Phase I Study Of E7046, A Novel Pge(2) Receptor Type 4 Inhibitor, In Patients With Advanced Solid Tumors: Clinical Results And Effects On Myeloid- And T-Lymphoid Cell-Mediated Immunosuppression.

49Background: E7046 is a selective inhibitor of the prostaglandin E2 (PGE2) receptor EP4, which transduces potent immunosuppressive activity of PGE2 in myeloid and T-lymphoid cells. In preclinical studies, E7046 reversed PGE2-mediated activities and facilitated activation of cytotoxic T-cells. Here, we present initial clinical, PK and PD results from a first-in-human study of E7046 in patients (pts) with cancers having high myeloid cell infiltration. Methods: E7046 was given orally, once-daily, in 21-day cycles in sequential dose-escalating cohorts (125, 250, 500 and 750mg). Tumor responses were evaluated by irRECIST and metabolic responses by 18FDG-PET. Immune response modulation was assessed in tumors and peripheral blood. Results: Thirty pts were treated, with no dose-limiting toxicities observed. The most common adverse events were fatigue (37%), diarrhea (33%), and nausea (30%). Grade 3/4 AEs in u003e 1 pt were abdominal pain (3 pts) and vomiting (2 pts). Grade 3/4 treatment-related AEs occurred in 4 pts...