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The primary objective was dose-limiting toxicities (DLTs). Maximum-tolerated dose (MTD) was investigated using an accelerated titration design. <jats:italic>Methods<\/jats:italic> The starting 10-mg\/m<jats:sup>2<\/jats:sup> dose was followed by an initial accelerated stage (weekly dosing; <jats:italic>n<\/jats:italic>\u2009=\u200911). Based on liver function test (LFT) results, a 14-day, 20-mg\/m<jats:sup>2<\/jats:sup> dose lead-in period was implemented (weekly dosing with lead-in; <jats:italic>n<\/jats:italic>\u2009=\u20096). <jats:italic>Results<\/jats:italic> Abnormal LFT changes and gastrointestinal effects were the most common treatment-related adverse events (AEs). DLTs with 56-mg\/m<jats:sup>2<\/jats:sup> weekly dosing occurred in 1\/5 patients; five patients had grade\u2009\u2265\u20092 abnormal LFT changes at 40- and 56-mg\/m<jats:sup>2<\/jats:sup> weekly doses. Further dose escalation ceased because of the possibility of severe abnormal LFT changes occurring. DLTs with weekly dosing with lead-in occurred in 1\/5 patients at a 56-mg\/m<jats:sup>2<\/jats:sup> dose; MTD could not be determined because discontinuation criteria for additional enrollment at that particular dose level were met. As no further enrollment at lower doses occurred, dose escalation assessment was discontinued. Serious treatment-related AEs, AEs leading to treatment discontinuation, and DLTs were all related to abnormal LFT changes, suggesting that TAS4464 administration could affect liver function. This effect was dose-dependent but considered reversible. Complete or partial responses to TAS4464 were not observed; one patient achieved prolonged stable disease. <jats:italic>Conclusions<\/jats:italic> MTD could not be determined due to TAS4464 effects on liver function. Further evaluation of the mechanism of NEDD8-activating enzyme inhibitor-induced abnormal liver function is required. <jats:italic>Trial registration number<\/jats:italic> JapicCTI-173,488 (registered with Japan Pharmaceutical Information Center). <jats:italic>Registration date<\/jats:italic> 13 January 2017<\/jats:p>","DOI":"10.1007\/s10637-020-01055-5","type":"journal-article","created":{"date-parts":[[2021,2,10]],"date-time":"2021-02-10T05:01:46Z","timestamp":1612933306000},"page":"1036-1046","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["A first-in-human, phase 1 study of the NEDD8 activating enzyme E1 inhibitor TAS4464 in patients with advanced solid tumors"],"prefix":"10.1007","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0787-2851","authenticated-orcid":false,"given":"Noboru","family":"Yamamoto","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshio","family":"Shimizu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kan","family":"Yonemori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigehisa","family":"Kitano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunsuke","family":"Kondo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoru","family":"Iwasa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takafumi","family":"Koyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuki","family":"Sudo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Sato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenji","family":"Tamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junichi","family":"Tomomatsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makiko","family":"Ono","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoki","family":"Fukuda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunji","family":"Takahashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,2,9]]},"reference":[{"issue":"6","key":"1055_CR1","doi-asserted-by":"publisher","first-page":"394","DOI":"10.3322\/caac.21492","volume":"68","author":"F Bray","year":"2018","unstructured":"Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. 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The study was conducted in compliance with the guidelines provided in the Declaration of Helsinki, Good Clinical Practice, and all applicable local and national regulations.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval\/Research involving human participants"}},{"value":"All patients provided written informed consent prior to study participation.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}},{"value":"Not applicable.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"Not applicable.","order":6,"name":"Ethics","group":{"name":"EthicsHeading","label":"Code availability"}}]}}