title: Protocol of a randomised phase III clinical trial of sequential capecitabine or 5-fluorouracil plus bevacizumab (Cape/5-FU-Bmab) to capecitabine or 5-fluorouracil plus oxaliplatin plus bevacizumab (CapeOX/mFOLFOX6-Bmab) versus combination CapeOX/mFOLFOX6-Bmab in advanced colorectal cancer: the C-cubed (C3) study.
abstract: Results from several randomised trials suggest that the sequential use of cytotoxic agents in patients with metastatic colorectal cancer (mCRC) has the potential to improve overall survival compared with combination chemotherapy. This study is designed to investigate whether sequential treatment with bevacizumab-based first-line treatment with oxaliplatin is superior to combination treatment of mCRC.
  
  
  
  The C-cubed (C(3)) study is a two-arm, multicentre, open-label, randomised phase III trial in Japan comparing the efficacy and safety of sequential capecitabine or 5-fluorouracil plus bevacizumab (Cape/5-FU-Bmab) with escalation to capecitabine or 5-fluorouracil plus oxaliplatin plus bevacizumab (CapeOX/mFOLFOX6-Bmab) versus combination CapeOX/mFOLFOX6-Bmab as the first-line treatment of mCRC. In the sequential arm (Arm A: oxaliplatin 'wait-and-go'), treatment escalation from Cape/5-FU-Bmab to CapeOX/mFOLFOX6-Bmab is recommended in the case of progressive disease. In the combination arm (Arm B: oxaliplatin 'stop-and-go'), de-escalation from CapeOX/mFOLFOX6-Bmab to Cape/5-FU-Bmab is possible after 12 weeks of treatment. Re-escalation to CapeOX/mFOLFOX6-Bmab after progressive disease is considered only for patients who received de-escalation of oxaliplatin after 12 weeks of treatment not caused by oxaliplatin-associated toxicity. A target sample size of 304 evaluable patients is considered sufficient to validate an expected HR for time to failure of strategy of the sequential approach 'wait-and-go' compared to the combination approach 'stop-and go' with 80% power and 2-sided 5% α in case of a true HR<0.69.
  
  
  
  This study is conducted according to the standards of Good Clinical Practice and in compliance with the Declaration of Helsinki 2013 and local regulations, and has been submitted and approved by the Ethical Committee of the Non-Profit Organization MINS Institutional Review Board. The protocol and the trial results, even inconclusive, will be presented at international oncology congresses and published in peer-reviewed journals.
  
  
  
  UMIN000015405, Pre-results.
authors.affiliation: Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Takeshi
authors.identifier: 0000-0002-4236-350X
authors.initials: T
authors.lastname: Nagasaka
authors.affiliation: Cancer Center, Aichi Medical University, Yazakokarimata, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Mishima
authors.affiliation: Department of Clinical Oncology, Kawasaki Medical School, Okayama, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Sawaki
authors.affiliation: Cancer Biostatistics Lab, Clinical Research Institute, National Hospital Organization Kyusyu Cancer Center, Fukuoka, Japan.
authors.forename: Mototsugu
authors.initials: M
authors.lastname: Shimokawa
authors.affiliation: Department of Integrated Medicine, Kagawa University Hospital, Kagawa, Japan.
authors.forename: Michio
authors.initials: M
authors.lastname: Inukai
authors.affiliation: Division of Clinical Oncology, Hiroshima Prefectural Hospital, Hiroshima, Japan.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Shinozaki
authors.affiliation: Department of Medical Oncology, Okayama Rosai Hospital, Okayama, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Tanioka
authors.affiliation: Department of Internal Medicine, Okayama Saiseikai General Hospital, Okayama, Japan.
authors.forename: Junichiro
authors.initials: J
authors.lastname: Nasu
authors.affiliation: Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama City, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Nishina
authors.affiliation: Department of Digestive Surgery and Surgical Oncology, Yamaguchi University Graduate School of Medicine, Ube, Japan.
authors.forename: Shoichi
authors.initials: S
authors.lastname: Hazama
authors.affiliation: Department of Surgery, Hiroshima City Hospital, Hiroshima City, Japan.
authors.forename: Masazumi
authors.initials: M
authors.lastname: Okajima
authors.affiliation: Department of Clinical Oncology, Kawasaki Medical School, Okayama, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Yamaguchi
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy*; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000627:therapeutic use; D000069287:Capecitabine / Q000627:therapeutic use; D002985:Clinical Protocols; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D000077150:Oxaliplatin; D012107:Research Design; D012449:Safety; D016019:Survival Analysis; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000068258:Bevacizumab; D000069287:Capecitabine; D005472:Fluorouracil
keywords: CHEMOTHERAPY; bevacizumab; combination approach; oxaliplatin; sequential approach; unresectable colorectal cancer