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Hahn NM , Bivalacqua TJ , Ross AE , Netto GJ , Baras A , Park JC , Chapman C , Masterson TA , Koch MO , Bihrle R , Foster RS , Gardner TA , Cheng L , Jones DR , McElyea K , Sandusky GE , Breen T , Liu Z , Albany C , Moore ML , Loman RA , Reed A , Turner SA , de Abreu FB , Gallagher TL , Tsongalis GJ , Plimack ER , Greenberg RE , Geynisman DM
A Phase Ii Trial of Dovitinib in Bcg-Unresponsive Urothelial Carcinoma with Fgfr3 Mutations or over-Expression: Hoosier Cancer Research Network Trial Hcrn 12-157
Clin Cancer Res. 2017 Jun15;23(12) :3003-3011
PMID: 27932416    PMCID: PMC5462889    URL: https://www.ncbi.nlm.nih.gov/pubmed/27932416
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PURPOSE: To assess the clinical and pharmacodynamic activity of dovitinib in a treatment resistant, molecularly enriched NMIUC population. EXPERIMENTAL DESIGN: A multi-site pilot phase 2 trial was conducted. Key eligibility criteria included: BCG unresponsive NMIUC (> 2 prior intravesical regimens) with increased phosphorylated FGFR3 (pFGFR3) expression by centrally analyzed immunohistochemistry (IHC+) or FGFR3 mutations (Mut+) assessed in a CLIA-licensed laboratory. Patients received oral dovitinib 500 mg daily (5 days on / 2 days off). The primary endpoint was 6-month TURBT-confirmed complete response (CR) rate. RESULTS: Between 1(1/2)013 and 10/2014, 13 patients enrolled (10 IHC+ Mut-, 3 IHC+ Mut+). Accrual ended prematurely due to cessation of dovitinib clinical development. Demographics included: median age 70 years; 85% male; CIS (3 pts), Ta/T1 (8 pts), and Ta/T1 + CIS (2 pts); median prior regimens 3. Toxicity was frequent with all patients experiencing at least one grade 3-4 event. 6-month CR rate was 8% (0% in IHC+ Mut-; 33% in IHC+ Mut+). The primary endpoint was not met. Pharmacodynamically active (94-5812 nM) dovitinib concentrations in urothelial tissue were observed in all evaluable patients. Reductions in pFGFR3 IHC staining were observed post-dovitinib treatment. CONCLUSIONS: Dovitinib consistently achieved biologically active concentrations within the urothelium and demonstrated pharmacodynamic pFGFR3 inhibition. These results support systemic administration as a viable approach to clinical trials in NMIUC patients. Long-term dovitinib administration was not feasible due to frequent toxicity. Absent clinical activity suggests that patient selection by pFGFR3 IHC alone does not enrich for response to FGFR3 kinase inhibitors in UC.
Hahn, Noah M Bivalacqua, Trinity J Ross, Ashley E Netto, George J Baras, Alexander S Park, Jong Chul Chapman, Carolyn Masterson, Timothy A Koch, Michael O Bihrle, Richard Foster, Richard S Gardner, Thomas A Cheng, Liang Jones, David R McElyea, Kyle Sandusky, George E Breen, Timothy Liu, Ziyue Albany, Costantine Moore, Marietta L Loman, Rhoda A Reed, Angela Turner, Scott A de Abreu, Francine B Gallagher, Torrey L Tsongalis, Gregory J Plimack, Elizabeth R Greenberg, Richard E Geynisman, Daniel M Journal Article United States Clin Cancer Res. 2016 Dec 8. pii: clincanres.2267.2016.