Randomized phase II trial of Hange-shasin-to versus placebo to prevent diarrhea in patients with metastatic colorectal cancer under IRIS+Bev second-line treatment

INTERVENTION: S‐1+CPT‐11+bevacizumab+Placebo S‐1 80‐120mg/day day1‐14 q4w CPT‐11 100mg/m2 day1,15 q4w Bevacizumab 5mg/kg day1, 15 q4w Placebo day1‐28 q4w S‐1+CPT‐11+bevacizumab+hange‐shashin‐to S‐1 80‐120mg/day day1‐14 q4w CPT‐11 100mg/m2 day1,15 q4w Bevacizumab 5mg/kg day1, 15 q4w Hange‐shashin‐to 7.5g/day day1‐28 q4w CONDITION: Metastatic colorectal cancer PRIMARY OUTCOME: Incidence of grade 3 or more diarrhea until the end of 3rd cycle SECONDARY OUTCOME: Response rate; Progression Free Survival; Time to Treatment Failure; Overall Survival; Incidence and severity of adverse events; Dose intensity; Frequency of rescue medication for diarrhea; Compliance INCLUSION CRITERIA: 1) Histologically confirmed colorectal cancer (adenocarcinoma) except for appendiceal cancer 2) Unresectable or recurrent colorectal cancer 3) Age of 20 years or older 4) ECOG Performance status of 0‐2 5) Measurable or evaluable lesions 6) Received prior Oxaliplatin‐containing first line chemotherapy 7) Sufficient oral intake 8) Sufficient major organ functions below: Neutrophil count >= 1,500 /mm3 Platelet count >= 100,000 /mm3 Hemoglobin >= 9.0 g/dL AST <= 100 IU/L ALT <= 100 IU/L Total bilirubin <= 1.5 mg/dL Serum creatinine <= 1.2 mg/dL Creatinine clearance >= 60 mL/min Urine protein <= Grade 1 9) Life expectancy of at least 3 months 10) Written informed consent