Background: The RAISE study demonstrated the superiority of FOLFIRI + ramucirumab (Ram) to FOLFIRI in second-line metastatic colorectal cancer patients progressed after oxaliplatin, fluoropyrimidine with bevacizumab. But no prospective data is existed that the efficacy and toxicity of FOLFIRI + Ram pretreated oxaliplatin, fluoropyrimidine without an anti-angiogenesis therapy. Methods: RAINCLOUD study is a multicenter single-arm phase II trial. Key eligibility criteria is as follows: histologically or cytologically confirmed colorectal cancer, confirmed recurrent colorectal cancer, refractory to fluoropyrimidine, refractory or intolerant of oxaliplatin without pretreated anti-angiogenesis therapy, has measureable or non-measurable lesion, PS = 0 or 1, has adequate coagulation function, 20 years or older. Primary endpoint of this study is progression-free survival. Secondary endpoints are overall survival, time to treatment failure, response rate, disease control rate and safety. Patients receive FOLFIRI (irinotecan: 180 mg/m2, l-levofolinate: 200 mg/m2, bolus fluorouracil: 400mg/m2, and continuous fluorouracil: 2400 mg/m2) plus Ram (8 mg/kg) every two weeks until progression or the development of unacceptable toxicity. We hypothesized that threshold of PFS in FOLFIRI + Ram is 3.9 months and expected PFS is 6.9 months and designed to have an 80% power to detect clinically meaningful improvement in PFS at the one-sided significance level of 0.05, minimal patient registration number is 44 in order that power 1-β outperforms 0.8. Taking a few ineligibility patients and dropout patients into consideration, number of target patients is set to be 48. Study recruitment started on September 2017. The association of exploratory biomarker study will be planned. Clinical trial information: UMIN000028677.