A phase 1 dose-finding and dose-expansion study evaluating the safety, tolerability, pharmacokinetics, and efficacy of a highly selective WEE1 inhibitor (Debio 0123) in adult patients with advanced solid tumors.

TPS2702 Background: Debio 0123 is an oral, highly selective inhibitor of the tyrosine kinase WEE1. WEE1 is a key regulator of cell cycle progression that modulates the activity of CDK1 (CDC2), influencing entry into mitosis. WEE1 inhibition results in G2 checkpoint abrogation, triggering mitosis with unrepaired DNA leading to cell death. In vitro and in vivo tumor models have shown Debio 0123 antitumor activity. Continuous exposure seems to be needed to maximize monotherapy efficacy in preclinical models. Preliminary data from an ongoing phase 1 study of intermittent Debio 0123 combined with carboplatin, showed a manageable safety profile, and signals of antitumor activity in patients (pts) with advanced solid tumors. We present the design of a phase 1 study (NCT05109975) of continuous Debio 0123 administered as a single agent in pts with advanced solid tumors. Methods: The study comprises a dose escalation part and a dose expansion part. The primary objective of the dose escalation part of the study is to determine the maximum tolerated dose (MTD) and/or the recommended phase 2 dose (RP2D) of continuous Debio 0123 monotherapy in adults with previously treated advanced solid tumors. Key secondary objectives include characterization of safety and tolerability, pharmacokinetics (PK), and preliminary antitumor activity (overall response rate [ORR]). Key inclusion criteria are histologically or cytologically confirmed locally advanced or metastatic solid tumors, and ECOG-PS 0 or 1. Key exclusion criteria are asymptomatic or unstable brain metastases, history of cardiac disorders, inability to swallow oral medication or abnormalities affecting drug absorption. Approximately 30 dose-limiting toxicity (DLT)-evaluable pts are anticipated to be enrolled based on an escalation with overdose control (EWOC) approach for 21-day treatment cycles. When the pts of each cohort become evaluable, a safety monitoring committee will review safety and tolerability and based on EWOC recommendations will decide the next dose level or will declare the MTD and/or RP2D. Pharmacodynamic biomarkers will be correlated with tumor response and/or PK. The dose-expansion part may start after MTD and/or RP2D determination. The primary objective of this part will be to characterize the safety and tolerability (e.g. percentage of pts with DLTs, serious adverse events or discontinuations) of Debio 0123 monotherapy at the MTD/RP2D, and to evaluate the anti-tumor activity (ORR) in pts with selected recurrent/progressive solid tumors. Key inclusion criteria are measurable disease per RECIST 1.1 and specific tumor types. Based on a Simon 2-stage design, up to 34 pts per tumor type cohort may be enrolled. Currently accrual to the dose escalation is ongoing in the United States and Switzerland. Clinical trial information: NCT05109975.