Background: Clinical studies with anti-VEGF agents, such as regorafenib (R), demonstrate that angiogenesis is critical to CRC tumor growth and metastasis. R has provided proof of principle in patients (pts) with refractory CRC, but is associated with a specific safety profile; there is a need for effective alternative treatments with different safety profiles. Nintedanib (N) is a triple angiokinase inhibitor of VEGF, PDGF and FGF signaling. N is approved in the European Union for the treatment of pts with advanced adenocarcinoma NSCLC after 1^st-line chemotherapy and has shown clinical benefit in trials in several tumor types. In a phase I study of N in CRC, a clinically relevant anti-angiogenic effect was observed in 67% of pts. These findings and a manageable safety profile provide a rationale to examine N in refractory CRC. The objective of this study (NCT02149108; 1199.52) is to evaluate the efficacy and safety of N in pts with refractory CRC after failure with standard chemotherapy and biologic agents. Methods: 764 pts worldwide (including 10 US sites) – age ≥ 18 years, ECOG-PS 0–1, and histologically/cytologically confirmed CRC adenocarcinoma not amenable to surgery and/or radiotherapy – will be randomized 1:1 to receive either N (200 mg bid) + BSC or placebo (bid) + BSC in 21-day courses until disease progression or undue toxicity. The study is powered to distinguish a clinically meaningful effect in the co-primary endpoints PFS and OS. Secondary endpoints are objective tumor response and disease control. Pts will be stratified at randomization based on previous R treatment, time from onset of metastatic disease to randomization and region. PFS and OS will be evaluated by the log-rank test to determine the effect of N independently at the two-sided alpha level of 0.05. Other assessments include frequency and severity of adverse events and changes in laboratory parameters to measure safety; health-related quality of life; and biomarker analyses focusing on exploring predictive biomarkers and drug resistance mechanisms. As of Jan 7, 2015, 180 pts were randomized and recruitment is ongoing. Results are expected in 2016. Clinical trial information: NCT02149108