Background: Refractory metastatic colorectal cancer patients (mCRC) have a median survival of 4-6 months. Nintedanib is a TKI which inhibits VEGFR, PDGFR, and FGFR with preclinical efficacy in bevacizumab resistant CRC. This phase I/II study sought to evaluate the recommended phase II dose (RP2D) and efficacy of nintedanib and capecitabine in refractory mCRC patients. Methods: Key eligibility criteria included histologically proven mCRC, ECOG PS of 0 or 1, progression/intolerance to a fluoropyrimidine, oxaliplatin, irinotecan, and anti-EGFR therapy for RAS wt patients. Prior regorafenib was exclusionary. The primary endpoint was 18-week progression free survival (PFS). A one-sided binomial test (at α = 0.1) compared the observed 18-week PFS to a historic control of 0.25. Secondary endpoints included median PFS, median OS, ORR, and AE profile. Results: 40 patients were enrolled across 2 dose levels. Nintedanib 200 mg po bid and Capecitabine 1000 mg/m2 po bid was established to be the RP2D. 36 patients were treated at the RP2D and evaluable for efficacy. The 18 week progression free survival (PFS) was 36% (13/36 patients), p = 0.0922, indicating a statistically significant increase in PFS over historic control. No responses were observed; 19 (53%) patients experienced SD. Median PFS was 3.3 mos. Median OS was 7 mo. 16 (44%) patients experienced a grade 3/4 AE, with the most common evens being fatigue (8%), palmoplantar erythrodysesthesia (8%), AST elevation (6%), asthenia (6%), pulmonary embolus (6%), and dehydration. PK/PD and plasma biomarker data will be presented. Conclusions: The combination of Capecitabine and Nintedanib was well tolerated. Efficacy compares favorably to historic data with regorafenib or TAS-102 monotherapy and is similar to results from other investigations of multi-kinase TKIs and flouropyrimidines in the refractory setting. Further investigation is warranted. This study was approved and funded by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by Boehringer Ingelheim Pharmaceuticals, Inc.Clinical trial information: NCT02393755