{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T19:48:59Z","timestamp":1790711339214,"version":"4.1.0"},"reference-count":18,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2013,6,21]],"date-time":"2013-06-21T00:00:00Z","timestamp":1371772800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2013,8]]},"abstract":"<jats:p>Tivozanib is a potent and selective inhibitor of vascular endothelial growth factor receptor (<jats:styled-content style=\"fixed-case\">VEGFR<\/jats:styled-content>) tyrosine kinases. A previous clinical trial in the <jats:styled-content style=\"fixed-case\">EU<\/jats:styled-content> and <jats:styled-content style=\"fixed-case\">USA<\/jats:styled-content> indicated that tivozanib at the maximum tolerated dose of 1.5\u00a0mg\/day showed an antitumor activity in patients with renal cell carcinoma. This Japanese phase <jats:styled-content style=\"fixed-case\">I<\/jats:styled-content> study was designed to determine the recommended phase <jats:styled-content style=\"fixed-case\">II<\/jats:styled-content> dose of tivozanib for <jats:styled-content style=\"fixed-case\">J<\/jats:styled-content>apanese patients; secondary objectives included pharmacokinetic\/pharmacodynamic profiles and preliminary efficacy. Daily treatment with tivozanib in a 3\u2010weeks\u2010on\/1\u2010week\u2010off cycle was examined in nine <jats:styled-content style=\"fixed-case\">J<\/jats:styled-content>apanese patients with advanced solid tumors in the 3\u00a0+\u00a03 design (Level 1, 1.0\u00a0mg; Level 2, 1.5\u00a0mg). No dose\u2010limiting toxicity was observed throughout the study, and the maximum tolerated dose was not reached. The most commonly observed drug\u2010related adverse events were diarrhea, dysphonia, rash, thyroid stimulating hormone increase, and with severity grade \u22653, hand\u2010foot skin reaction, hypertension, and proteinuria. Those adverse events were generally well\u2010manageable and mostly resolved within the tolerability evaluation period. Serum exposure to tivozanib resulted in <jats:italic>t<\/jats:italic><jats:sub>1\/2<\/jats:sub> of more than &gt;60\u00a0h. Increase of plasma <jats:styled-content style=\"fixed-case\">VEGF<\/jats:styled-content> and decrease of plasma <jats:styled-content style=\"fixed-case\">VEGFR<\/jats:styled-content>\u20101 and <jats:styled-content style=\"fixed-case\">VEGFR<\/jats:styled-content>\u20102 were observed 1\u20133\u00a0weeks after tivozanib treatment. Although no complete or partial response was observed, long\u2010term stable disease continuing more than 170\u00a0days was observed in three renal cell carcinoma patients who had failed prior <jats:styled-content style=\"fixed-case\">VEGFR<\/jats:styled-content> inhibitors. In conclusion, 1.5\u00a0mg\/day of tivozanib in a 3\u2010weeks\u2010on\/1\u2010week\u2010off setting was tolerable in <jats:styled-content style=\"fixed-case\">J<\/jats:styled-content>apanese patients, and was recommended for further clinical trials in the <jats:styled-content style=\"fixed-case\">J<\/jats:styled-content>apanese population. Clinical trial Registration No: Japic<jats:styled-content style=\"fixed-case\">CTI<\/jats:styled-content>\u2010090854.<\/jats:p>","DOI":"10.1111\/cas.12197","type":"journal-article","created":{"date-parts":[[2013,5,16]],"date-time":"2013-05-16T08:33:08Z","timestamp":1368693188000},"page":"1039-1044","source":"Crossref","is-referenced-by-count":12,"title":["Phase <scp>I<\/scp> study of highly selective inhibitor of VEGFR tyrosine kinase, tivozanib, in <scp>J<\/scp>apanese patients with solid tumors"],"prefix":"10.1111","volume":"104","author":[{"given":"Masashi","family":"Niwakawa","sequence":"first","affiliation":[{"name":"Division of Urology Shizuoka Cancer Center Shizuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raizo","family":"Yamaguchi","sequence":"additional","affiliation":[{"name":"Division of Urology Shizuoka Cancer Center Shizuoka 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