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


Authors: Milowsky, M. I.; Dittrich, C.; Durán, I.; Jagdev, S.; Millard, F. E.; Sweeney, C. J.; Bajorin, D.; Cerbone, L.; Quinn, D. I.; Stadler, W. M.; Rosenberg, J. E.; Lochheed, M.; Sen, P.; Squires, M.; Shi, M.; Sternberg, C. N.
Article 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 (FGFR3MUT; n = 12), wild-type (FGFR3WT; 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 FGFR3MUT (0%; 95% confidence interval [CI], 0.0-26.5) and FGFR3WT (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. © 2014 Elsevier Ltd. All rights reserved.
Keywords: treatment outcome; aged; middle aged; genetics; mutation; clinical trial; antineoplastic agents; antineoplastic agent; metastasis; phase 2 clinical trial; drug administration schedule; fibroblast growth factor receptor 3; urologic neoplasms; multicenter study; urothelial carcinoma; neoplasm metastasis; drug administration; administration, oral; benzimidazole derivative; benzimidazoles; fibroblast growth factor; receptor, fibroblast growth factor, type 3; oral drug administration; kinase; receptor tyrosine; quinolone derivative; quinolones; dovitinib; fgfr3; humans; human; male; female; vegfr; 4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1h-benzimidazol-2-yl)quinolin-2(1h)-one; fgfr3 protein, human
Journal Title: European Journal of Cancer
Volume: 50
Issue: 18
ISSN: 0959-8049
Publisher: Elsevier Inc.  
Date Published: 2014-12-01
Start Page: 3145
End Page: 3152
Language: English
DOI: 10.1016/j.ejca.2014.10.013
PUBMED: 25457633
PROVIDER: scopus
DOI/URL:
Notes: Export Date: 2 April 2015 -- Source: Scopus
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MSK Authors
  1. Dean Bajorin
    433 Bajorin
  2. Jonathan Eric Rosenberg
    237 Rosenberg