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Hence, we conducted the randomized phase II QUATTRO-II study (ClinicalTrials.gov identifier: NCT04097444; Japan Registry of Clinical Trials identifier: jRTCs041190072) to evaluate the safety and efficacy of capecitabine, oxaliplatin, and irinotecan (CAPOXIRI) combination plus bevacizumab versus FOLFOXIRI plus bevacizumab, expecting a lower incidence of neutropenia without compromising the efficacy. <jats:italic>Methods\u00a0<\/jats:italic>We investigated the recommended doses (RD) of oxaliplatin and irinotecan as a safety lead-in portion of Step 1 before initiating the randomized portion as Step 2. Four dose levels of CAPOXIRI (fixed dose of capecitabine, 1600\u00a0mg\/m<jats:sup>2<\/jats:sup>; escalated\/de-escalated doses of oxaliplatin and irinotecan) plus bevacizumab (7.5\u00a0mg\/kg) were investigated in a 3\u2009+\u20093 manner. A dose level of \u2264\u20092\/6 of dose-limiting toxicity (DLT) cases was expected as the RD. <jats:italic>Results\u00a0<\/jats:italic>In Step 1, we included nine patients (three and six in levels 0 and +\u20091, respectively). Level 0 (irinotecan, 200\u00a0mg\/m<jats:sup>2<\/jats:sup>; oxaliplatin, 100\u00a0mg\/m<jats:sup>2<\/jats:sup>) did not demonstrate DLTs. In level\u2009+\u20091 (irinotecan, 200\u00a0mg\/m<jats:sup>2<\/jats:sup>; oxaliplatin, 130\u00a0mg\/m<jats:sup>2<\/jats:sup>), although one patient experienced grade 4 febrile neutropenia, no further safety concerns were observed. As a preliminary efficacy result, the objective response rate in all nine patients was 89\u2009% (100 and 83\u2009% in levels 0 and +\u20091, respectively). <jats:italic>Conclusions\u00a0<\/jats:italic>The RD of CAPOXIRI plus bevacizumab was 200, 130, and 1600\u00a0mg\/m<jats:sup>2<\/jats:sup> for irinotecan, oxaliplatin, and capecitabine, respectively, and 7.5\u00a0mg\/kg for bevacizumab. The randomized portion is still ongoing.<\/jats:p>","DOI":"10.1007\/s10637-021-01125-2","type":"journal-article","created":{"date-parts":[[2021,5,21]],"date-time":"2021-05-21T14:03:12Z","timestamp":1621605792000},"page":"1649-1655","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Combination therapy of capecitabine, irinotecan, oxaliplatin, and bevacizumab as a first\u2010line treatment for metastatic colorectal cancer: Safety lead\u2010in results from the QUATTRO-II study"],"prefix":"10.1007","volume":"39","author":[{"given":"Daisuke","family":"Kotani","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takayuki","family":"Yoshino","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masahito","family":"Kotaka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akihito","family":"Kawazoe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshiki","family":"Masuishi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroya","family":"Taniguchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kentaro","family":"Yamazaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takeharu","family":"Yamanaka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eiji","family":"Oki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kei","family":"Muro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshito","family":"Komatsu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hideaki","family":"Bando","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hironaga","family":"Satake","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takeshi","family":"Kato","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4034-1945","authenticated-orcid":false,"given":"Akihito","family":"Tsuji","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,5,21]]},"reference":[{"key":"1125_CR1","unstructured":"NCCN Clinical Practice Guidelines in Oncology, Colon Cancer, Version 1. 2021 \u2013 December 2020. https:\/\/www.nccn.org\/professionals\/physician_gls\/pdf\/colon.pdf. 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A.Tsuji received honoraria from Taiho, grants from Taiho, Sanofi, and Bayer. T.Kato received honoraria from Ono, Chugai, Takeda, Taiho, Bayer, and Boehringer-Ingelheim; research funding from Chugai and Takeda. T.Yoshino received grants from Taiho, Sumitomo Dainippon Pharma, Ono, Chugai, Amgen, Parexel International, MSD, Daiichi Sankyo, and Sanofi. H.Satake received honoraria from Chugai, Yakult Honsha, Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, Merck Biopharma, MSD, Ono, Sanofi, Taiho, Takeda, and Asahi Kasei. H.Bando received honoraria from Taiho and Eli Lilly; grants from AstraZeneca and Sysmex. T.Yamanaka received honoraria and grants from Chugai, Takeda, Boehringer-Ingelheim, Taiho, Daiichi Sankyo, and Bayer; honoraria from Pfizer, Sysmex, HUYA Bioscience International, and Gilead Sciences; grants from Ono, Merck Biopharma, Astellas, and Eli Lilly. Y.Komatsu received honoraria and grants from Eli Lilly, MSD, Taiho, Kyowa Kirin, Ono, Sanofi, and Yakult Honsha; honoraria from Bristol-Myers Squibb, Chugai, EA Pharma, Takeda, Merck Biopharma, Nipro, Pfizer, Sawai, Asahi Kasei, Mitsubishi Tanabe Pharma, Nippon Kayaku, Otsuka, and Novartis Pharma; grants from Sysmex and Astellas. H.Taniguchi received honoraria and grants from Takeda and Taiho; honoraria from Eli Lilly, Chugai, and Ono. K.Muro received research funding from MSD, Daiichi Sankyo, Parexel International, Shionogi, Sumitomo Dainippon Pharma, Sanofi, Pfizer, Mediscience Planning, Solasia Pharma, Merck Biopharma; fees for speakers\u2019 bureau from Ono, Sanofi, Eli Lilly, Chugai, Takeda, Taiho, Bristol-Myers Squibb, and Bayer. K.Yamazaki received honoraria from Daiichi Sankyo, Eli Lilly, Yakult Honsha, Merck Biopharma, Bristol-Myers Squibb, Ono, MSD, Sanofi, Chugai, Takeda, Bayer, and Taiho. E.Oki received lecture fees from Chugai, Taiho, Bayer, Eli Lilly, Takeda, and Ono. M.Kotaka received honoraria from Chugai and Yakult Honsha. A.Kawazoe received honoraria and grants from Taiho and Ono; grants from Sumitomo Dainippon Pharma and MSD. T.Masuishi received honoraria and grants from Ono; honoraria from Takeda, Chugai, Merck Biopharma, Taiho, Bayer, Eli Lilly, Yakult Honsha, Sanofi, and Bristol-Myers Squibb; grants from MSD, Daiichi Sankyo, and Novartis Pharma.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"Before initiation, the principal investigator must consult the Certified Review Board* and receive approval from the study site\u2019s manager and must submit a trial plan to the Minister of Health, Labor and Welfare. * An application for this study will be submitted to the following Certified Review Board: Shizuoka Cancer Center Institutional Review Board (Certification No. CRB4180010).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"All participants provided written and informed consent before enrollment.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"Not applicable.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}}]}}