A Phase II Trial of Dovitinib in BCG-Unresponsive Urothelial Carcinoma with FGFR3 Mutations 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 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 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: 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.

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“…HistoGel plugs were paraffin embedded and slides were prepared by the laboratory of Dr. Keith Condon (Indiana University School of Medicine; Indianapolis, IN). Samples were stained with the specified antibodies by the Indiana University School of Medicine Research Immunohistochemistry Facility (Indianapolis, IN) and quantified using the HALO image analysis platform (Indica Labs) as before 45 .…”

FGFR3 mutation increases bladder tumourigenesis by suppressing acute inflammation

“…Current clinical trials are based on proof‐of‐principle studies in cell lines and xenograft models . Phase II clinical trials of dovitinib, a multi‐targeted RTK inhibitor that prevents phosphorylation of FGFR3, showed limited activity in advanced bladder cancer and in BCG‐unresponsive bladder cancer with mutations or overexpression of FGFR3 . In contrast, a phase I trial of BGJ398 showed anti‐tumour activity in FGFR3 ‐mutated advanced bladder cancer after failure of platinum‐based chemotherapy .…”

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“…Besides Pazopanib, several other substances targeting FGFRs are currently under investigation 35 and AZ12908010, AZD4547, PD173074, TKI-258/Dovitinib, SU5402 and BGJ-398 showed promising results in vitro 36 – 39 . Yet, clinical data is scarce and partially controversial: By systemic administration of Dovitinib biologically active concentrations could be consistently achieved in 13 patients with NMIBC 40 . However, long-term administration was not possible due to frequent toxicities.…”