A phase II trial of dovitinib in BCG-unresponsive urothelial carcinoma with FGFR3 mutations or overexpression

Hoosier Cancer Research Network trial HCRN 12-157

Noah M. Hahn, Trinity J. Bivalacqua, Ashley E. Ross, George J. Netto, Alex Baras, Jong Chul Park, Carolyn Chapman, Timothy Masterson, Michael Koch, Richard Bihrle, Richard Foster, Thomas Gardner, Liang Cheng, David R. Jones, Kyle McElyea, George Sandusky, Timothy Breen, Ziyue Liu, Costantine Albany, Marietta L. Moore & 9 others Rhoda L. Loman, Angela Reed, Scott A. Turner, Francine B. De Abreu, Torrey Gallagher, Gregory J. Tsongalis, Elizabeth R. Plimack, Richard E. Greenberg, Daniel M. Geynisman

Research output: Contribution to journalArticle

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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+) 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 the following: median age 70 years; 85% male; carcinoma in 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.

Original languageEnglish (US)
Pages (from-to)3003-3011
Number of pages9
JournalClinical Cancer Research
Volume23
Issue number12
DOIs
StatePublished - Jun 15 2017

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Mycobacterium bovis
Carcinoma
Mutation
Research
Neoplasms
Urinary Bladder
Urothelium
4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one
Carcinoma in Situ
Patient Selection
Research Design
Phosphotransferases
Immunohistochemistry
Demography
Clinical Trials
Staining and Labeling
Therapeutics
Population

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

A phase II trial of dovitinib in BCG-unresponsive urothelial carcinoma with FGFR3 mutations or overexpression : Hoosier Cancer Research Network trial HCRN 12-157. / Hahn, Noah M.; Bivalacqua, Trinity J.; Ross, Ashley E.; Netto, George J.; Baras, Alex; Park, Jong Chul; Chapman, Carolyn; Masterson, Timothy; Koch, Michael; Bihrle, Richard; Foster, Richard; Gardner, Thomas; Cheng, Liang; Jones, David R.; McElyea, Kyle; Sandusky, George; Breen, Timothy; Liu, Ziyue; Albany, Costantine; Moore, Marietta L.; Loman, Rhoda L.; Reed, Angela; Turner, Scott A.; De Abreu, Francine B.; Gallagher, Torrey; Tsongalis, Gregory J.; Plimack, Elizabeth R.; Greenberg, Richard E.; Geynisman, Daniel M.

In: Clinical Cancer Research, Vol. 23, No. 12, 15.06.2017, p. 3003-3011.

Research output: Contribution to journalArticle

Hahn, NM, Bivalacqua, TJ, Ross, AE, Netto, GJ, Baras, A, Park, JC, Chapman, C, Masterson, T, Koch, M, Bihrle, R, Foster, R, Gardner, T, Cheng, L, Jones, DR, McElyea, K, Sandusky, G, Breen, T, Liu, Z, Albany, C, Moore, ML, Loman, RL, Reed, A, Turner, SA, De Abreu, FB, Gallagher, T, Tsongalis, GJ, Plimack, ER, Greenberg, RE & Geynisman, DM 2017, 'A phase II trial of dovitinib in BCG-unresponsive urothelial carcinoma with FGFR3 mutations or overexpression: Hoosier Cancer Research Network trial HCRN 12-157', Clinical Cancer Research, vol. 23, no. 12, pp. 3003-3011. https://doi.org/10.1158/1078-0432.CCR-16-2267
Hahn, Noah M. ; Bivalacqua, Trinity J. ; Ross, Ashley E. ; Netto, George J. ; Baras, Alex ; Park, Jong Chul ; Chapman, Carolyn ; Masterson, Timothy ; Koch, Michael ; Bihrle, Richard ; Foster, Richard ; Gardner, Thomas ; Cheng, Liang ; Jones, David R. ; McElyea, Kyle ; Sandusky, George ; Breen, Timothy ; Liu, Ziyue ; Albany, Costantine ; Moore, Marietta L. ; Loman, Rhoda L. ; Reed, Angela ; Turner, Scott A. ; De Abreu, Francine B. ; Gallagher, Torrey ; Tsongalis, Gregory J. ; Plimack, Elizabeth R. ; Greenberg, Richard E. ; Geynisman, Daniel M. / A phase II trial of dovitinib in BCG-unresponsive urothelial carcinoma with FGFR3 mutations or overexpression : Hoosier Cancer Research Network trial HCRN 12-157. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 12. pp. 3003-3011.
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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+) 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 the following: median age 70 years; 85{\%} male; carcinoma in 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.",
author = "Hahn, {Noah M.} and Bivalacqua, {Trinity J.} and Ross, {Ashley E.} and Netto, {George J.} and Alex Baras and Park, {Jong Chul} and Carolyn Chapman and Timothy Masterson and Michael Koch and Richard Bihrle and Richard Foster and Thomas Gardner and Liang Cheng and Jones, {David R.} and Kyle McElyea and George Sandusky and Timothy Breen and Ziyue Liu and Costantine Albany and Moore, {Marietta L.} and Loman, {Rhoda L.} and Angela Reed and Turner, {Scott A.} and {De Abreu}, {Francine B.} and Torrey Gallagher and Tsongalis, {Gregory J.} and Plimack, {Elizabeth R.} and Greenberg, {Richard E.} and Geynisman, {Daniel M.}",
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TY - JOUR

T1 - A phase II trial of dovitinib in BCG-unresponsive urothelial carcinoma with FGFR3 mutations or overexpression

T2 - Hoosier Cancer Research Network trial HCRN 12-157

AU - Hahn, Noah M.

AU - Bivalacqua, Trinity J.

AU - Ross, Ashley E.

AU - Netto, George J.

AU - Baras, Alex

AU - Park, Jong Chul

AU - Chapman, Carolyn

AU - Masterson, Timothy

AU - Koch, Michael

AU - Bihrle, Richard

AU - Foster, Richard

AU - Gardner, Thomas

AU - Cheng, Liang

AU - Jones, David R.

AU - McElyea, Kyle

AU - Sandusky, George

AU - Breen, Timothy

AU - Liu, Ziyue

AU - Albany, Costantine

AU - Moore, Marietta L.

AU - Loman, Rhoda L.

AU - Reed, Angela

AU - Turner, Scott A.

AU - De Abreu, Francine B.

AU - Gallagher, Torrey

AU - Tsongalis, Gregory J.

AU - Plimack, Elizabeth R.

AU - Greenberg, Richard E.

AU - Geynisman, Daniel M.

PY - 2017/6/15

Y1 - 2017/6/15

N2 - 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+) 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 the following: median age 70 years; 85% male; carcinoma in 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.

AB - 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+) 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 the following: median age 70 years; 85% male; carcinoma in 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.

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U2 - 10.1158/1078-0432.CCR-16-2267

DO - 10.1158/1078-0432.CCR-16-2267

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JO - Clinical Cancer Research

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SN - 1078-0432

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