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 with refractory CRC, but is associated with a specific safety profile; there is a need for an effective alternative treatment with a different safety profile. Nintedanib (N) is a triple angiokinase inhibitor of VEGF, PDGF, and FGF signaling that has shown clinical benefit and a manageable safety profile in trials in several tumor types, including NSCLC, ovarian cancer, and renal cell carcinoma. In a recent Phase I study of N in CRC, one patient had a confirmed partial response, and a clinically relevant anti-angiogenic effect was observed in 67% of patients. 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 patients with refractory CRC after failure with standard chemotherapy and biologic agents. Methods: 764 patients worldwide (≥18 years of age, ECOG-PS 0–1, and histologically/cytologically confirmed CRC adenocarcinoma unamenable 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. Patients will be stratified at randomization based on previous R treatment (yes vs. no), time from onset of metastatic disease to randomization (<24 months vs. ≥24 months), 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 that will focus on exploring predictive biomarkers and drug resistance mechanisms. Results are expected in 2016. Clinical trial information: NCT02149108