Neoadjuvant dasatinib for muscle-invasive bladder cancer with tissue analysis of biologic activity

Noah Hahn, Beatrice S. Knudsen, Siamak Daneshmand, Michael O. Koch, Richard Bihrle, Richard S. Foster, Thomas A. Gardner, Liang Cheng, Ziyue Liu, Timothy Breen, Mark T. Fleming, Raymond Lance, Christopher L. Corless, Ajjai S. Alva, Steven S. Shen, Fangjin Huang, Arkadiusz Gertych, Gary E. Gallick, Jayati Mallick, Christopher Ryan & 4 others Matthew D. Galsky, Seth P. Lerner, Edwin M. Posadas, Guru Sonpavde

Research output: Contribution to journalArticle

Abstract

OBJECTIVES: Preclinical urothelial carcinoma models suggest activity of dasatinib, an oral SRC-family kinase (SFK) inhibitor. We sought to determine the feasibility and biologic activity of neoadjuvant dasatinib (Neo-D) in patients with muscle-invasive urothelial carcinoma of the bladder (miUCB) preceding radical cystectomy (RC).

MATERIALS AND METHODS: A prospective multisite phase II trial was conducted. Key eligibility criteria included: resectable miUCB (T2-T4a, N0, M0), and Eastern Cooperative Oncology Group performance status 0 to 1. Patients received oral Neo-D 100mg once daily for 28±7 days followed by RC 8 to 24 hours after the last dose. The primary end point was feasibility, defined as≥60% of patients with miUCB completing therapy without treatment-related dose-limiting toxicity (DLT). Pre- and posttreatment tumor immunohistochemistry of phosphorylated SFK (pSFK), Ki-67, and cleaved caspase (Cas)-3 results were analyzed by paired t test.

RESULTS: The study completed full accrual with enrollment of 25 patients of whom 23 were evaluable for feasibility. The study achieved its primary end point with 15 patients (65%) completing therapy without treatment-related DLTs. DLTs included: fatigue (n = 2), pulmonary embolism, abdominal pain, supraventricular tachycardia, enteric fistula, hematuria, and dyspnea (n = 1 each). At RC, 5 patients (23%) had<pT2 disease. Analysis of pre- and posttreatment tumors demonstrated significantly decreased pSFK (P = 0.003) but no overall significant changes in Ki-67 or Cas3. In total, 4 cases demonstrated a nonsignificant decrease in Ki-67, of which 3 cases also demonstrated a decrease in pSFK and 2 cases had marginal increase in Cas3.

CONCLUSIONS: Neo-D in miUCB patients was feasible and safe. Overall, significant inhibition of pSFK was observed without overall reduction of cellular proliferation or increase of apoptosis, although biologic anti-tumor activity may exist in a small subset of patients. These results highlight the potential utility of the neoadjuvant trial paradigm and suggest that clinical benefit of single-agent SFK inhibition in unselected patients with miUCB is unlikely.

Original languageEnglish (US)
JournalUrologic Oncology
Volume34
Issue number1
DOIs
StatePublished - Jan 1 2016

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Urinary Bladder Neoplasms
Muscles
Urinary Bladder
Carcinoma
Cystectomy
Phosphotransferases
Dasatinib
Neoplasms
Supraventricular Tachycardia
Hematuria
Therapeutics
Pulmonary Embolism
Caspase 3
Dyspnea
Abdominal Pain
Fistula
Fatigue
Immunohistochemistry
Cell Proliferation
Apoptosis

Keywords

  • Bladder
  • Dasatinib
  • Neoadjuvant therapy
  • Protein kinase inhibitors
  • Src-family kinases
  • Translational medical research
  • Urothelial carcinoma

ASJC Scopus subject areas

  • Oncology
  • Urology

Cite this

Neoadjuvant dasatinib for muscle-invasive bladder cancer with tissue analysis of biologic activity. / Hahn, Noah; Knudsen, Beatrice S.; Daneshmand, Siamak; Koch, Michael O.; Bihrle, Richard; Foster, Richard S.; Gardner, Thomas A.; Cheng, Liang; Liu, Ziyue; Breen, Timothy; Fleming, Mark T.; Lance, Raymond; Corless, Christopher L.; Alva, Ajjai S.; Shen, Steven S.; Huang, Fangjin; Gertych, Arkadiusz; Gallick, Gary E.; Mallick, Jayati; Ryan, Christopher; Galsky, Matthew D.; Lerner, Seth P.; Posadas, Edwin M.; Sonpavde, Guru.

In: Urologic Oncology, Vol. 34, No. 1, 01.01.2016.

