Abstract LB469: Pharmacokinetics of the EP4 antagonist HTL0039732, a CRUK first-in-human phase I trial in patients with advanced solid tumours

Abstract Background: HTL0039732 is an orally administered antagonist of EP4. Following successful preclinical trials, a first-in-human phase I trial of HTL0039732, both as monotherapy and in combination with immune checkpoint inhibition, was initiated. We report the pharmacokinetics of HTL0039732 in this CRUK study. Methods: 13 and 22 patients with advanced solid tumours were allocated to the monotherapy and combination cohorts, respectively. On Day -7, monotherapy patients received a single oral dose of HTL0039732 (80-640 mg) in a fasted state. From Day 1, all patients received daily administration (80-640 mg) in 21-day cycles. Atezolizumab was introduced to the combination cohort from Cycle 2 onwards as a 1200 mg infusion once every 21 days. Pharmacokinetic sampling took place on Day -7 (monotherapy only), following a single dose at 1, 2, 4, 6, 10, 24, 48 and 72 hours, and in all cohorts on Days 1 (up to 24 hours) and 8 (up to 10 hours) of the first cycle. Monotherapy patients on the 80, 160 and 320 mg doses received 25% of the nominal dose on Day 1 of Cycle 1, followed by a return to the nominal dose from Day 2 onwards to evaluate dose dependency, while the 640 mg monotherapy cohort was used to evaluate food effect. Samples were analysed using a fully validated LC-MS/MS assay with a LLOQ of 10 ng/mL. Pharmacokinetic analysis was performed to determine Cmax, Tmax, area under the curve (AUC), plasma half-life, apparent clearance (CL/F) and apparent volume of distribution (Vz/F). Results: Pharmacokinetic data following a single dose of HTL0039732 are presented in Table 1 (expressed as range or mean ±SD as appropriate). Exposure was generally proportional to dose level (based on Cmax and AUC). Half-life, CL/F and Vz/F were consistent across dose levels. No food effect was observed. Conclusion: Pharmacokinetic data generated from a first-in-human phase I trial of HTL0039732 show dose dependent increases in drug exposure. A once daily 160 mg dose level has been selected as the RP2D. Citation Format: Dan Astley, Shelby Barnett, Bristi Basu, Debashis Sarker, Natalie Cook, Stefan N. Symeonides, Svatopluk Svetlik, Derrick Spencer-Briggs, Graeme Scarfe, Nigel Swain, Gareth J. Veal. Pharmacokinetics of the EP4 antagonist HTL0039732, a CRUK first-in-human phase I trial in patients with advanced solid tumours [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB469.