Results of a phase 1, dose-finding study of Debio 0123 as monotherapy in adult patients with advanced solid tumors: Safety, pharmacokinetic, and preliminary antitumor activity data.

3120 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. Debio 0123 has demonstrated significant growth inhibition in vitro in a broad range of cancer cell lines and antitumor activity in vivo in human xenograft tumor models. Methods: Debio 0123-102 (NCT05109975) is a phase 1 dose-escalation study evaluating the safety, tolerability, pharmacokinetics (PKs) and preliminary antitumor activity of Debio 0123 in patients (pts) with advanced solid tumors who have recurred or progressed following prior therapy and/or for whom no standard therapy is available. Debio 0123 is given as monotherapy, once daily, over a 21-day cycle, using a Bayesian Logistic Regression Model-guided dose escalation. The primary objective of this study is to determine the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D). Results: As of October 24, 2023, 27 pts were treated with 2 pts ongoing (67% female, mean age 63 years; most common primary tumors: ovarian 33%, colon 18%). Debio 0123 was escalated from 30 mg to 350 mg. Three pts had dose limiting toxicities (DLTs) Grade (Gr) 3 fatigue and Gr3 Fridericia-corrected QT (QTcF) prolongation at 350 mg, and Gr3 rash at 260 mg. The MTD was determined at 260 mg. The most frequent treatment related adverse events (TRAEs) (≥20%) were blood creatinine increased (37%), QTcF prolongation (37%), nausea (33%), vomiting (26%), dysgeusia (22%) and fatigue (22%). The most common TRAEs Gr≥ 3 were QTcF prolongation (n = 3, 11%) and fatigue (n = 2, 7%). Retalted adverse events led to dose interruptions, reductions, or discontinuations in 6 (22%), 4 (15%) and 2 (7%) pts, respectively. Debio 0123 plasma exposure increased proportionally with dose from 150 to 350 mg, with steady state achieved after 15-21 days. Target engagement, assessed by reduction of phosphorylated CDC2 levels in skin biopsies, was observed consistently from a dose of 200 mg. Median duration of treatment was 6 weeks (3-30 weeks). Of the 25 pts with post-baseline tumor assessment, 8 (32%) pts had stable disease as best response of ≥5 weeks duration. Two ovarian pts achieved 17% and 20% reduction in the target lesions as per RECIST 1.1, despite requiring dose reductions from 350mg during the 1 st cycle. One of these pts had CA-125 response. Based on cumulative safety, exposure-response data, and additional PK modeling, 260 mg once daily of Debio 0123 was selected as RP2D. Conclusions: Continuous dosing of Debio 0123 as monotherapy has a manageable safety profile and linear pharmacokinetics. A multi cohort expansion, including biomarker-selected and unselected cohorts, will further evaluate the safety and antitumor activity of Debio 0123. Clinical trial information: NCT05109975 .