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The optimal dosing schedule, safety, pharmacokinetics, and preliminary antitumor effects were also evaluated. A multicenter, open-label trial with a standard 3\u2009+\u20093 design and dose escalation by dose-limiting toxicity (DLT) was conducted. The treatment schedules were once daily for 7, 14, and 21\u00a0days every 3\u00a0weeks as one cycle. The total dose per cycle was increased from 175 to 840\u00a0mg\/m<jats:sup>2<\/jats:sup>. Eighteen patients were enrolled in this study. DLT occurred in one of six patients at 75\u00a0mg\/m<jats:sup>2<\/jats:sup>\/day\u2009\u00d7\u20097\u00a0days, and one of three patients at 37.5\u00a0mg\/m<jats:sup>2<\/jats:sup>\/day\u2009\u00d7\u200914\u00a0days and 25\u00a0mg\/m<jats:sup>2<\/jats:sup>\/day\u2009\u00d7\u200921\u00a0days. However, the delayed recovery from a decrease in neutrophil or platelet count hampered the start of subsequent treatment cycles, and the trend was more prominent at 37.5\u00a0mg\/m<jats:sup>2<\/jats:sup>\/day\u2009\u00d7\u200914\u00a0days and 25\u00a0mg\/m<jats:sup>2<\/jats:sup>\/day\u2009\u00d7\u200921\u00a0days than in 75\u00a0mg\/m<jats:sup>2<\/jats:sup>\/day\u2009\u00d7\u20097\u00a0days. MTD was determined as 75\u00a0mg\/m<jats:sup>2<\/jats:sup>\/day\u2009\u00d7\u20097\u00a0days to allow acceptable hematologic recovery. The pharmacokinetics of orally-administered bendamustine were generally dose-dependent; however, the inter-individual variability is relatively large. The major adverse events were hematologic toxicities; gastrointestinal disorders were generally mild. Adverse drug reactions did not lead to the discontinuation of the drug. A partial response was observed in two of six patients (prostatic small cell carcinoma and thymic carcinoma) at 75\u00a0mg\/m<jats:sup>2<\/jats:sup>\/day\u2009\u00d7\u20097\u00a0days. The RD and optimal dosing schedule of orally-administered bendamustine was 75\u00a0mg\/m<jats:sup>2<\/jats:sup> once daily for 7\u00a0days every 3\u00a0weeks for the treatment of advanced solid tumors. (<jats:italic>Trial registration number<\/jats:italic> ClinicalTrials.gov NCT03604679. Registration date July 27, 2018).<\/jats:p>","DOI":"10.1007\/s10637-022-01307-6","type":"journal-article","created":{"date-parts":[[2022,11,4]],"date-time":"2022-11-04T10:03:37Z","timestamp":1667556217000},"page":"1-12","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Oral formulation of bendamustine hydrochloride for patients with advanced solid tumors; a phase 1 study"],"prefix":"10.1007","volume":"41","author":[{"given":"Toshio","family":"Shimizu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuhiko","family":"Nakagawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hidetoshi","family":"Hayashi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tsutomu","family":"Iwasa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hisato","family":"Kawakami","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Satomi","family":"Watanabe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noboru","family":"Yamamoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kan","family":"Yonemori","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takafumi","family":"Koyama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Sato","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenji","family":"Tamura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keiichi","family":"Kikuchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenichiro","family":"Akaike","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shiho","family":"Takeda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masayuki","family":"Takeda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2022,11,4]]},"reference":[{"key":"1307_CR1","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1002\/prac.19630200310","volume":"20","author":"W Ozegowski","year":"1963","unstructured":"Ozegowski W, Krebs D (1963) \u03c9-[Bis-(\u03b2-chlor\u00e4thyl)-amino-benzimidazolyl-(2)]-propion- bzw. -butters\u00e4uren als potentielle Cytostatika. 