title: Phase I study of dovitinib (TKI258), an oral FGFR, VEGFR, and PDGFR inhibitor, in advanced or metastatic renal cell carcinoma.
abstract: OBJECTIVE
  Signaling through the fibroblast growth factor (FGF) pathway may account for tumor resistance to antiangiogenic therapies targeting the VEGF pathway. Here, dovitinib (TKI258), a potent oral inhibitor of FGF receptor, VEGF receptor (VEGFR), and platelet-derived growth factor receptor tyrosine kinases, is studied in a dose escalation trial.
  
  
  METHODS
  Patients with advanced or metastatic renal cell carcinoma (RCC) with predominant clear cell histology were treated with oral dovitinib 500 or 600 mg/day (5-days-on/2-days-off schedule).
  
  
  RESULTS
  Twenty heavily pretreated patients (median 3 prior regimens) were enrolled, with 16, 11, and 12 patients having previously received at least 1: VEGFR inhibitor, mTOR inhibitor, and immunotherapy, respectively. Fifteen and 5 patients were treated in 500- and 600-mg cohorts, respectively. Three patients experienced dose-limiting toxicities: grade 2 bradycardia (500 mg), grade 4 hypertensive crisis (600 mg), and grade 3 asthenia with grade 2 nausea and vomiting (600 mg). The most common adverse events related to dovitinib were nausea (75%), diarrhea (70%), vomiting (70%), and asthenia (50%), the majority of which were mild (grade 1 or 2), with grade 3 events 5% or less (except asthenia, 15%) and only one grade 4 event (hypertensive crisis). Two patients achieved a partial response (500 mg), and 12 patients had stable disease, including 2 patients with long lasting disease stabilizations (>1 year) in the 500-mg cohort.
  
  
  CONCLUSIONS
  Dovitinib was tolerable and showed antitumor activity at a maximum tolerated dose of 500 mg on a 5-days-on/2-days-off schedule in heavily pretreated RCC patients.
authors: Institut de Cancérologie Gustave Roussy, Villejuif, France. eric.angevin@igr.fr
authors: Eric
authors: E
authors: Angevin
authors: Jose A
authors: JA
authors: Lopez-Martin
authors: Chia-Chi
authors: CC
authors: Lin
authors: Jürgen E
authors: JE
authors: Gschwend
authors: Andrea
authors: A
authors: Harzstark
authors: Daniel
authors: D
authors: Castellano
authors: Jean-Charles
authors: JC
authors: Soria
authors: Paramita
authors: P
authors: Sen
authors: Julie
authors: J
authors: Chang
authors: Michael
authors: M
authors: Shi
authors: Andrea
authors: A
authors: Kay
authors: Bernard
authors: B
authors: Escudier
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D000328:Adult; D000368:Aged; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D001562:Benzimidazoles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D004353:Drug Evaluation, Preclinical; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009367:Neoplasm Staging; D009536:Niacinamide / Q000031:analogs & derivatives / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000627:therapeutic use; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D015363:Quinolones / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077157:Sorafenib; D015996:Survival Rate; D014018:Tissue Distribution; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C500007:4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one; D001562:Benzimidazoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D015363:Quinolones; D009536:Niacinamide; D000077157:Sorafenib; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D020797:Receptor, Platelet-Derived Growth Factor beta; D040281:Vascular Endothelial Growth Factor Receptor-1