Abstract 3276: Clinical PK, PD and safety analysis of a phase I clinical trial of DT-9081, an EP4R-antagonist, for RP2D determination in patients with advanced solid tumours

Prostaglandin E2 (PGE2) is a lipid known to promote tumor growth and immune evasion through the EP4 receptor (EP4R). DT-9081, a novel EP4R antagonist, is under investigation for its potential to inhibit tumor growth and enhance immune response. Here are presented the preliminary pharmacokinetic (PK), pharmacodynamic (PD) and safety assessments from the dose escalation phase 1 clinical trial (NCT05582850) allowing the determination of the recommended phase 2 dose (RP2D). This dose-escalation study employed a modified 3+3 design. DT-9081 was administered orally once daily in doses ranging from 25 to 600 mg. Plasma concentrations of DT-9081 were quantified using LC-MS/MS for PK analysis. PD endpoints included changes in immune activation markers as well as blocking of EP4R agonist (TCS2510)-induced cytokine modulation in blood. Safety assessments were based on NCI-CTCAE v5.0 criteria, with adverse events (AEs) recorded by occurrence and severity.Currently, a total of 29 patients treated with DT-9081 over 6 dose levels (25 mg to 600 mg) are available for analysis. Primary cancer sites included head and neck, ovary, kidney, oesophagus, cervix, gall bladder, lung, pancreas, stomach, prostate, thyroid and rectum carcinoma. Overall, DT-9081 was well tolerated at all tested dose levels. MTD was not reached. Treatment-related AEs (TRAEs) were mostly grade 1 or 2. The most frequent TRAEs (n≥5) were diarrhoea, decreased appetite, nausea and abdominal pain across all cohorts. Grade ≥3 TEAEs included diarrhoea and abdominal pain in one participant from the 50 mg cohort. One dose-limiting toxicity (hepatic enzyme increased grade 3) was observed for another participant at the 50 mg cohort.PK data showed linear increases of Cmax and AUC in a dose-dependent fashion, with suitable exposure to cover the target IC50 for 24h with once-daily dosing. Blood PD data demonstrated that DT-9081 was able to prevent the immunosuppressive activity of TCS2510 by restoring IFN-γ and TNF-α secretion at all dose levels, with a maximum reversion observed around 2h post dosing, in line with PK profile (Tmax). A long-lasting effect until 10h post-dosing was also observed after 15 days of treatment. Analysis of paired biopsies and PBMCs is ongoing to evaluate the impact of DT-9081 on intra-tumoral and peripheral immune response. DT-9081 was well tolerated and exhibited a linear PK profile and an exposure supportive of once-daily dosing scheme. PD findings demonstrated the EP4R engagement and inhibition induced by DT-9081 across all dose levels tested and were consistent with the PK data. The collective evaluation of the available PK, PD, safety and tolerability data appoints the 600 mg dose as the potential RP2D, upon finalization of the last ongoing cohort at this dose. Additional PD assessments in peripheral blood and paired tumor biopsies will be available in the poster presentation. Citation Format: Christophe Le Tourneau, Zahra Castel-Ajgal, Jean-Pascal Machiels, Rachel Galot, Nuria Kotecki, Christiane Jungels, Jean-Pierre Delord, Iphigenie Korakis, Anne-Laure Blayo, Lola Lecru, Thibaut Brugat, Stephan Schann, Nathalie Lenne, Samira El-Farouk, Claire Jouffroy-Zeller, Anne Quesnel, Carolina Duarte, Karim Taamma. Clinical PK, PD and safety analysis of a phase I clinical trial of DT-9081, an EP4R-antagonist, for RP2D determination in patients with advanced solid tumours [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3276.