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
2016
Introduction 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
oxaliplatinis superior to combination treatment of mCRC. Methods and analysis 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
capecitabineor 5-fluorouracil plus
bevacizumab(Cape/5-FU-Bmab) with escalation to
capecitabineor 5-fluorouracil plus
oxaliplatinplus
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-escalationfrom CapeOX/mFOLFOX6-Bmab to Cape/5-FU-Bmab is possible after 12 weeks of treatment. Re-escalation to CapeOX/mFOLFOX6-Bmab after
progressive diseaseis considered only for patients who received
de-escalationof
oxaliplatinafter 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-sided5% α in case of a true HR Ethics and dissemination This study is conducted according to the standards of
Good Clinical Practiceand in compliance with the
Declarationof
Helsinki2013 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. Trial registration number UMIN000015405, Pre-results.
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