Phase 2 trial of dovitinib in patients with progressive FGFR3-mutated or FGFR3 wild-type advanced urothelial carcinoma

Eur J Cancer. 2014 Dec;50(18):3145-52. doi: 10.1016/j.ejca.2014.10.013. Epub 2014 Oct 30.

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%).

Conclusion: 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.

Keywords: Dovitinib; FGFR3; Fibroblast growth factor; Receptor tyrosine kinase; Urothelial carcinoma; VEGFR.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Aged
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics
  • Benzimidazoles / administration & dosage*
  • Benzimidazoles / adverse effects
  • Benzimidazoles / pharmacokinetics
  • Drug Administration Schedule
  • Female
  • Humans
  • Male
  • Middle Aged
  • Mutation / genetics*
  • Neoplasm Metastasis
  • Quinolones / administration & dosage*
  • Quinolones / adverse effects
  • Quinolones / pharmacokinetics
  • Receptor, Fibroblast Growth Factor, Type 3 / genetics*
  • Treatment Outcome
  • Urologic Neoplasms / drug therapy*
  • Urologic Neoplasms / genetics

Substances

  • 4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one
  • Antineoplastic Agents
  • Benzimidazoles
  • Quinolones
  • FGFR3 protein, human
  • Receptor, Fibroblast Growth Factor, Type 3

Associated data

  • ClinicalTrials.gov/NCT00790426