First-in-human phase I study of DT-9081, a selective EP4 receptor antagonist, in advanced solid tumors.
Rachel Galot, Zahra Castel-Ajgal, Nuria Kotecki et al.
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In 30 seconds
This open-label, multicentre, first-in-human phase I dose-escalation study evaluated oral DT-9081, a selective EP4 receptor antagonist, in 29 patients with advanced solid tumors refractory to standard therapies. The primary aims were to assess safety and select a recommended phase II dose. One dose-limiting toxicity—grade 3 increased hepatic enzymes—occurred at 50 mg; the maximum tolerated dose was not reached. Integrated safety, pharmacokinetic, and pharmacodynamic findings supported selection of 600 mg once daily as the recommended phase II dose, although meaningful clinical activity was not observed.
Key findings
- One dose-limiting toxicity, grade 3 increased hepatic enzymes, occurred at 50 mg; the maximum tolerated dose was not reached.
- Grade 3 DT-9081-related adverse events occurred in 2 (6.9%) patients; most treatment-emergent adverse events were grade 1-2.
- At higher dose levels, plasma exposure exceeded preclinical IC50 thresholds, and pharmacodynamic analyses showed dose-dependent reversal of EP4-mediated TNF-α suppression.
- The recommended phase II dose was 600 mg once daily, despite no meaningful clinical activity.
Why it matters
The study provides early human safety, pharmacokinetic, and target-engagement data for EP4 antagonism in advanced solid tumors. Dose-dependent pharmacodynamic activity supports the intended mechanism, while the absence of meaningful clinical activity means these findings do not establish antitumor benefit. The results provide a basis for further evaluation, including the combination approaches proposed by the study authors.
What to keep in mind
This was a small, open-label, dose-escalation phase I study in patients with refractory advanced tumors; it was not designed to establish clinical efficacy.