Abstract CT064: Impact of food and high gastric pH on the bioavailability of the WEE1 inhibitor Debio 0123 assessed in a phase 1 dose escalation study
Authors: Bellon Anne , Saavedra Omar , Desar Ingrid M. , Jalving Mathilde , Gietema Jourik A. , van Herpen Carla , van Ravensteijn Stefan , Imedio Esteban Rodrigo , van Haren Sylvia , Wirth Melanie , Micallef Sandrine , Dozio Vito , Franzen Rikke Frederiksen , Roubaudi-Fraschini Marie-Claude , Nicolas-Metral Valerie , Gelderblom Hans 
Published: April 2024

Abstract
Debio 0123 (D0123), an oral, brain-penetrant, highly selective WEE1 inhibitor, is currently in clinical development, both in combination and as monotherapy, for the treatment of patients with solid tumors. Food and gastric acid-reducing agents e.g. proton pump inhibitors (PPIs) may modify the solubility, bioavailability, safety and efficacy of oral cancer drugs. Polymedication in cancer patients is common and food restrictions can impact patient compliance and wellbeing. In order to adequately inform drug dosing in clinical trials, effects of food and high gastric pH on D0123 bioavailability were studied over three cycles in patients treated in the dose escalation of a Phase 1 study of D0123 in combination with Carboplatin (CTID NCT03968653).D0123 was given on Days 1-3 and 8-10 of each 21-day cycle in combination with carboplatin on Day 1. Current standard administration of D0123 is in fasted conditions and PPIs are prohibited. Dose-limiting toxicities were evaluated in cycle 1. The effect of food and high-gastric pH were assessed in cycles 2 and 3, respectively. In cycle 2 on Day 10, patients were receiving a high-fat meal and in cycle 3, the PPI lanzoprazole 30 mg BID was administered from Day 7 to 11. PK parameters (area under the curve (AUC), maximum concentration (Cmax)) were determined post-Day 10 dose and compared between cycle 1 (fasted) and cycle 2 (fed) or 3 (high gastric pH). Preliminary data from 3 cohorts, 3 dose levels (n=10) resulted in about 5 pairwise comparisons for food and for high gastric pH effects. Absence of D0123 accumulation between cycles was confirmed, allowing for inter-cycle comparison.
Oral bioavailability of D0123 appears pH-dependent, suggesting that co-medication with PPIs should be avoided. In contrast, food intake has a limited impact on drug absorption, at all doses tested. Furthermore, D0123 administration with food may increase treatment convenience and tolerability, leading to its implementation in other D0123 trials.
TABLE 1. NAND Mean change [ min ; max ] Effect of food (cycle 2 versus cycle 1) Effect of high gastric pH (cycle 3 versus cycle 1) AUC24 -3% [ -17% ; +8% ] -31% [ -39%; -23% ] Cmax -10% [ -26% ; 0% ] -33% [ -41% ; -20% ]
Citation Format: Anne Bellon, Omar Saavedra, Ingrid M. Desar, Mathilde Jalving, Jourik A. Gietema, Carla van Herpen, Stefan van Ravensteijn, Esteban Rodrigo Imedio, Sylvia van Haren, Melanie Wirth, Sandrine Micallef, Vito Dozio, Rikke Frederiksen Franzen, Marie-Claude Roubaudi-Fraschini, Valerie Nicolas-Metral, Hans Gelderblom. Impact of food and high gastric pH on the bioavailability of the WEE1 inhibitor Debio 0123 assessed in a phase 1 dose escalation study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT064.