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The protocol was approved by the institutional review boards of all participating sites.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Written informed consent was obtained from all the participants included in the study.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"Permission to submit the manuscript for publication was obtained from all named authors.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to publish"}},{"value":"TS: speaker fees from Eli Lilly, Chugai, Taiho, and Boehringer Ingelheim; research grants from Novartis, Eli Lilly, Daiichi-Sankyo, AbbVie, Bristol-Myers Squibb, Eisai, AstraZeneca, Pfizer, Loxo Oncology, Takeda Oncology, Incyte, Chordia Therapeutics, 3D-Medicine, SymBio, PharmaMar, Five Prime, and Astellas; and advisory board fees from AbbVie, Daiichi-Sankyo, and Takeda Oncology. KN: speaker\u2019s fees from Astellas, Takeda, Nanzando, AstraZeneca, Chugai, Roche Diagnostics, MSD, Eli Lilly, Nippon Kayaku, Ono, Merck Biopharma, Bayer, Daiichi Sankyo, Novartis, Kyowa Kirin, Taiho, Pfizer, AbbVie, Bristol Myers Squibb, CareNet, Amgen, Medical Review, Yodosha, 3H Clinical Trial, Thermo Fisher, Hisamitsu, Nichi-Iko, Kyorun, Medicus Shuppan, Nippon Boehringer Ingelheim, Nikkei Business, Yomiuri Telecasting and Medical Mobile; research grants from MSD, AstraZeneca, Pfizer, Icon, Astellas, Bayer, Takeda, Novartis, Eli Lilly, EPS, Bayer, Bristol Myers Squibb, CMIC Shift Zero, PRA HEALTHSCIENCES, Taiho, Eisai, Merck Biopharma, PAREXEL, Mochida, Covance, Ono, Kissei, Medical Research Support, Sysmex, GlaxoSmithKline, Sanofi, A2 Healthcare, Kyowa Hakko Kirin, Syneos Health, AbbVie Inc. EPS, Pfizer R&D, Chugai, Daiichi Sankyo, PPD-SNBL, Nippon Boehringer Ingelheim, IQVIA, Quintiles, Clinical Research and SymBio; consulting fees from Astellas, Takeda, Eli Lilly, Pfizer, KYORIN and Ono. HH: speaker fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Eli Lilly, Kyorin, Merck Biopharma, MSD, Novartis, Ono, Shanghai Haihe Biopharm, Taiho, and Takeda; research grants from AstraZeneca, Boehringer Ingelheim, Chugai, and Ono; advisory board fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Eli Lilly, Pfizer, Shanghai Haihe Biopharm, Takeda, and Merck Biopharma. TI: No conflict of interest. HK: speaker fees from Glaxo Smith Kline, Bristol-Myers Squibb, Eli Lilly, MSD, Ono, Chugai, Takeda, and Taiho; research grants from Chugai, Taiho, Kobayashi, and Eisai; consulting fees from Bristol-Myers Squibb, Eli Lilly, MSD, Ono, Daiichi-Sankyo, and Taiho; and honoraria from Bristol-Myers Squibb, AstraZeneca, Bayer, Eli Lilly, MSD, Ono, Chugai, Daiichi Sankyo, Merck Biopharma, Takeda, Yakult, and Taiho. SW: No conflict of interest. NY: speaker fees from AstraZeneca, Pfizer, Eli Lilly, ONO, Chugai, Sysmex, Daiichi-Sankyo, and Eisai; research grants from Astellas, Chugai, Eisai, Taiho, Bristol-Myers Squibb, Pfizer, Novartis, Eli Lilly, AbbVie, Daiichi-Sankyo, Bayer, Boehringer Ingelheim, Kyowa-Hakko Kirin, Takeda, ONO, Janssen Pharma, MSD, MERCK, GSK, Sumitomo Dainippon, Chiome Bioscience, Otsuka, Carna Biosciences, and Genmab; and advisory board fees from Eisai, Takeda, Otsuka, Boehringer Ingelheim, Cimic, and Chugai. KY: speaker fees from Eisai, Astrazeneca, Pfizer, Eli Lilly, Fuji Film, Chugai, Taiho, and Takeda; research grants from Daiichi Sankyo, Eisai, AstraZeneca, Pfizer, Eli Lilly, Fuji Film, Chugai, Taiho, Takeda, Sanofi, Genmab, Ono, Novartis, Boeringer Ingelheim, MSD, Seagen, and Nihon-Kayaku; and advisory board fees from Ono, Genmab, Novartis, Eisai, Chugai, Takeda, Daiichi Sankyo, and MSD. TK: Speaker\u2019s fees from Sysmex and Chugai; research grants from PACT Pharma. JS: Speaker fees from AstraZeneca and Chugai. KT: Research grants from Pfizer, Eisai, Daiich-Sankyo, and Chugai. MT: Speaker fees from AstraZeneca, ONO, Chugai Novartis, Bristol-Myers Squibb, and Boehringer Ingelheim. KK, KA, and ST are full-time employees of SymBio Pharmaceuticals, Ltd..","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interests"}}]}}