TY - JOUR T1 - First-in-human phase I study of immunomodulatory E7046, an antagonist of PGE<sub>2</sub>-receptor E-type 4 (EP4), in patients with advanced cancers JF - Journal for ImmunoTherapy of Cancer JO - J Immunother Cancer DO - 10.1136/jitc-2019-000222 VL - 8 IS - 1 SP - e000222 AU - David S Hong AU - Aparna Parikh AU - Geoffrey I Shapiro AU - Andrea Varga AU - Aung Naing AU - Funda Meric-Bernstam AU - Özlem Ataman AU - Larisa Reyderman AU - Terri A Binder AU - Min Ren AU - Mingjie Liu AU - Satish Dayal AU - Amy Y Siu AU - Pallavi Sachdev AU - Lucy Xu AU - Vijay Bhagawati-Prasad AU - Ilian Tchakov AU - Chean Eng Ooi AU - Xingfeng Bao AU - Aurelien Marabelle Y1 - 2020/06/01 UR - http://jitc.bmj.com/content/8/1/e000222.abstract N2 - Background E7046 is a highly selective, small-molecule antagonist of the E-type prostanoid receptor 4 (EP4) for prostaglandin E2, an immunosuppressive mediator of the tumor immune microenvironment. This first-in-human phase 1 study assessed the safety, tolerability, pharmacokinetics, pharmacodynamics, maximum tolerated dose (MTD) and recommended phase 2 dose of E7046.Methods This first-in-human study enrolled 30 patients with advanced tumors of cancer types associated with high levels of myeloid infiltrates. E7046 was administered orally once-daily in sequential escalating dose cohorts (125, 250, 500, and 750 mg) with ≥6 patients per cohort. Tumor assessments were performed every 6 weeks. Paired tumor biopsies and blood samples, before and on treatment, were collected for pharmacokinetic and pharmacodynamic characterization of the treatment.Results No dose-limiting toxicities were observed, and the MTD was not reached. E7046 had an elimination half-life (t1/2) of 12 hours, and drug exposure increased dose-dependently from 125 to 500 mg. Target modulation by E7046 was supported by changes in genes downstream of EP4 with concurrent enhanced antitumoral immune responses. A best response of stable disease (per irRECIST) was reported in 23% of patients treated with E7046 (n=30) (125 mg: n=2; 250 mg: n=2; 750 mg: n=3). Over half (4/7) of the patients with stable disease had treatment duration of 18 weeks or more, and three patients (3/15; 20%) achieved metabolic responses.Conclusions In this first-in-human study, E7046 administered orally once daily demonstrated manageable tolerability, immunomodulatory effects, and a best response of stable disease (≥18 weeks) in several heavily pretreated patients with advanced malignancies. The 250 and 500 mg doses are proposed for further development in the combination setting.Trial registration number NCT02540291. ER -