Combination therapy of capecitabine, irinotecan, oxaliplatin, and bevacizumab as a first-line treatment for metastatic colorectal cancer: Safety lead-in results from the QUATTRO-II study

Daisuke Kotani, Takayuki Yoshino, Masahito Kotaka, Akihito Kawazoe, Toshiki Masuishi, Hiroya Taniguchi, Kentaro Yamazaki, Takeharu Yamanaka, Eiji Oki, Kei Muro, Yoshito Komatsu, Hideaki Bando, Hironaga Satake, Takeshi Kato, Akihito Tsuji, Daisuke Kotani, Takayuki Yoshino, Masahito Kotaka, Akihito Kawazoe, Toshiki Masuishi, Hiroya Taniguchi, Kentaro Yamazaki, Takeharu Yamanaka, Eiji Oki, Kei Muro, Yoshito Komatsu, Hideaki Bando, Hironaga Satake, Takeshi Kato, Akihito Tsuji

Abstract

Background FOLFOXIRI plus bevacizumab is the first-line treatment for metastatic colorectal cancer (mCRC) but demonstrates high neutropenia incidence among Asian patients. 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. Methods 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 mg/m2; escalated/de-escalated doses of oxaliplatin and irinotecan) plus bevacizumab (7.5 mg/kg) were investigated in a 3 + 3 manner. A dose level of ≤ 2/6 of dose-limiting toxicity (DLT) cases was expected as the RD. Results In Step 1, we included nine patients (three and six in levels 0 and + 1, respectively). Level 0 (irinotecan, 200 mg/m2; oxaliplatin, 100 mg/m2) did not demonstrate DLTs. In level + 1 (irinotecan, 200 mg/m2; oxaliplatin, 130 mg/m2), 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 % (100 and 83 % in levels 0 and + 1, respectively). Conclusions The RD of CAPOXIRI plus bevacizumab was 200, 130, and 1600 mg/m2 for irinotecan, oxaliplatin, and capecitabine, respectively, and 7.5 mg/kg for bevacizumab. The randomized portion is still ongoing.

Keywords: Bevacizumab; CAPOXIRI; FOLFOXIRI; Metastatic colorectal cancer; Triplet.

Conflict of interest statement

D.Kotani received honoraria from Taiho, Ono, Takeda, Lilly, Merck Biopharma, Bristol-Myers Squibb, Chugai, and Sysmex. 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’ 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.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Swimmer plots according to dose level. Study treatment was ongoing in four patients (Pt 01, Pt 02, Pt 03, Pt 05). Study treatment was discontinued due to conversion surgery (Pt 06, Pt 07, Pt 08), disease progression (Pt 04), and toxicity (Pt 09)
Fig. 2
Fig. 2
Waterfall plot of the maximum percent change in tumor size from baseline, as measured according to Response Evaluation Criteria in Solid Tumors

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