Rtid-03. a phase 1/2 study of the wee1 inhibitor debio 0123 in combination with temozolomide +- radiotherapy in adults with recurrent or newly diagnosed glioblastoma

Abstract BACKGROUND: Debio 0123 is an oral, brain-penetrant, highly selective WEE1 inhibitor. WEE1 inhibition leads to S phase and G2/M cell cycle checkpoint abrogation, permitting mitosis without DNA repair, leading to mitotic catastrophe and subsequent cell death. Preclinically, Debio 0123 has been shown to effectively penetrate the brain and demonstrated improved response to radiotherapy (RT) in vitro and temozolomide (TMZ) in mouse models of GBM, supporting the clinical investigation of Debio 0123 with TMZ +/- RT. Trial design: This Phase 1/2 multi-center study (NCT05765812) is evaluating Debio 0123 in combination with TMZ in patients (pts) with recurrent GBM isocitrate dehydrogenase (IDH)-wildtype (WT) or astrocytoma, IDH-mutant, Grade 3 (per WHO 2021 criteria) after first-line, TMZ-based chemoradiotherapy (CxRT) (Phase 1 Arm A) and Debio 0123 combined with TMZ-based CxRT in pts with newly diagnosed GBM IDH-WT (Phase 1 Arm B). In Arm A, pts will receive escalating doses of Debio 0123 with TMZ in 28-day cycles supported by a Bayesian logistic regression model (BLRM). Arm B is a Debio 0123 dose escalation with concomitant TMZ/RT for up to 6 weeks. The primary objective of both Phase 1 arms is to identify the recommended Phase 2 dose (RP2D). Secondary objectives include safety, pharmacokinetics, and preliminary antitumor activity. Key inclusion criteria are ≤2 prior treatment lines (only 1 systemic line allowed) and Karnofsky Performance Status (KPS) ≥60 (Phase 1 Arm A). In Phase 1 Arm B, pts with KPS ≥70 who are eligible for standard TMZ-based CxRT will be included. Phase 2 will be an externally controlled, open-label study comparing the efficacy (overall survival) of Debio 0123 combined with TMZ at the Phase 1 Arm A RP2D vs. standard of care in pts with recurrent GBM IDH-WT. The control arm will include patient-level data from recently completed clinical trials. Accrual is currently ongoing.