Phase I study of E7046, a novel PGE2 receptor type 4 inhibitor, in patients with advanced solid tumors: Clinical results and effects on myeloid- and T-lymphoid cell-mediated immunosuppression.

49 Background: E7046 is a selective inhibitor of the prostaglandin E 2 (PGE 2 ) receptor EP4, which transduces potent immunosuppressive activity of PGE 2 in myeloid and T-lymphoid cells. In preclinical studies, E7046 reversed PGE 2 -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 18 FDG-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 > 1 pt were abdominal pain (3 pts) and vomiting (2 pts). Grade 3/4 treatment-related AEs occurred in 4 pts (rash in 2 pts, and diarrhea, allergic reaction, anaphylaxis, hypersensitivity, and hyperuricemia, in 1 pt each). Four pts discontinued E7046 due to an AE (bowel obstruction, allergic reaction, abdominal pain, acute renal failure). No objective tumor responses were reported. Treatment duration of ≥20 wks with best response of stable disease (SD) was observed in 5 pts, 3 of whom had partial metabolic responses. E7046 exposure was dose-proportional up to 500 mg. Elimination half-life (12 hr) justified once-daily dosing. E7046 treatment significantly increased tumor CD3 + and CD8 + T-cell infiltration, and blood levels of the T-cell-recruiting chemokine CXCL10. E7046 also modulated blood expression of EP4 signaling genes (IDO1, EOMES, PD-L1). Longer duration of therapy with SD was associated with higher baseline tumor infiltrate of CD8 + T-cells and CD163 + macrophages. Conclusions: E7046 demonstrated favorable tolerability with preliminary evidence of anti-tumor activity and immune modulation in tumor and peripheral blood. MTD was not reached. Further studies of E7046 in combination with other agents are planned. Clinical trial information: NCT02540291.