An open-label phase I study to evaluate the safety, tolerability and preliminary efficacy of YY001 in patients with advanced solid tumors.

e15104 Background: Prostaglandin E2 (PGE2) receptor 4 (EP4) is the master regulator of immunosuppressive myeloid cells (IMCs), one of the major drivers of resistance to immune checkpoint blockade therapy. YY001, a novel and selective EP4 antagonist, effectively blocked the function of IMCs and enhanced cytotoxic T-cell mediated tumor elimination in preclinical studies. Here we report the preliminary data of YY001 in Chinese patients with advanced solid tumors from a phase I study approaching completion. Methods: The key eligibility criteria include: patients aged 18 to 75 years with histologically or pathologically confirmed advanced or metastatic solid tumors; refractory to or intolerant of standard treatment; at least one measurable lesion per RECIST v1.1; ECOG PS 0-1. Accelerated titration and classic 3+3 design were applied for dose escalation. The first dose was administrated once orally within 1 hour after a meal. After 3-days observation, patients took YY001 QD orally continuously in each 21-day treatment cycle. Results: 16 eligible patients were enrolled, including 100mg (n = 1)、200mg (n = 1)、300mg (n = 4)、400mg (n = 3)、500mg (n = 7), and no dose limiting toxicity (DLT) occurred. All patients have received multiple prior treatments before enrolling and the median number of prior treatment lines was five. As of the cut-off date (December 18, 2023), the median of treatment duration is 44 days and the longest is 194 days. No treatment-related adverse events (TRAEs) of ≥ Grade 3 were reported. The most common TRAEs were gastrointestinal disorders, alanine aminotransferase increased, fibrin D-dimer increased, alkaline phosphatase increased and hypoalbuminemia. No patients have DLT or AE leading death. 14 patients were evaluated and 2 patients withdrew from the study before tumor assessment. 6 of 14 patients (42.9%) achieved stable disease and 1 patient achieved Non-CR/Non-PD. The disease control rate was 46.2% (95% Cl 19.2, 74.9). The median progression-free survival and median overall survival were 2.38 (95% Cl 1.93, 4.00) and 10.12 (95% Cl 4.01, -) months, respectively. By the cut-off date, 11 patients were still alive, 1 patient was lost to follow-up and 1 patient is still under treatment. PK analysis concluded YY001 exposure increased in human plasma with increasing dose gradients from 100mg to 300mg. From 300mg to 500mg, the drug exposure in human plasma remained essentially the same, suggesting the PK value peak has been reached. The recommended phase II dose would be 300mg to 500mg. In addition, a median t1/2 of 8.7h was derived from 100mg to 500mg dose groups. Conclusions: The preliminary results suggest that YY001 had a manageable safety/tolerability profile and promising efficacy in patients with advanced solid tumors. YY001 will be combined with immune checkpoint inhibitor in a phase II study subsequently. Clinical trial information: NCT06228846 .