First-in-human study of ONO-4578, an antagonist of prostaglandin E2 receptor 4, alone and with nivolumab in solid tumors

Satoru Iwasa, Takafumi Koyama, Makoto Nishino, Shunsuke Kondo, Kazuki Sudo, Kan Yonemori, Tatsuya Yoshida, Kenji Tamura, Toshio Shimizu, Yutaka Fujiwara, Shigehisa Kitano, Akihiko Shimomura, Jun Sato, Fumiharu Yokoyama, Hiroyuki Iida, Maki Kondo, Noboru Yamamoto, Satoru Iwasa, Takafumi Koyama, Makoto Nishino, Shunsuke Kondo, Kazuki Sudo, Kan Yonemori, Tatsuya Yoshida, Kenji Tamura, Toshio Shimizu, Yutaka Fujiwara, Shigehisa Kitano, Akihiko Shimomura, Jun Sato, Fumiharu Yokoyama, Hiroyuki Iida, Maki Kondo, Noboru Yamamoto

Abstract

EP4, a prostaglandin E2 receptor, has shown an immunosuppressive activity on cancer cells. This first-in-human study evaluated ONO-4578, a highly selective EP4 antagonist, as monotherapy and in combination with nivolumab in patients with advanced or metastatic solid tumors. A daily dose ranging from 30 mg to 100 mg of ONO-4578 monotherapy and that ranging from 2 mg to 60 mg of ONO-4578 with biweekly nivolumab 240 mg were administered. A total of 31 patients were enrolled, 10 receiving monotherapy and 21 receiving combination therapy. Overall, 26 patients experienced treatment-related adverse events. Dose-limiting toxicities were observed in three patients; one of six patients receiving 100 mg monotherapy developed grade 3 duodenal ulcer and two of six patients receiving 60 mg combination therapy developed either grade 3 erythema multiforme or grade 3 increased amylase and grade 4 increased lipase. One patient with small-cell lung cancer who received 40 mg combination therapy had a partial response, and three patients with monotherapy and six patients with combination therapy had stable disease. Pharmacodynamics analyses showed that ONO-4578 had EP4 antagonistic activity at doses as low as 2 mg. In conclusion, the maximum tolerated dose of ONO-4578 alone or in combination with nivolumab was not reached. ONO-4578 was well tolerated at the tested doses and showed signs of antitumor activity. Considering safety, efficacy, and pharmacokinetics/pharmacodynamics results, ONO-4578 40 mg daily with nivolumab 240 mg biweekly was selected as the recommended dose for future clinical trials. (Registration: JapicCTI-173,496 and NCT03155061).

Keywords: maximum tolerated dose; nivolumab; phase I; prostaglandin E2 receptor EP4; solid tumor.

© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Figures

FIGURE 1
FIGURE 1
(A) Swimmer plot showing the duration of treatment with ONO‐4578 alone or in combination with patients with solid tumors treated with nivolumab in patients with solid tumors. (B) In a patient with small‐cell lung cancer, computed tomography highlighted metastatic tumors at the right hilar lymph node and the left adrenal gland before and 11.7 months after treatment with 40 mg combination therapy. PD, progressive disease; PR, partial response
FIGURE 2
FIGURE 2
Plasma concentration of ONO‐4578 at day 28 of cycle 1 in patients with solid tumors treated with ONO‐4578 monotherapy or in combination with nivolumab. Mean value of each patient's data is shown. Error bars represent standard deviation. In the 60 and 100 mg monotherapy cohorts and the 5 and 60 mg combination therapy cohorts, some patients' data were missing
FIGURE 3
FIGURE 3
Pharmacodynamic parameters in patients with solid tumors treated with ONO‐4578 monotherapy or in combination with nivolumab. (A) Tumor necrosis factor‐α (TNF‐α) release in whole blood samples collected on days 1, 2, and 28 were divided by baseline. Change in the median fold is shown. Error bars represent minimum and maximum values. (B, C) Plasma prostaglandin E2 metabolites (PGEM) (B) and tetranor‐PGEM in urine (C) of individual patients are shown. Data were missing in some patients due to discontinuation of study treatment before the completion of the 28‐day cycle or technical difficulties in the analysis

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