{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T03:30:30Z","timestamp":1790998230930,"version":"4.1.0"},"reference-count":15,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T00:00:00Z","timestamp":1767830400000},"content-version":"vor","delay-in-days":7,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Experimental Dermatology"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:label\/>\n                    <jats:p>TM5614, a plasminogen activator inhibitor\u20101 (PAI\u20101) inhibitor, has demonstrated potential in overcoming nivolumab resistance in patients with unresectable, anti\u2010PD\u20101 antibody\u2010refractory malignant melanoma. Previous Phase II trials have shown promising response rates, warranting further investigation through a randomised, placebo\u2010controlled Phase III trial. This Phase III, randomised, double\u2010blind, placebo\u2010controlled, investigator\u2010initiated clinical trial aims to evaluate the efficacy and safety of TM5614 in combination with nivolumab for treating patients with unresectable, anti\u2010PD\u20101 antibody\u2010refractory malignant melanoma. The study will enrol 124 participants across 18 medical institutions in Japan. Patients will receive either TM5614 plus nivolumab or placebo plus nivolumab for 48\u2009weeks. The primary endpoint is overall survival (OS), while secondary endpoints include objective response rate (ORR), progression\u2010free survival (PFS), disease control rate (DCR), and the incidence of treatment\u2010related adverse events. This study is designed to compare OS between the TM5614 plus nivolumab group and the placebo plus nivolumab group. Statistical analyses will be conducted using the Kaplan\u2013Meier method and Cox proportional hazards models. This Phase III trial will provide critical insights into the efficacy of TM5614 in combination with nivolumab as a novel treatment strategy for unresectable, anti\u2010PD\u20101 antibody\u2010refractory malignant melanoma. The results may offer new therapeutic options to improve patient outcomes and overcome resistance to immune checkpoint inhibitors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial Registration<\/jats:title>\n                    <jats:p>\n                      jRCT2021240049 (\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/jrct.niph.go.jp\/en-latest-detail\/jRCT2021240049\">https:\/\/jrct.niph.go.jp\/en\u2010latest\u2010detail\/jRCT2021240049<\/jats:ext-link>\n                      ). Protocol version: Ver.1.2 (3rd February, 2025)\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/exd.70202","type":"journal-article","created":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T14:59:36Z","timestamp":1767884376000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Phase\n                    <scp>III<\/scp>\n                    Study Investigating the Safety and Efficacy of\n                    <scp>TM5614<\/scp>\n                    in Combination With Nivolumab for the Treatment of Unresectable Malignant Melanoma: Protocol"],"prefix":"10.1111","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6809-5833","authenticated-orcid":false,"given":"Taku","family":"Fujimura","sequence":"first","affiliation":[{"name":"Department of Dermatology Tohoku University School of Medicine  Sendai 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