Temporally-Modulated Pulsed Radiation Therapy plus TMZ for MGMT-Unmethylated Glioblastoma

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.