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

Inclusion 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) orgliosarcoma, IDH wild-type

• Documentation of MGMT unmethylated GBM per testing at any Clinical LaboratoryImprovement Amendment (CLIA) certified laboratory

• Patients must have undergone brain surgery or biopsy and must not have had anyfurther treatments following surgery

• Have Karnofsky performance status (KPS) of >= 60 or Eastern Cooperative OncologyGroup (ECOG) =< 2

• A baseline magnetic resonance imaging (MRI) of brain obtained no more than 14 daysprior to study enrollment on a stable or tapering dose of steroids no greater than 4mg 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 thestudy)

• 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 calculatedcreatinine clearance (glomerular filtration rate [GFR] can also be used in place ofcreatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatininelevels > 1.5 x institutional ULN (within 14 days prior to day 1 of the study) o Creatinine clearance should be calculated per institutional standard

• Serum total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for subjects withtotal 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 today 1 of the study)

• Have provided tissue from an archival tissue sample

• Female subjects of childbearing potential should have a negative serum pregnancytest within 14 days of day 1 of the study

• Female subjects of childbearing potential should be willing to use 2 methods ofbirth control or be surgically sterile o Female subjects of childbearing potential are those who have not been surgicallysterilized or have not been free from menses for > 1 year

• Male subjects should agree to use an adequate method of contraception during thecourse of the study

• STAGE I: In the case stage I patients need resection as determined by the treatingphysicians during or after completion of radiation therapy (RT) and that pathologyof resected lesion is not consistent with recurrent GBM, the patient can continue onthe study (complete 6 weeks of RT + M3814) if deemed appropriate by the treatingphysicians. The tissue obtained in such circumstances will be analyzed as in StageII subjects. However, these cases will not count towards the 5 patients who will beenrolled during Stage II. These patients will contribute to the correlativeendpoints detailed above and ORR, OS, and PFS as Stage II patients

• STAGE II: Patients meet above criteria, would benefit from further non-urgentsurgical resection of at least one enhancing lesion per the treating physician, andwould provide consent to undergo surgery after treatment with RT and M3814

Exclusion Criteria:

• Has received prior interstitial brachytherapy, implanted chemotherapy, ortherapeutics delivered by local injection or convection enhanced delivery. Priortreatment with Gliadel® wafers and laser interstitial thermal therapy (LITT) will beexcluded. Active treatment with the tumor treating filed devices such as Optuneduring radiation will be excluded. Concurrent use of Optune during the adjuvanttemozolomide cycles is allowed.

• Currently participating or previously participated in any other newly diagnosed GBMtherapeutic 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 thestudy, with the exception of those with a negligible risk of metastasis or death andwith expected curative outcome (such as adequately treated carcinoma in situ of thecervix, basal or squamous cell skin cancer, localized prostate cancer treatedsurgically with curative intent, or ductal carcinoma in situ treated surgically withcurative 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, leptomeningealdisease, extracranial disease or multicentric enhancing disease. Multicentricdisease is defined as discrete sites of contrast enhancing disease withoutcontiguous T2/FLAIR abnormality that require distinct radiotherapy ports. Satellitelesions that are associated with a contiguous area of T2/FLAIR abnormality as themain lesion(s) and that are encompassed within the same radiotherapy port as themain lesion(s) are permitted.

• Has a history or current evidence of any condition, therapy, or laboratoryabnormality that might confound the results of the trial, interfere with thesubject's participation for the full duration of the trial, or is not in the bestinterest of the subject to participate, in the opinion of the treating physician.

• Has known psychiatric or substance abuse disorders that would interfere withcooperation with the requirements of the trial.

• Is pregnant or breastfeeding, or expecting to conceive children within the projectedduration 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 IVantibiotics within 2 weeks prior to Day 1 of the study.

• Patients receiving prophylactic antibiotics (e.g., for prevention of a urinarytract infection or chronic obstructive pulmonary disease) are eligible.

• Patients receiving oral antibiotics for minor infections such as urinary tractinfection are eligible.

• History of HIV infection.

• Administration of a live, attenuated vaccine within 4 weeks before Day 1 of thestudy or anticipation that such a live, attenuated vaccine will be required duringthe study

• Influenza vaccination can be given. Patients must not receive live, attenuatedinfluenza vaccine (e.g., FluMist®) within 4 weeks prior to Day 1 of the study or atany 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 clinicallaboratory finding giving reasonable suspicion of a disease or condition thatcontraindicates the use of M3814 or that may affect the interpretation of theresults 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 collagenvascular disease (example; scleroderma, Sjogren's disease, etc) or other inheritedradiation hypersensitivity syndromes (example; Gorlin syndrome, Fanconi anemia,ataxia-telangiectasia, etc.)

• Active difficulty swallowing, malabsorption or other chronic gastrointestinaldisease or conditions (including pancreas deficiency requiring Creon therapy) thatmay 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).