title: Phase I/II and pharmacodynamic study of dovitinib (TKI258), an inhibitor of fibroblast growth factor receptors and VEGF receptors, in patients with advanced melanoma.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA.
authors: Kevin B
authors: KB
authors: Kim
authors: Jason
authors: J
authors: Chesney
authors: Douglas
authors: D
authors: Robinson
authors: Humphrey
authors: H
authors: Gardner
authors: Michael M
authors: MM
authors: Shi
authors: John M
authors: JM
authors: Kirkwood
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000097:blood; D004334:Drug Administration Schedule; D005260:Female; D000089703:Fibroblast Growth Factor-23; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D015363:Quinolones / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors*; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*
chemical_list: C500007:4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D014408:Biomarkers, Tumor; C000717427:FGF23 protein, human; D047428:Protein Kinase Inhibitors; D015363:Quinolones; D017468:Receptors, Fibroblast Growth Factor; D000089703:Fibroblast Growth Factor-23; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor