · Recruiting
• Saint Anthony Regional Hospital, Carroll, Iowa · Recruiting
• UI Health Care Mission Cancer and Blood - West Des Moines Clinic, Clive, Iowa · Recruiting
• Iowa Methodist Medical Center, Des Moines, Iowa · Recruiting
• UI Health Care Mission Cancer and Blood - Des Moines Clinic, Des Moines, Iowa · Recruiting
• Broadlawns Medical Center, Des Moines, Iowa · Recruiting
• UI Health Care Mission Cancer and Blood - Laurel Clinic, Des Moines, Iowa · Recruiting
• UI Healthcare Mission Cancer and Blood - Pella, Pella, Iowa · Recruiting
• UI Health Care Mission Cancer and Blood - Waukee Clinic, Waukee, Iowa · Recruiting
• University of Kansas Cancer Center, Kansas City, Kansas · Recruiting
• University of Kansas Cancer Center-Overland Park, Overland Park, Kansas · Recruiting
• University of Kansas Hospital-Westwood Cancer Center, Westwood, Kansas · Recruiting
• Maryland Proton Treatment Center, Baltimore, Maryland · Recruiting
• University of Maryland/Greenebaum Cancer Center, Baltimore, Maryland · Recruiting
• UM Upper Chesapeake Medical Center, Bel Air, Maryland · Recruiting
• UM Baltimore Washington Medical Center/Tate Cancer Center, Glen Burnie, Maryland · Recruiting
• Siteman Cancer Center at Saint Peters Hospital, City of Saint Peters, Missouri · Recruiting
• MU Health - University Hospital/Ellis Fischel Cancer Center, Columbia, Missouri · Recruiting
• Siteman Cancer Center at West County Hospital, Creve Coeur, Missouri · Recruiting
• University of Kansas Cancer Center - Briarcliff, Kansas City, Missouri · Recruiting
• University of Kansas Cancer Center - North, Kansas City, Missouri · Recruiting
• University of Kansas Cancer Center - Lee's Summit, Lee's Summit, Missouri · Recruiting
• Washington University School of Medicine, St Louis, Missouri · Recruiting
• Siteman Cancer Center-South County, St Louis, Missouri · Recruiting
• Siteman Cancer Center at Christian Hospital, St Louis, Missouri · Recruiting
• Renown Regional Medical Center, Reno, Nevada · Recruiting
• NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center, New York, New York · Recruiting
• Montefiore Medical Center-Einstein Campus, The Bronx, New York · Recruiting
• Montefiore Medical Center-Weiler Hospital, The Bronx, New York · Recruiting
• Montefiore Medical Center - Moses Campus, The Bronx, New York · Recruiting
• Case Western Reserve University, Cleveland, Ohio · Recruiting
• University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma · Recruiting
• ThedaCare Regional Cancer Center, Appleton, Wisconsin · Recruiting
• University of Wisconsin Carbone Cancer Center - Johnson Creek, Johnson Creek, Wisconsin · Recruiting
• University of Wisconsin Carbone Cancer Center - Eastpark Medical Center, Madison, Wisconsin · Recruiting
• University of Wisconsin Carbone Cancer Center - University Hospital, Madison, Wisconsin · Recruiting
• Froedtert Menomonee Falls Hospital, Menomonee Falls, Wisconsin · Recruiting
• Medical College of Wisconsin, Milwaukee, Wisconsin · Recruiting
• Froedtert and MCW Moorland Reserve Health Center, New Berlin, Wisconsin · Recruiting
• Drexel Town Square Health Center, Oak Creek, Wisconsin · Recruiting
• Froedtert West Bend Hospital/Kraemer Cancer Center, West Bend, Wisconsin · Recruiting