PURPOSE: Dovitinib (TKI258) is an orally available inhibitor of fibroblast 
growth factor (FGF), VEGF, and platelet-derived growth factor receptors. This 
phase I/II dose-escalation study was conducted to evaluate the safety, 
pharmacodynamics, and preliminary efficacy of dovitinib in the treatment of 
advanced melanoma.
EXPERIMENTAL DESIGN: Patients with advanced melanoma resistant or refractory to 
standard therapies or for whom no standard therapy was available were enrolled. 
Dovitinib was administered at doses ranging from 200 to 500 mg/d.
RESULTS: Forty-seven patients were enrolled. The most frequently reported 
adverse events were fatigue (77%; grade ≥3, 28%), diarrhea (77%; grade ≥3, 11%), 
and nausea (77%; grade ≥3, 9%). Six dose-limiting toxicities were observed in 
the 400-mg and 500-mg dose cohorts, which consisted of grade 3 nausea, fatigue, 
and diarrhea and grade 4 fatigue events. The maximum tolerated dose was 400 
mg/d. The best tumor response was stable disease, which was observed in 12 
patients. Increases in plasma FGF23, VEGF, and placental growth factor and 
decreases in soluble VEGF receptor 2 were noted during the first cycle of 
treatment, consistent with FGF receptor (FGFR) and VEGF receptor (VEGFR) 
inhibition. Dynamic contrast-enhanced MRI analysis showed a dose-dependent 
decrease in tumor blood flow and vascular permeability with dovitinib therapy. A 
decrease in FGFR phosphorylation was observed in paired tumor biopsy samples 
from a patient treated with dovitinib at a dose of 400 mg/d.
CONCLUSIONS: At a dose of 400 mg/d, dovitinib showed an acceptable safety 
profile and limited clinical benefit and inhibited FGFR and VEGFR.