title: A Phase II Trial of Dovitinib in BCG-Unresponsive Urothelial Carcinoma withFGFR3Mutations or Overexpression: Hoosier Cancer Research Network Trial HCRN 12-157.
abstract: Purpose:To assess the clinical and pharmacodynamic activity of dovitinib in a treatment-resistant, molecularly enriched non-muscle-invasive urothelial carcinoma of the bladder (NMIUC) population.Experimental Design:A multi-site pilot phase II trial was conducted. Key eligibility criteria included the following: Bacillus Calmette-Guerin (BCG)-unresponsive NMIUC (>2 prior intravesical regimens) with increased phosphorylated FGFR3 (pFGFR3) expression by centrally analyzed immunohistochemistry (IHC+) orFGFR3mutations (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 11/2013 and 10/2014, 13 patients enrolled (10 IHC+ Mut-, 3 IHC+ Mut+). Accrual ended prematurely due to cessation of dovitinib clinical development. Demographics included the following: median age 70 years; 85% male; carcinomain situ(CIS; 3 patients), Ta/T1 (8 patients), and Ta/T1 + CIS (2 patients); median prior regimens 3. Toxicity was frequent with all patients experiencing at least one grade 3-4 event. Six-month CR rate was 8% (0% in IHC+ Mut-; 33% in IHC+ Mut+). The primary endpoint was not met. Pharmacodynamically active (94-5,812 nmol/L) 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 patients with NMIUC. 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 urothelial carcinoma.Clin Cancer Res; 23(12); 3003-11. ©2016 AACR.
authors.affiliation: Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland. nhahn4@jhmi.edu.|The Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, Maryland.|The James Buchanan Brady Urological Institute, Baltimore, Maryland.
authors.forename: Noah M
authors.initials: NM
authors.lastname: Hahn
authors.affiliation: Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.|The Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, Maryland.|The James Buchanan Brady Urological Institute, Baltimore, Maryland.
authors.forename: Trinity J
authors.initials: TJ
authors.lastname: Bivalacqua
authors.affiliation: Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.|The Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, Maryland.|The James Buchanan Brady Urological Institute, Baltimore, Maryland.
authors.forename: Ashley E
authors.initials: AE
authors.lastname: Ross
authors.affiliation: Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.|The Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, Maryland.|The James Buchanan Brady Urological Institute, Baltimore, Maryland.
authors.forename: George J
authors.initials: GJ
authors.lastname: Netto
authors.affiliation: Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.|The Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, Maryland.|The James Buchanan Brady Urological Institute, Baltimore, Maryland.
authors.forename: Alex
authors.initials: A
authors.lastname: Baras
authors.affiliation: Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
authors.forename: Jong Chul
authors.initials: JC
authors.lastname: Park
authors.affiliation: Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Chapman
authors.affiliation: Department of Urology, Indiana University Simon Cancer Center, Indianapolis, Indiana.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Masterson
authors.affiliation: Department of Urology, Indiana University Simon Cancer Center, Indianapolis, Indiana.
authors.forename: Michael O
authors.initials: MO
authors.lastname: Koch
authors.affiliation: Department of Urology, Indiana University Simon Cancer Center, Indianapolis, Indiana.
authors.forename: Richard
authors.initials: R
authors.lastname: Bihrle
authors.affiliation: Department of Urology, Indiana University Simon Cancer Center, Indianapolis, Indiana.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Foster
authors.affiliation: Department of Urology, Indiana University Simon Cancer Center, Indianapolis, Indiana.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Gardner
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University Simon Cancer Center, Indianapolis, Indiana.
authors.forename: Liang
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Department of Clinical Pharmacology, Indiana University Simon Cancer Center, Indianapolis, Indiana.
authors.forename: David R
authors.initials: DR
authors.lastname: Jones
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University Simon Cancer Center, Indianapolis, Indiana.
authors.forename: Kyle
authors.initials: K
authors.lastname: McElyea
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University Simon Cancer Center, Indianapolis, Indiana.
authors.forename: George E
authors.initials: GE
authors.lastname: Sandusky
authors.affiliation: Hoosier Cancer Research Network, Indianapolis, Indiana.
authors.forename: Timothy
authors.initials: T
authors.lastname: Breen
authors.affiliation: Indiana University Department of Biostatistics, Schools of Public Health and Medicine, Indianapolis, Indiana.
authors.forename: Ziyue
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Division of Hematology and Oncology, Indiana University Simon Cancer Center, Indianapolis, Indiana.
authors.forename: Costantine
authors.initials: C
authors.lastname: Albany
authors.affiliation: Division of Hematology and Oncology, Indiana University Simon Cancer Center, Indianapolis, Indiana.
authors.forename: Marietta L
authors.initials: ML
authors.lastname: Moore
authors.affiliation: Division of Hematology and Oncology, Indiana University Simon Cancer Center, Indianapolis, Indiana.
authors.forename: Rhoda L
authors.initials: RL
authors.lastname: Loman
authors.affiliation: Division of Hematology and Oncology, Indiana University Simon Cancer Center, Indianapolis, Indiana.
authors.forename: Angela
authors.initials: A
authors.lastname: Reed
authors.affiliation: Department of Pathology and Laboratory Medicine, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center and Norris Cotton Cancer Center, Lebanon, New Hampshire.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Turner
authors.affiliation: Department of Pathology and Laboratory Medicine, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center and Norris Cotton Cancer Center, Lebanon, New Hampshire.
authors.forename: Francine B
authors.initials: FB
authors.lastname: De Abreu
authors.affiliation: Department of Pathology and Laboratory Medicine, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center and Norris Cotton Cancer Center, Lebanon, New Hampshire.
authors.forename: Torrey
authors.initials: T
authors.lastname: Gallagher
authors.affiliation: Department of Pathology and Laboratory Medicine, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center and Norris Cotton Cancer Center, Lebanon, New Hampshire.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Tsongalis
authors.affiliation: Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Plimack
authors.affiliation: Department of Urology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Greenberg
authors.affiliation: Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Geynisman
mesh_terms: D000368:Aged; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000009:adverse effects; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009163:Mycobacterium bovis; D015363:Quinolones / Q000008:administration & dosage* / Q000009:adverse effects; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019459:Urothelium / Q000473:pathology
chemical_list: C500007:4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one; D001562:Benzimidazoles; D015363:Quinolones; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3