title: Phase 2 trial of dovitinib in patients with progressive FGFR3-mutated or FGFR3 wild-type advanced urothelial carcinoma.
abstract: BACKGROUND
  Second-line treatment options for patients with advanced urothelial carcinoma (UC) are limited. Fibroblast growth factor receptor 3 (FGFR3) is dysregulated in UC by activating mutations or protein overexpression in non-mutant tumours. In this study, the efficacy, pharmacodynamics and safety of dovitinib-a broad-targeted inhibitor of tyrosine kinases, including FGFR3-were evaluated in patients with previously treated advanced UC with and without FGFR3 mutations.
  
  
  METHODS
  Forty-four adults with advanced UC who had progressed after one to three platinum-based and/or combination chemotherapy regimens were classified as having mutant (FGFR3(MUT); n=12), wild-type (FGFR3(WT); n=31), or unknown (n=1) FGFR3 status. Patients received 500 mg dovitinib once daily on a 5-days-on/2-days-off schedule. The primary end-point of this two-stage study was the investigator-assessed overall response rate (ORR).
  
  
  RESULTS
  Most of the patients were men (75%) and over half of the patients were aged ⩾65 years (61%). All patients had received ⩾1 prior antineoplastic therapy for UC. The study was terminated at the end of stage 1, when it was determined by investigator review that the ORR of both the FGFR3(MUT) (0%; 95% confidence interval [CI], 0.0-26.5) and FGFR3(WT) (3.2%; 95% CI, 0.1-16.7) groups did not meet the criteria to continue to stage 2. The most common grade 3/4 adverse events, suspected to be study-drug related, included thrombocytopenia (9%), fatigue (9%), and asthenia (9%).
  
  
  CONCLUSIONS
  Although generally well tolerated, dovitinib has very limited single-agent activity in patients with previously treated advanced UC, regardless of FGFR3 mutation status. clinicaltrials.gov NCT00790426.
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. Electronic address: matt_milowsky@med.unc.edu.
authors.forename: Matthew I
authors.initials: MI
authors.lastname: Milowsky
authors.affiliation: LBI-ACR VIEnna & ACR-ITR VIEnna, Center for Oncology and Haematology, Kaiser Franz Josef-Spital, Vienna, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Dittrich
authors.affiliation: Centro Integral Oncologico Clara Campal, Universidad CEU San Pablo, Madrid, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Durán
authors.affiliation: St. James's Institute of Oncology, Leeds, UK.
authors.forename: Satinder
authors.initials: S
authors.lastname: Jagdev
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, University of California, San Diego, San Diego, CA, USA.
authors.forename: Frederick E
authors.initials: FE
authors.lastname: Millard
authors.affiliation: Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Sweeney
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Dean
authors.initials: D
authors.lastname: Bajorin
authors.affiliation: Department of Medical Oncology, San Camillo and Forlanini Hospitals, Rome, Italy.
authors.forename: Linda
authors.initials: L
authors.lastname: Cerbone
authors.affiliation: Division of Medical Oncology, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
authors.forename: David I
authors.initials: DI
authors.lastname: Quinn
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL, USA.
authors.forename: Walter M
authors.initials: WM
authors.lastname: Stadler
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Rosenberg
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Lochheed
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Paramita
authors.initials: P
authors.lastname: Sen
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Matthew
authors.initials: M
authors.lastname: Squires
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Shi
authors.affiliation: Department of Medical Oncology, San Camillo and Forlanini Hospitals, Rome, Italy.
authors.forename: Cora N
authors.initials: CN
authors.lastname: Sternberg
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009362:Neoplasm Metastasis; D015363:Quinolones / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics*; D016896:Treatment Outcome; D014571:Urologic Neoplasms / Q000188:drug therapy* / Q000235:genetics
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; D015363:Quinolones; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3
keywords: Dovitinib; FGFR3; Fibroblast growth factor; Receptor tyrosine kinase; Urothelial carcinoma; VEGFR