This phase I trial investigates the side effects and best dose of Peposertib, and to see how well it works in combination with radiation therapy in treating patients with newly diagnosed MGMT unmethylated glioblastoma or gliosarcoma. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Peposertib may further stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving Peposertib with radiation therapy may work better than radiation therapy alone in treating patients with glioblastoma or gliosarcoma.

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of Peposertib in combination with standard of care radiation dose (60 Gy, 2 Gy/fraction over 6 weeks) in patients with newly diagnosed MGMT unmethylated glioblastoma (GBM). (Stage I) II. To determine the ability of Peposertib to cross the blood brain barrier and to evaluate their pharmacodynamic properties in resected tissue. (Stage II)

SECONDARY AND EXPLORATORY OBJECTIVES:

I. To evaluate the dose limiting toxicities (DLT). (Stage I) (Secondary Objective) II. To determine the overall response rate (ORR), median progression free survival (mPFS) and median overall survival (mOS) of Peposertib in combination with radiation. (Stage I) (Secondary Objective) II. To determine the overall response rate (ORR), median progression free survival (mPFS) and median overall survival (mOS) of Peposertib in combination with radiation. (Stage II) (Exploratory Objective)

CORRELATIVE OBJECTIVES:

I. To evaluate pharmacodynamic properties of Peposertib. II. To assess the alterations in tumor immune microenvironment as a result of deoxyribonucleic acid (DNA)-dependent protein kinase (DNA-PK) inhibition.

OUTLINE: This is a dose-escalation study of Peposertib. Patients are assigned to 1 of 2 stages.

STAGE I (CONCURRENT): Patients undergo standard of care radiation therapy daily (Monday-Friday) for 30 fractions. Patients also receive Peposertib orally (PO) on each day of radiation therapy and given 1-2 hours before each treatment fraction. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity.

STAGE I (ADJUVANT): Patients receive temozolomide PO once daily (QD) on days 1-5. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

STAGE II (CONCURRENT): Patients receive Peposertib and undergo standard of care radiation therapy as in Stage I. Within 1-14 days after the completion of radiation therapy, patients undergo surgical resection.

STAGE II (ADJUVANT): Patients receive temozolomide as in Stage I.

After completion of study treatment, patients are followed up every 3 months.

Inclusion Criteria:

• Signed Informed Consent Form (ICF)
• Be willing and able to provide written informed consent for the trial. Participants with cognitive impairment will be enrolled. Cognitive function will be assessed by the treating physician or designee through a neurological examination. The formal consent for such participants will be obtained from their legally authorized representative. For cognitively impaired adults who are enrolling in the study by consent of a legally authorized representative, assent of the subject is required for the subjects with the ability to communicate assent. This assent will be documented in subject fs consent note.
• Age 18 years or older
• Histologically confirmed World Health Organization (WHO) grade 4 glioma (GBM) or gliosarcoma, IDH wild-type, per WHO 2021 classification .IDH status is to be determined by IDH1 R132H immunohistochemistry except for patients ≤ age 54 in whom IDH sequencing will be required to detect non-canonical IDH mutations.
• Have KPS of 3 60 or ECOG . 2 according to appendix 5.
• A baseline MRI of brain obtained no more than 14 days prior to study enrollment on a stable or tapering dose of steroids for at least 3 days
• Demonstrate adequate organ function as defined below.
• All screening labs should be performed within 14 days prior to Day 1 of the study.
• 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.
• All screening labs should be performed within 14 days prior to Day 1 of the study.
• 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.
• Female subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.
• Male subjects should agree to use an adequate method of contraception during the course of the study.

Newly diagnosed GBM only

• 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 cancer treatments following surgery Recurrent GBM only
• Any number of recurrences
• Presence of enhancing, resectable disease
• Candidate for re-radiation with ability to meet optic nerve and brainstem departmental dose constraints per treating physicians
• 6 mos or more since last radiation
• Has not received re-radiation for GBM in the past except for stereotactic radiosurgery

Exclusion Criteria:

• Has received prior interstitial brachytherapy or implanted chemotherapy.
• 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.
• 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. 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.

oPatients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible.

oPatients receiving oral antibiotics for minor infections such as urinary tract infection are eligible.

• 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., FluMistâ) 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 PEPOSERTIB 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 PEPOSERTIB.
• Patients may not receive concomitant chemotherapy, immunotherapy, or radiotherapy (other than as pertained to GBM as described in section 1.1) while patients are on study.

Newly diagnosed GBM only

• History of MGMT methylated status performed at any CLIA certified laboratory. Recurrent GBM only
• Prior history of scalp / surgical wound infection or wound dehiscence
• Prior exposure to bevacizumab 6 weeks before enrollment.
• Patients in Stage IIC and D (recurrent GBM) may receive bevacizumab during the adjuvant phase of treatment at the discretion of the treating physician, provided at least 6 weeks have elapsed since surgery and there are no wound healing concerns. A minimum washout period of 6-8 weeks is required from the last dose of prior bevacizumab before study enrollment.

Medication-Related Exclusion Criteria:

PEPOSERTIB

• No clinical drug-drug interaction (DDI) studies have been conducted with peposertib. Based on nonclinical data and basic static modeling using the proposed maximum therapeutic doses of 200 mg BID or 300 mg QD (tablet formulation), the following guidance applies: Subjects receiving or unable to discontinue foods, medications, or herbal supplements that are strong inducers or inhibitors of CYP3A4/5, CYP2C19, or CYP2C9 should be excluded from treatment with peposertib due to potential impact on drug exposure.
• Substrates of CYP1A2, CYP2B6, CYP2C8, and CYP3A4/5 should be used with caution and monitored. Substrates with a narrow therapeutic index are prohibited during treatment with peposertib.

Please refer to https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers for a list of drugs metabolized by the above mentioned enzymes. H2-blockers may be allowed but should be taken at least 2 hours after peposertib dosing and stopped at least 6 hours before the next dose of peposertib. Calcium carbonate use is acceptable.