Tinostamustine With or Without Radiation Therapy in Treating Patients With Newly Diagnosed MGMT-Unmethylated Glioblastoma

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PRIMARY OBJECTIVES: I. To characterize the safety profile and determine the maximum tolerated dose (MTD) of tinostamustine (EDO-S101) in the adjuvant phase of therapy for patients with newly diagnosed MGMT-promoter unmethylated glioblastoma (GB) post chemoradiation with temozolomide. (Stage 1) II. T...

PRIMARY OBJECTIVES: I. To characterize the safety profile and determine the maximum tolerated dose (MTD) of tinostamustine (EDO-S101) in the adjuvant phase of therapy for patients with newly diagnosed MGMT-promoter unmethylated glioblastoma (GB) post chemoradiation with temozolomide. (Stage 1) II. To characterize the safety profile and determine the MTD of EDO-S101 when given as a single agent in the concomitant phase with radiation therapy (RT) in patients with newly diagnosed GB who are O6-methylGuanine deoxyribonucleic acid (DNA) methyltransferase (MGMT)-promoter unmethylated. (Stage 2) III. To confirm the MTD of EDO-S101 in the concomitant phase and adjuvant phase in an expanded population of newly diagnosed GB patients who are MGMT-promoter un-methylated. (Dose Expansion Group) SECONDARY OBJECTIVE: I. To assess anti-tumor activity for patients with newly diagnosed GB who are MGMT-promoter unmethylated based on progression-free survival (PFS), overall survival (OS), and overall response rate (ORR). EXPLORATORY OBJECTIVE: I. Profiling tumor DNA, messenger ribonucleic acid (mRNA), microRNA and epigenetic profiling (DNA methylation) and evaluation of whole exome sequencing, RNA sequencing, microRNA sequencing and cell-free circulating tumor DNA (ctDNA) and correlate with outcome. OUTLINE: This is a dose escalation study of tinostamustine. Patients who have completed temozolomide (TMZ) and radiation therapy (RT) are assigned to Stage 1A or Stage 1B. Patients who have received no treatment other than surgery are assigned to Stage 2. STAGE 1A: Patients receive tinostamustine intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. STAGE 1B: Patients receive tinostamustine IV over 30 minutes on days 1 and 15. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. STAGE 2: Patients undergo RT 5 days a week for up to 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive tinostamustine IV on day 1 or days 1 and 15 (to be determined following stage 1). Treatment repeats every 21 days (day 1) or 28 days (days 1 and 15) for up to 12 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days and then every 3 months.

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