Background: Prior work identified the fibroblast growth factor (FGF) pathway as a mediator of resistance to anti-VEGF therapy. We tested dovitinib, an oral inhibitor of both FGFRs and VEGFRs in pts progressing on anti-VEGF treatment. Methods: Pts with measurable advanced colorectal cancer (CRC) or non-small cell lung cancer (NSCLC) with progression despite treatment with an anti-VEGF agent within 56 days, good performance status (PS) and adequate organ function were eligible. A pre-treatment tumor biopsy was followed by treatment with dovitinib 500 mg on a 5 day on / 2 day off schedule for 28-day cycles. The primary endpoint of response (RECIST 1.1) was evaluated every 2 cycles. Secondary endpoints included toxicity and the disease control rate at 8 weeks. Intratumor mRNA expression was analyzed using a Next Generation Sequencing based expression array and circulating angiogenic factors analyzed by a multiplex bead-based assays and ELISAs. Results: Ten pts (9 CRC, 1 NSCLC) treated previously with bevacizumab (8) or ziv-aflibercept (2) enrolled. The study closed with termination of dovitinib development. No responses were observed in 7 evaluable pts; 3 withdrew consent during cycle 1. The best response was stable disease in 1 patient. Common toxicities included gastrointestinal, metabolic, and biochemical derangements. All pts experienced at least 1 grade 3 or higher treatment-related adverse event, most commonly fatigue, elevated GGT, and lymphopenia. Expression of multiple angiogenic mediators was common in tumors progressing on anti-VEGF therapy including high levels of FGFR1 and VEGFA. Dovitinib modulated circulating VEGF pathway components; however, no hyperphosphatemia was observed and plasma FGF2 increased continuously. Conclusions: We found no evidence for the activity of dovitinib in pts with CRC progressing on anti-VEGF therapy and could not confirm potent FGFR inhibition. Toxicities were significant. In tumors progressing despite anti-VEGF therapy, a multitude of pro-angiogenic mediators are expressed, including members of the FGF pathway. Clinical trial information: NCT01676714