1 3 Cancer Chemother Pharmacol DOI 10.1007/s00280-014-2672-9 ORIGINAL ARTICLE A dose-escalation study of oxaliplatin/capecitabine/irinotecan (XELOXIRI) and bevacizumab as a first-line therapy for patients with metastatic colorectal cancer Yasushi Sato · Hiroyuki Ohnuma · Masahiro Hirakawa · Minoru Takahashi · Takahiro Osuga · Yutaka Okagawa · Kazuyuki Murase · Kohichi Takada · Yutaka Kawano · Satoshi Iyama · Tsuyoshi Hayashi · Tsutomu Sato · Koji Miyanishi · Rishu Takimoto · Masayoshi Kobune · Kenji Okita · Toru Mizuguchi · Tomohisa Furuhata · Koichi Hirata · Junji Kato Received: 4 August 2014 / Accepted: 30 December 2014 © Springer-Verlag Berlin Heidelberg 2015 (17 %), diarrhea (8 %), and febrile neutropenia (8 %). The response rate and median progression-free survival were 83 % and 15 months, respectively. Conclusions XELOXIRI/bevacizumab is a feasible regi- men for patients with mCRC, neutropenia was the DLT, and the RD of irinotecan is 150 mg/m 2 . The response rate observed is very promising and warrants further investigation. Keywords Bevacizumab · Capecitabine · Colorectal cancer · Irinotecan · Oxaliplatin Introduction In the past few years, several different combinations of the newer cytotoxic agents, such as irinotecan and oxalipl- atin, with fluorouracil [5-FU; with leucovorin (LV; folinic acid)] and targeted agents including bevacizumab, cetuxi- mab, and panitumumab, have increased significantly the tumor response and prolonged the survival of patients with unresectable, advanced colorectal cancer [1]. Several studies have suggested that administering all three active cytotoxic drugs (5-FU, irinotecan, or oxaliplatin) during the course of treatment has been associated with longer overall survival (OS) times [2, 3]. However, in a sequen- tial strategy, 20–50 % of patients who progress after first- line chemotherapy cannot receive second-line treatment, mainly because of deterioration of their performance sta- tus and liver function [2]. Furthermore, another pooled analysis indicated that there is a strong correlation between the response rate (RR) to first-line chemotherapy and the possibility of post-chemotherapy radical resection of iso- lated liver metastases that may be associated with long- term survival [3]. In order to enhance treatment results Abstract Purpose The aim of this study was to determine the recommended dose (RD) of a triweekly capecitabine, oxaliplatin, irinotecan, and bevacizumab (XELOXIRI/ bevacizumab) regimen that was easier to administer than FOLFOXIRI/bevacizumab, using capecitabine instead of 5-fuorouracil (5-FU), in patients with metastatic colorectal cancer (mCRC). Methods Patients received oxaliplatin (100 mg/m 2 , day 1), capecitabine (1,700 mg/m 2 per day from day 2 to 15), irinotecan (100, 120, 150 mg/m 2 for dose levels 1, 2, 3, day 1), and bevacizumab (7.5 mg/kg, day 1), repeated every 3 weeks. Dose-limiting toxicities (DLTs) were assessed in the first two cycles to determine the maximum tolerated dose (MTD). Results Twelve patients received a median of 6.5 cycles of therapy (range 2–12). The DLT was grade 4 neutrope- nia, observed in one of six patients at dose level 2. The MTD was not reached at dose level 3. Therefore, the RD of irinotecan was defined as 150 mg/m 2 . The most com- mon grade ≥3 toxicities were neutropenia (41 %), anemia Y. Sato · H. Ohnuma · M. Hirakawa · T. Osuga · Y. Okagawa · K. Murase · K. Takada · Y. Kawano · S. Iyama · T. Hayashi · T. Sato · K. Miyanishi · R. Takimoto · M. Kobune · J. Kato (*) Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, South 1 West 16, Chuo-ku, Sapporo 060-8543, Japan e-mail: jkato@sapmed.ac.jp M. Takahashi Division of Gastroenterology, Sapporo Kyoritsu Gorinbashi Hospital, Sapporo, Japan K. Okita · T. Mizuguchi · T. Furuhata · K. Hirata Department of Surgery, Surgical Oncology and Science, Sapporo Medical University School of Medicine, Sapporo, Japan