{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T01:16:38Z","timestamp":1789434998785,"version":"build-2803163510"},"reference-count":37,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2022,11,4]],"date-time":"2022-11-04T00:00:00Z","timestamp":1667520000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100013170","name":"Ono Pharmaceutical","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100013170","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2023,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>EP4, a prostaglandin E<jats:sub>2<\/jats:sub> receptor, has shown an immunosuppressive activity on cancer cells. This first\u2010in\u2010human study evaluated ONO\u20104578, 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\u2009mg to 100\u2009mg of ONO\u20104578 monotherapy and that ranging from 2\u00a0mg to 60\u2009mg of ONO\u20104578 with biweekly nivolumab 240\u2009mg were administered. A total of 31 patients were enrolled, 10 receiving monotherapy and 21 receiving combination therapy. Overall, 26 patients experienced treatment\u2010related adverse events. Dose\u2010limiting toxicities were observed in three patients; one of six patients receiving 100\u2009mg monotherapy developed grade 3 duodenal ulcer and two of six patients receiving 60\u2009mg combination therapy developed either grade 3 erythema multiforme or grade 3 increased amylase and grade 4 increased lipase. One patient with small\u2010cell lung cancer who received 40\u2009mg 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\u20104578 had EP4 antagonistic activity at doses as low as 2\u00a0mg. In conclusion, the maximum tolerated dose of ONO\u20104578 alone or in combination with nivolumab was not reached. ONO\u20104578 was well tolerated at the tested doses and showed signs of antitumor activity. Considering safety, efficacy, and pharmacokinetics\/pharmacodynamics results, ONO\u20104578 40\u2009mg daily with nivolumab 240\u2009mg biweekly was selected as the recommended dose for future clinical trials. (Registration: JapicCTI\u2010173,496 and NCT03155061).<\/jats:p>","DOI":"10.1111\/cas.15574","type":"journal-article","created":{"date-parts":[[2022,9,9]],"date-time":"2022-09-09T18:29:25Z","timestamp":1662748165000},"page":"211-220","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["First\u2010in\u2010human study of <scp>ONO<\/scp>\u20104578, an antagonist of prostaglandin <scp>E<sub>2<\/sub><\/scp> receptor 4, alone and with nivolumab in solid tumors"],"prefix":"10.1111","volume":"114","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3863-9582","authenticated-orcid":false,"given":"Satoru","family":"Iwasa","sequence":"first","affiliation":[{"name":"Department of Experimental Therapeutics National Cancer Center Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5807-8458","authenticated-orcid":false,"given":"Takafumi","family":"Koyama","sequence":"additional","affiliation":[{"name":"Department of Experimental Therapeutics National Cancer Center Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5543-6379","authenticated-orcid":false,"given":"Makoto","family":"Nishino","sequence":"additional","affiliation":[{"name":"Department of Experimental Therapeutics National Cancer Center Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9565-117X","authenticated-orcid":false,"given":"Shunsuke","family":"Kondo","sequence":"additional","affiliation":[{"name":"Department of Experimental Therapeutics National Cancer Center Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4600-9428","authenticated-orcid":false,"given":"Kazuki","family":"Sudo","sequence":"additional","affiliation":[{"name":"Department of Experimental Therapeutics National Cancer Center Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7624-7611","authenticated-orcid":false,"given":"Kan","family":"Yonemori","sequence":"additional","affiliation":[{"name":"Department of Experimental Therapeutics National Cancer Center Hospital  Tokyo Japan"},{"name":"Department of Medical Oncology National Cancer Center Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuya","family":"Yoshida","sequence":"additional","affiliation":[{"name":"Department of Experimental Therapeutics National Cancer Center Hospital  Tokyo Japan"},{"name":"Department of Thoracic Oncology National Cancer Center Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3514-9927","authenticated-orcid":false,"given":"Kenji","family":"Tamura","sequence":"additional","affiliation":[{"name":"Department of Breast and Medical Oncology National Cancer Center Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshio","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Department of Experimental Therapeutics National Cancer Center Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6981-0800","authenticated-orcid":false,"given":"Yutaka","family":"Fujiwara","sequence":"additional","affiliation":[{"name":"Department of Experimental Therapeutics National Cancer Center Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4041-8298","authenticated-orcid":false,"given":"Shigehisa","family":"Kitano","sequence":"additional","affiliation":[{"name":"Department of Experimental Therapeutics National Cancer Center Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2557-8170","authenticated-orcid":false,"given":"Akihiko","family":"Shimomura","sequence":"additional","affiliation":[{"name":"Department of Experimental Therapeutics National Cancer Center Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9249-6522","authenticated-orcid":false,"given":"Jun","family":"Sato","sequence":"additional","affiliation":[{"name":"Department of Experimental Therapeutics National Cancer Center Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumiharu","family":"Yokoyama","sequence":"additional","affiliation":[{"name":"Translational Research Laboratories Ono Pharmaceutical Co., Ltd.  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