Phase I Trial of DNA-PK Inhibitor (PEPOSERTIB ) in Combination With Radiation and Adjuvant Temozolomide in Newly Diagnosed MGMT Unmethylated and Recurrent Glioblastoma

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.

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.

What this study is about