Debio 0123 (zedoresertib), a selective WEE1 inhibitor, in combination with carboplatin in adult patients with platinum-resistant ovarian cancer: Expansion part of the Debio0123-101 phase 1 study.

Abstract

e15154 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, allowing mitosis without DNA repair, leading to mitotic catastrophe and subsequent cell death. Debio 0123 is in clinical development for solid tumors, as monotherapy and in combination with various therapeutic agents. Here, we report the safety, pharmacokinetics, pharmacodynamics, and antitumor efficacy of Debio 0123 in combination with carboplatin in adult patients (pts) with platinum-resistant, high-grade epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer (PROC) during the expansion phase and for all pts with PROC treated at the recommended phase 2 dose (RP2D) of the Debio 0123-101 study. Methods: Pts with PROC were treated at the selected RP2D of Debio 0123 of 520 mg administered on Days 1–3 and 8–10, plus carboplatin on Day 1 of 21-day cycles. Pharmacokinetics was assessed in Cycle 1 and Cycle 2. Paired skin biopsies were performed at baseline (screening or pre-dose C1D1) and on treatment (C1D10 post-dose) to evaluate target engagement. The primary objective was to assess safety and tolerability, as well as to evaluate preliminary antitumor activity. Secondary objectives included additional parameters of efficacy and pharmacokinetics. Results: As of November 18, 2025, Debio 0123 was administered to 21 pts in the expansion phase (females with mean age of 63 years [range 48–79]). The most common Debio 0123 treatment-related adverse events (TRAEs) were nausea (66.7%), vomiting (52.4%), fatigue (52.4%),anemia (38.1%), ECG QT prolonged (38.1%), thrombocytopenia (33.3%), and neutropenia (23.8%). Additionally, 'ECG QT interval normal' was reported in 28.6% of patients (defined as QTc interval < 450 msec and change from baseline of > 30 msec and ≤60 msec). The most common Grade ≥3 Debio 0123 TRAEs were thrombocytopenia (23.8%), fatigue (19%), and anemia (14.3%). TRAEs led to Debio 0123 dose interruptions in 13 (61.9%) pts, dose reductions in 5 (23.8%), and treatment discontinuation in 5 (23.8%). Among 20 response-evaluable pts, 3 (15%) had partial response and 11 (55%) stable disease resulting in a disease control rate (DCR) of 70%. Median PFS was 3.8 months (95% CI, 2.1–5.5). Considering all pts with PROC treated at the RP2D (dose escalation + expansion), 4 (19%) out of 21 pts had PR, for a DCR of 71.4%. CA-125 decrease from baseline of more than 50% was observed in 10 (pts with SD/PR) out of 21 (47.6%) pts. A relationship between Debio 0123 plasma exposure and skin pCDC2 level decrease (pharmacodynamics marker) was observed. Conclusions: Debio 0123, combined with carboplatin, has a manageable safety profile at the tested dose of 520 mg; the combination showed signals of antitumor activity in pts with PROC. Clinical trial information: NCT03968653 .