000860: A Phase I/II Study of Zotiraciclib for Recurrent Malignant Gliomas With Isocitrate Dehydrogenase 1 or 2 (IDH1 or IDH2) Mutations

Background: * Zotiraciclib is a multi-kinase inhibitor that has been shown to have anti-glioma effects through transcriptional suppression, mitochondrial dysfunction, and adenosine 5'-triphosphate (ATP) reduction in glioblastoma in our preclinical studies * Zotiraciclib is orally administered and likely penetrates the blood brain barrier (BBB). There has been a clinical experience in using zotiraciclib as a single agent and in combination with other chemotherapy agents in cancers, including malignant gliomas * Our phase I study of zotiraciclib and temozolomide (TMZ) in recurrent high-grade astrocytomas determined the maximum tolerated dose (MTD) of zotiraciclib in combination with TMZ and demonstrated the safety of the treatment in recurrent high-grade glioma patients * Preliminary efficacy analysis of Phase I demonstrated an improved response to zotiraciclib in combination with TMZ in IDH-mutant gliomas compared to the IDH-wildtype counterpart * A selective vulnerability to zotiraciclib as a single agent was demonstrated in the preclinical models of IDH-mutant gliomas Objectives: * Phase I: To estimate recommended phase II dose (RP2D) of zotiraciclib * Phase II: To determine 12-months progression free survival (PFS) in participants with recurrent glioma, IDH1/2-mutant, World Health Organization (WHO) grade 3 treated with zotiraciclib in comparison with the established brain tumor database matched for tumor molecular characteristics and clinical prognostic factors Eligibility: * Age \>=15; Karnofsky performance status (KPS) \>=70% * Histological confirmation of diffuse glioma, WHO grades 2-4 with IDH1/2 mutation status confirmed by DNA sequencing * Have recurrent disease * Have prior treatment of radiation and/or conventional chemotherapies * No prior use of bevacizumab as a treatment for a brain tumor Design: * This is a phase I/II study to evaluate the safety and efficacy of zotiraciclib as a single agent in recurrent IDH-mutant gliomas. * Initially, 9-24 participants (Cohort 1) will be assigned to Phase I to estimate recommended phase 2 dose (RP2D) of zotiraciclib. * Once RP2D is estimated, we will start enrollment into cohorts for Phase II, non-surgical participants (Cohorts 2-4), and surgical (Cohort 5). This trial plans to enroll up 64 evaluable participants. * Drug will be administered on days 1, 4, 8, 11, 15, 18 in cycles of 28 days for a maximum of 18 cycles. Starting dose is 200 mg. In the case that 200 mg is not tolerable, a lower dose 150 mg, will be evaluated. If 200 mg is tolerated well, a higher dose level will be evaluated at 250 mg. * Participants in the surgical cohort will get an additional single pre-treatment with one dose of study drug at the RP2D on Day 1 of Cycle 0, followed by brain tumor biopsy or surgical resection within 24 hours on Day 2 of Cycle 0. Approximately 2-4 weeks after surgery or biopsy participants in this Cohort will continue treatment with the study drug and start Day 1 of Cycle 1.