Background: Dovitinib is a potent oral inhibitor of angiogenic factors, including the fibroblast growth factor (FGFR) and vascular endothelial growth factor receptors (VEGFR). Phase (ph) I of the study established the maximum tolerated dose of dovitinib as 500 mg/day on a 5 day on/ 2 day off dosing schedule in 28-day cycles. Methods: The primary objective was to assess the efficacy of dovitinib in clear cell mRCC patients (pts) previously treated with a VEGFR inhibitor and/or mammalian target of rapamycin (mTOR) inhibitor by assessing tumor response every 8 weeks. Results: Pt characteristics (N = 59) evaluable for safety: median age, 60 years; ECOG PS 0/1, 39%/61%; 97% received prior antineoplastic therapy; common metastatic sites of lung (37%), lymph nodes (10%), bone (14%), and liver (12%). The most common adverse events were nausea (73%; grade 3 [g3]: 9%), diarrhea (64%; g3: 9%), vomiting (56%; g3: 5%), decreased appetite (48%; g3: 7%), asthenia (36%; g3: 12%), and fatigue (36%; g3: 10%). In pts evaluable for efficacy (n = 51): the average duration of exposure was 89 days; 11 (22%) pts were ongoing, with 26 (51%) discontinuing due to progressive disease (PD). Best overall responses (ORs) per central review included: partial response (PR), 4 (8%); stable disease (SD) ≥ 4 months (mos), 19 (37%); PD, 11 (22%); unknown/not assessed, 7 (14%). Median progression-free survival (PFS) and overall survival (OS) were 6.1 and 16 mos, respectively. In pts who previously failed VEGFR and mTOR inhibitor treatment (n = 31), best ORs per central review included: PR, 3 (10%); SD ≥ 4 mos, 13 (42%); PD, 6 (19%); unknown/not assessed, 4 (13%). Median PFS and OS in these pts were 6.1 and 10.2 mos, respectively. Modest increases in VEGF (P = .193) and placental growth factor (P = .074) and a significant decrease in soluble VEGFR2 (P < .0001) were noted, suggesting VEGFR inhibition. Plasma FGF23 significantly (P < .0001) increased after 1 cycle and paired tumor biopsy demonstrated pERK inhibition, both suggesting FGFR inhibition. Conclusions: The study met the primary efficacy criteria, and 30 additional pts will be treated. Updated data will be presented. A randomized phase III (vs sorafenib) study in mRCC is planned.