title: Phase II results of Dovitinib (TKI258) in patients with metastatic renal cell cancer.
abstract: OBJECTIVE
  Fibroblast growth factor (FGF) signaling regulates tumor growth and vascularization and partly mediates antiangiogenic escape from VEGF receptor (VEGFR) inhibitors. Dovitinib (TKI258) is a tyrosine kinase inhibitor (TKI) that inhibits FGF receptor (FGFR), VEGFR, and platelet-derived growth factor receptor, which are known drivers of antiangiogenic escape, angiogenesis, and tumor growth in renal cell carcinoma (RCC).
  
  
  METHODS
  Patients with advanced or metastatic RCC were treated with oral dovitinib 500 mg/day (5-days-on/2-days-off schedule). The study population was enriched for patients previously treated with a VEGFR TKI and an mTOR inhibitor.
  
  
  RESULTS
  Of 67 patients enrolled, 55 patients (82.1%) were previously treated with ≥1 VEGFR TKI and ≥1 mTOR inhibitor (per-protocol efficacy set). The 8-week overall response rate and disease control rate in this population were 1.8% and 52.7%, respectively. Disease control rate during the entire study period was 56.4% (50.9% ≥4 months). Median progression-free survival and overall survival in the entire population were 3.7 and 11.8 months, respectively. Pharmacodynamic analyses demonstrated dovitinib-induced inhibition of VEGFR (as determined by increased levels of placental growth factor and decreased levels of soluble VEGFR2) and FGFR (as determined by increased FGF23 serum measures). The most frequently reported treatment-related adverse events of all grades included nausea (65.7%), diarrhea (62.7%), vomiting (61.2%), decreased appetite (47.8%), and fatigue (32.8%).
  
