Rachel Galot, Zahra Castel-Ajgal, Nuria Kotecki, Christiane Jungels, Jean-Pierre Delord, Iphigenie Korakis, Samira El-Farouk, Claire Jouffroy-Zeller, Anne Quesnel, Carolina Duarte, Abdelkrim Taamma, Thomas Maurin, Lola Lecru, Antoine Mousson, Orphée Blanchard, Anne-Laure Blayo, Nathalie Lenne, Stephan Schann, Xavier Leroy, Jean-Marie Cuillerot, Christophe Le Tourneau, Jean-Pascal Machiels
DT-9081 is a selective antagonist of the prostaglandin E2 receptor EP4, developed to counteract tumor-driven immunosuppression. This first-in-human phase I study aimed at determining the dose-limiting toxicity/maximum tolerated dose (DLT/MTD) of DT-9081 and identifying the recommended phase II dose (RP2D) in patients with advanced solid tumors. This open-label, dose-escalation study enrolled patients with advanced (unresectable, recurrent or metastatic) solid tumors refractory to standard therapies. DT-9081 was administered orally once daily across six sequential dose cohorts (25-600 mg, daily). Primary objectives were safety and determination of the RP2D. Secondary objectives included efficacy, pharmacokinetics (PK) characterization, and pharmacodynamic (PD) assessment. Twenty-nine patients were treated. One dose-limiting toxicity (grade 3 increased hepatic enzymes) was observed at the 50 mg dose level. The most frequently reported treatment-emergent adverse events (TEAEs) were diarrhea (55.2%), decreased appetite (24.1%), nausea (20.7%), vomiting (20.7%), and asthenia (20.7%). Most TEAEs were grade 1-2. Grade ≥ 3 DT-9081-related adverse events occurred in 2 (6.9%) patients (grade 3 diarrhea and grade 3 increased hepatic enzymes). DT-9081 exhibited dose-proportional PK with sustained plasma exposure exceeding preclinical IC50 thresholds at higher dose levels. Pharmacodynamic analyses demonstrated dose-dependent reversal of EP4-mediated suppression of TNF-α production, confirming target engagement. Based on integrated safety, PK, and PD data, 600 mg once daily was selected as the RP2D, despite the absence of meaningful clinical activity. MTD was not reached and pharmacodynamic activity was consistent with EP4R antagonism. These findings support further clinical development of DT-9081, including evaluation in immunotherapy-based combination regimens.EUCT Number: 2024-516206-28-00;NCT05582850.Study registration date: 10/10/2022.