Peposertib and Radiation Therapy, Followed by Temozolomide for the Treatment of Patients With Newly Diagnosed MGMT Unmethylated Glioblastoma or Gliosarcoma

Eligibility Criteria

• * Signed informed consent form (ICF)
• * Ability and willingness to comply with the requirement of the study protocol
• * Histologically confirmed World Health Organization (WHO) grade IV glioma (GBM) or gliosarcoma, IDH wild-type
• * Documentation of MGMT unmethylated GBM per testing at any Clinical Laboratory Improvement Amendment (CLIA) certified laboratory
• * Patients must have undergone brain surgery or biopsy and must not have had any further treatments following surgery
• * Have Karnofsky performance status (KPS) of \>= 60 or Eastern Cooperative Oncology Group (ECOG) =\< 2
• * A baseline magnetic resonance imaging (MRI) of brain obtained no more than 14 days prior to study enrollment on a stable or tapering dose of steroids no greater than 4 mg a day of dexamethasone (or equivalent dose of other steroids) for at least 3 days
• * Patients must start treatment within 8 weeks of last brain surgical procedure (biopsy or resection)
• * Absolute neutrophil count (ANC) \>= 1,500 /mcL (within 14 days prior to day 1 of the study)
• * Platelets \>= 100,000/mcL (within 14 days prior to day 1 of the study)
• * Hemoglobin \>= 9 g/dL or \>= 5.6 mmol/L (within 14 days prior to day 1 of the study)
• * Serum creatinine =\< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate \[GFR\] can also be used in place of creatinine or creatinine clearance \[CrCl\]) \>= 60 mL/min for subject with creatinine levels \> 1.5 x institutional ULN (within 14 days prior to day 1 of the study)
• * Serum total bilirubin =\< 1.5 x ULN OR direct bilirubin =\< ULN for subjects with total bilirubin levels \> 1.5 x ULN (within 14 days prior to day 1 of the study)
• * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 x ULN (within 14 days prior to day 1 of the study)
• * International normalized ratio (INR) or prothrombin time (PT) =\< 1.5 x ULN (within 14 days prior to day 1 of the study)
• * Activated partial thromboplastin time (aPTT) =\< 1.5 x ULN (within 14 days prior to day 1 of the study)
• * Have provided tissue from an archival tissue sample
• * Female subjects of childbearing potential should have a negative serum pregnancy test within 14 days of day 1 of the study
• * Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile
• * Male subjects should agree to use an adequate method of contraception during the course of the study
• * STAGE I: In the case stage I patients need resection as determined by the treating physicians during or after completion of radiation therapy (RT) and that pathology of resected lesion is not consistent with recurrent GBM, the patient can continue on the study (complete 6 weeks of RT + M3814) if deemed appropriate by the treating physicians. The tissue obtained in such circumstances will be analyzed as in Stage II subjects. However, these cases will not count towards the 5 patients who will be enrolled during Stage II. These patients will contribute to the correlative endpoints detailed above and ORR, OS, and PFS as Stage II patients
• * STAGE II: Patients meet above criteria, would benefit from further non-urgent surgical resection of at least one enhancing lesion per the treating physician, and would provide consent to undergo surgery after treatment with RT and M3814
• * Has received prior interstitial brachytherapy, implanted chemotherapy, or therapeutics delivered by local injection or convection enhanced delivery. Prior treatment with Gliadel® wafers and laser interstitial thermal therapy (LITT) will be excluded. Active treatment with the tumor treating filed devices such as Optune during radiation will be excluded. Concurrent use of Optune during the adjuvant temozolomide cycles is allowed.
• * Currently participating or previously participated in any other newly diagnosed GBM therapeutic trials.
• * History of MGMT methylated status performed at any CLIA certified laboratory.
• * Any serious medical condition that interferes with adherence to study procedures.
• * Malignancies other than the disease under study within 2 years prior to Day 1 of the study, with the exception of those with a negligible risk of metastasis or death and with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, or ductal carcinoma in situ treated surgically with curative intent) or undergoing active surveillance per standard-of-care management (e.g., chronic lymphocytic leukemia Rai Stage 0, prostate cancer with Gleason score =\< 6, and prostate-specific antigen \[PSA\] =\< 10 mg/mL, etc).
• * Has known disease in the posterior fossa, gliomatosis cerebri, leptomeningeal disease, extracranial disease or multicentric enhancing disease. Multicentric disease is defined as discrete sites of contrast enhancing disease without contiguous T2/FLAIR abnormality that require distinct radiotherapy ports. Satellite lesions that are associated with a contiguous area of T2/FLAIR abnormality as the main lesion(s) and that are encompassed within the same radiotherapy port as the main lesion(s) are permitted.
• * Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating physician.
• * Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• * Is pregnant or breastfeeding, or expecting to conceive children within the projected duration of the trial, starting with the screening visit.
• * Contraindication for undergoing MRIs.
• * Inability to comply with study and follow-up procedures.
• * Signs or symptoms of serious infection such as surgical wound infection, received IV antibiotics within 2 weeks prior to Day 1 of the study.
• * Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible.
• * Patients receiving oral antibiotics for minor infections such as urinary tract infection are eligible.
• * History of HIV infection.
• * Administration of a live, attenuated vaccine within 4 weeks before Day 1 of the study or anticipation that such a live, attenuated vaccine will be required during the study
• * Influenza vaccination can be given. Patients must not receive live, attenuated influenza vaccine (e.g., FluMist®) within 4 weeks prior to Day 1 of the study or at any time during the study and for 5 months after completion of adjuvant TMZ.
• * History of long QT syndrome.
• * Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of M3814 or that may affect the interpretation of the results or render the patient at high risk from treatment complications.
• * Anticipation of need for a major surgical procedure during the course of the study (excluding patients in Stage II with planed non-urgent neuro-surgical resection)
• * Subjects at increased risk for radiation toxicities, such as known active collagen vascular disease (example; scleroderma, Sjogren's disease, etc) or other inherited radiation hypersensitivity syndromes (example; Gorlin syndrome, Fanconi anemia, ataxia-telangiectasia, etc.)
• * Active difficulty swallowing, malabsorption or other chronic gastrointestinal disease or conditions (including pancreas deficiency requiring Creon therapy) that may hamper compliance and/or absorption of M3814.
• * Patients may not receive concomitant chemotherapy, immunotherapy, or radiotherapy (other than as pertained to standard of care for GBM as described in section 1.1) while patients are on study.
• * Prior treatment with DNA damage response inhibitors (including inhibitors of PARP, ATR, WEE).