  
  CONCLUSIONS
  Dovitinib was shown to be an effective and tolerable therapy for patients with metastatic RCC who had progressed following treatment with VEGFR TKIs and mTOR inhibitors. Clin Cancer Res; 20(11); 3012-22. ©2014 AACR.
authors.affiliation: Authors' Affiliations: Institut de Cancérologie Gustave Roussy, Villejuif; Hôpital Saint-André, Bordeaux University Hospital, Bordeaux, France; Medizinische Hochschule Hannover, Hannover; Technische Universität München, Munich, Germany; Taichung Veterans General Hospital, National Yang-Ming University School of Medicine; National Taiwan University Hospital, Taipei, Taiwan; 12 de Octubre University Hospital, Madrid, Spain; University of California, San Francisco, San Francisco, California; Novartis Pharmaceuticals Corporation, East Hanover, New Jersey; and Novartis Pharma AG, Basel, Switzerland escudier@igr.fr.
authors.forename: Bernard
authors.initials: B
authors.lastname: Escudier
authors.affiliation: Authors' Affiliations: Institut de Cancérologie Gustave Roussy, Villejuif; Hôpital Saint-André, Bordeaux University Hospital, Bordeaux, France; Medizinische Hochschule Hannover, Hannover; Technische Universität München, Munich, Germany; Taichung Veterans General Hospital, National Yang-Ming University School of Medicine; National Taiwan University Hospital, Taipei, Taiwan; 12 de Octubre University Hospital, Madrid, Spain; University of California, San Francisco, San Francisco, California; Novartis Pharmaceuticals Corporation, East Hanover, New Jersey; and Novartis Pharma AG, Basel, Switzerland.
authors.forename: Viktor
authors.initials: V
authors.lastname: Grünwald
authors.affiliation: Authors' Affiliations: Institut de Cancérologie Gustave Roussy, Villejuif; Hôpital Saint-André, Bordeaux University Hospital, Bordeaux, France; Medizinische Hochschule Hannover, Hannover; Technische Universität München, Munich, Germany; Taichung Veterans General Hospital, National Yang-Ming University School of Medicine; National Taiwan University Hospital, Taipei, Taiwan; 12 de Octubre University Hospital, Madrid, Spain; University of California, San Francisco, San Francisco, California; Novartis Pharmaceuticals Corporation, East Hanover, New Jersey; and Novartis Pharma AG, Basel, Switzerland.
authors.forename: Alain
authors.initials: A
authors.lastname: Ravaud
authors.affiliation: Authors' Affiliations: Institut de Cancérologie Gustave Roussy, Villejuif; Hôpital Saint-André, Bordeaux University Hospital, Bordeaux, France; Medizinische Hochschule Hannover, Hannover; Technische Universität München, Munich, Germany; Taichung Veterans General Hospital, National Yang-Ming University School of Medicine; National Taiwan University Hospital, Taipei, Taiwan; 12 de Octubre University Hospital, Madrid, Spain; University of California, San Francisco, San Francisco, California; Novartis Pharmaceuticals Corporation, East Hanover, New Jersey; and Novartis Pharma AG, Basel, Switzerland.
authors.forename: Yen-Chuan
authors.initials: YC
authors.lastname: Ou
authors.affiliation: Authors' Affiliations: Institut de Cancérologie Gustave Roussy, Villejuif; Hôpital Saint-André, Bordeaux University Hospital, Bordeaux, France; Medizinische Hochschule Hannover, Hannover; Technische Universität München, Munich, Germany; Taichung Veterans General Hospital, National Yang-Ming University School of Medicine; National Taiwan University Hospital, Taipei, Taiwan; 12 de Octubre University Hospital, Madrid, Spain; University of California, San Francisco, San Francisco, California; Novartis Pharmaceuticals Corporation, East Hanover, New Jersey; and Novartis Pharma AG, Basel, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Castellano
authors.affiliation: Authors' Affiliations: Institut de Cancérologie Gustave Roussy, Villejuif; Hôpital Saint-André, Bordeaux University Hospital, Bordeaux, France; Medizinische Hochschule Hannover, Hannover; Technische Universität München, Munich, Germany; Taichung Veterans General Hospital, National Yang-Ming University School of Medicine; National Taiwan University Hospital, Taipei, Taiwan; 12 de Octubre University Hospital, Madrid, Spain; University of California, San Francisco, San Francisco, California; Novartis Pharmaceuticals Corporation, East Hanover, New Jersey; and Novartis Pharma AG, Basel, Switzerland.
authors.forename: Chia-Chi
authors.initials: CC
authors.lastname: Lin
authors.affiliation: Authors' Affiliations: Institut de Cancérologie Gustave Roussy, Villejuif; Hôpital Saint-André, Bordeaux University Hospital, Bordeaux, France; Medizinische Hochschule Hannover, Hannover; Technische Universität München, Munich, Germany; Taichung Veterans General Hospital, National Yang-Ming University School of Medicine; National Taiwan University Hospital, Taipei, Taiwan; 12 de Octubre University Hospital, Madrid, Spain; University of California, San Francisco, San Francisco, California; Novartis Pharmaceuticals Corporation, East Hanover, New Jersey; and Novartis Pharma AG, Basel, Switzerland.
authors.forename: Jürgen E
authors.initials: JE
authors.lastname: Gschwend
authors.affiliation: Authors' Affiliations: Institut de Cancérologie Gustave Roussy, Villejuif; Hôpital Saint-André, Bordeaux University Hospital, Bordeaux, France; Medizinische Hochschule Hannover, Hannover; Technische Universität München, Munich, Germany; Taichung Veterans General Hospital, National Yang-Ming University School of Medicine; National Taiwan University Hospital, Taipei, Taiwan; 12 de Octubre University Hospital, Madrid, Spain; University of California, San Francisco, San Francisco, California; Novartis Pharmaceuticals Corporation, East Hanover, New Jersey; and Novartis Pharma AG, Basel, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Harzstark
authors.affiliation: Authors' Affiliations: Institut de Cancérologie Gustave Roussy, Villejuif; Hôpital Saint-André, Bordeaux University Hospital, Bordeaux, France; Medizinische Hochschule Hannover, Hannover; Technische Universität München, Munich, Germany; Taichung Veterans General Hospital, National Yang-Ming University School of Medicine; National Taiwan University Hospital, Taipei, Taiwan; 12 de Octubre University Hospital, Madrid, Spain; University of California, San Francisco, San Francisco, California; Novartis Pharmaceuticals Corporation, East Hanover, New Jersey; and Novartis Pharma AG, Basel, Switzerland.
authors.forename: Sarah
authors.initials: S
authors.lastname: Beall
authors.affiliation: Authors' Affiliations: Institut de Cancérologie Gustave Roussy, Villejuif; Hôpital Saint-André, Bordeaux University Hospital, Bordeaux, France; Medizinische Hochschule Hannover, Hannover; Technische Universität München, Munich, Germany; Taichung Veterans General Hospital, National Yang-Ming University School of Medicine; National Taiwan University Hospital, Taipei, Taiwan; 12 de Octubre University Hospital, Madrid, Spain; University of California, San Francisco, San Francisco, California; Novartis Pharmaceuticals Corporation, East Hanover, New Jersey; and Novartis Pharma AG, Basel, Switzerland.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Pirotta
authors.affiliation: Authors' Affiliations: Institut de Cancérologie Gustave Roussy, Villejuif; Hôpital Saint-André, Bordeaux University Hospital, Bordeaux, France; Medizinische Hochschule Hannover, Hannover; Technische Universität München, Munich, Germany; Taichung Veterans General Hospital, National Yang-Ming University School of Medicine; National Taiwan University Hospital, Taipei, Taiwan; 12 de Octubre University Hospital, Madrid, Spain; University of California, San Francisco, San Francisco, California; Novartis Pharmaceuticals Corporation, East Hanover, New Jersey; and Novartis Pharma AG, Basel, Switzerland.
authors.forename: Matthew
authors.initials: M
authors.lastname: Squires
authors.affiliation: Authors' Affiliations: Institut de Cancérologie Gustave Roussy, Villejuif; Hôpital Saint-André, Bordeaux University Hospital, Bordeaux, France; Medizinische Hochschule Hannover, Hannover; Technische Universität München, Munich, Germany; Taichung Veterans General Hospital, National Yang-Ming University School of Medicine; National Taiwan University Hospital, Taipei, Taiwan; 12 de Octubre University Hospital, Madrid, Spain; University of California, San Francisco, San Francisco, California; Novartis Pharmaceuticals Corporation, East Hanover, New Jersey; and Novartis Pharma AG, Basel, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Shi
authors.affiliation: Authors' Affiliations: Institut de Cancérologie Gustave Roussy, Villejuif; Hôpital Saint-André, Bordeaux University Hospital, Bordeaux, France; Medizinische Hochschule Hannover, Hannover; Technische Universität München, Munich, Germany; Taichung Veterans General Hospital, National Yang-Ming University School of Medicine; National Taiwan University Hospital, Taipei, Taiwan; 12 de Octubre University Hospital, Madrid, Spain; University of California, San Francisco, San Francisco, California; Novartis Pharmaceuticals Corporation, East Hanover, New Jersey; and Novartis Pharma AG, Basel, Switzerland.
authors.forename: Eric
authors.initials: E
authors.lastname: Angevin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D000089703:Fibroblast Growth Factor-23; D006801:Humans; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D015363:Quinolones / Q000493:pharmacokinetics / Q000627:therapeutic use*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D016879:Salvage Therapy / Q000379:methods
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; C000717427:FGF23 protein, human; D015363:Quinolones; D000089703:Fibroblast Growth Factor-23; D040262:Receptors, Vascular Endothelial Growth Factor