Research output: Contribution to journalArticle

Hahn, N, Knudsen, BS, Daneshmand, S, Koch, MO, Bihrle, R, Foster, RS, Gardner, TA, Cheng, L, Liu, Z, Breen, T, Fleming, MT, Lance, R, Corless, CL, Alva, AS, Shen, SS, Huang, F, Gertych, A, Gallick, GE, Mallick, J, Ryan, C, Galsky, MD, Lerner, SP, Posadas, EM & Sonpavde, G 2016, 'Neoadjuvant dasatinib for muscle-invasive bladder cancer with tissue analysis of biologic activity', Urologic Oncology, vol. 34, no. 1. https://doi.org/10.1016/j.urolonc.2015.08.005
Hahn, Noah ; Knudsen, Beatrice S. ; Daneshmand, Siamak ; Koch, Michael O. ; Bihrle, Richard ; Foster, Richard S. ; Gardner, Thomas A. ; Cheng, Liang ; Liu, Ziyue ; Breen, Timothy ; Fleming, Mark T. ; Lance, Raymond ; Corless, Christopher L. ; Alva, Ajjai S. ; Shen, Steven S. ; Huang, Fangjin ; Gertych, Arkadiusz ; Gallick, Gary E. ; Mallick, Jayati ; Ryan, Christopher ; Galsky, Matthew D. ; Lerner, Seth P. ; Posadas, Edwin M. ; Sonpavde, Guru. / Neoadjuvant dasatinib for muscle-invasive bladder cancer with tissue analysis of biologic activity. In: Urologic Oncology. 2016 ; Vol. 34, No. 1.
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abstract = "OBJECTIVES: Preclinical urothelial carcinoma models suggest activity of dasatinib, an oral SRC-family kinase (SFK) inhibitor. We sought to determine the feasibility and biologic activity of neoadjuvant dasatinib (Neo-D) in patients with muscle-invasive urothelial carcinoma of the bladder (miUCB) preceding radical cystectomy (RC).MATERIALS AND METHODS: A prospective multisite phase II trial was conducted. Key eligibility criteria included: resectable miUCB (T2-T4a, N0, M0), and Eastern Cooperative Oncology Group performance status 0 to 1. Patients received oral Neo-D 100mg once daily for 28±7 days followed by RC 8 to 24 hours after the last dose. The primary end point was feasibility, defined as≥60{\%} of patients with miUCB completing therapy without treatment-related dose-limiting toxicity (DLT). Pre- and posttreatment tumor immunohistochemistry of phosphorylated SFK (pSFK), Ki-67, and cleaved caspase (Cas)-3 results were analyzed by paired t test.RESULTS: The study completed full accrual with enrollment of 25 patients of whom 23 were evaluable for feasibility. The study achieved its primary end point with 15 patients (65{\%}) completing therapy without treatment-related DLTs. DLTs included: fatigue (n = 2), pulmonary embolism, abdominal pain, supraventricular tachycardia, enteric fistula, hematuria, and dyspnea (n = 1 each). At RC, 5 patients (23{\%}) hadCONCLUSIONS: Neo-D in miUCB patients was feasible and safe. Overall, significant inhibition of pSFK was observed without overall reduction of cellular proliferation or increase of apoptosis, although biologic anti-tumor activity may exist in a small subset of patients. These results highlight the potential utility of the neoadjuvant trial paradigm and suggest that clinical benefit of single-agent SFK inhibition in unselected patients with miUCB is unlikely.",
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T1 - Neoadjuvant dasatinib for muscle-invasive bladder cancer with tissue analysis of biologic activity

AU - Hahn, Noah

AU - Knudsen, Beatrice S.

AU - Daneshmand, Siamak

AU - Koch, Michael O.

AU - Bihrle, Richard

AU - Foster, Richard S.

AU - Gardner, Thomas A.

AU - Cheng, Liang

AU - Liu, Ziyue

AU - Breen, Timothy

AU - Fleming, Mark T.

AU - Lance, Raymond

AU - Corless, Christopher L.

AU - Alva, Ajjai S.

AU - Shen, Steven S.

AU - Huang, Fangjin

AU - Gertych, Arkadiusz

AU - Gallick, Gary E.

AU - Mallick, Jayati

AU - Ryan, Christopher

AU - Galsky, Matthew D.

AU - Lerner, Seth P.

AU - Posadas, Edwin M.

AU - Sonpavde, Guru

PY - 2016/1/1

Y1 - 2016/1/1

N2 - OBJECTIVES: Preclinical urothelial carcinoma models suggest activity of dasatinib, an oral SRC-family kinase (SFK) inhibitor. We sought to determine the feasibility and biologic activity of neoadjuvant dasatinib (Neo-D) in patients with muscle-invasive urothelial carcinoma of the bladder (miUCB) preceding radical cystectomy (RC).MATERIALS AND METHODS: A prospective multisite phase II trial was conducted. Key eligibility criteria included: resectable miUCB (T2-T4a, N0, M0), and Eastern Cooperative Oncology Group performance status 0 to 1. Patients received oral Neo-D 100mg once daily for 28±7 days followed by RC 8 to 24 hours after the last dose. The primary end point was feasibility, defined as≥60% of patients with miUCB completing therapy without treatment-related dose-limiting toxicity (DLT). Pre- and posttreatment tumor immunohistochemistry of phosphorylated SFK (pSFK), Ki-67, and cleaved caspase (Cas)-3 results were analyzed by paired t test.RESULTS: The study completed full accrual with enrollment of 25 patients of whom 23 were evaluable for feasibility. The study achieved its primary end point with 15 patients (65%) completing therapy without treatment-related DLTs. DLTs included: fatigue (n = 2), pulmonary embolism, abdominal pain, supraventricular tachycardia, enteric fistula, hematuria, and dyspnea (n = 1 each). At RC, 5 patients (23%) hadCONCLUSIONS: Neo-D in miUCB patients was feasible and safe. Overall, significant inhibition of pSFK was observed without overall reduction of cellular proliferation or increase of apoptosis, although biologic anti-tumor activity may exist in a small subset of patients. These results highlight the potential utility of the neoadjuvant trial paradigm and suggest that clinical benefit of single-agent SFK inhibition in unselected patients with miUCB is unlikely.

AB - OBJECTIVES: Preclinical urothelial carcinoma models suggest activity of dasatinib, an oral SRC-family kinase (SFK) inhibitor. We sought to determine the feasibility and biologic activity of neoadjuvant dasatinib (Neo-D) in patients with muscle-invasive urothelial carcinoma of the bladder (miUCB) preceding radical cystectomy (RC).MATERIALS AND METHODS: A prospective multisite phase II trial was conducted. Key eligibility criteria included: resectable miUCB (T2-T4a, N0, M0), and Eastern Cooperative Oncology Group performance status 0 to 1. Patients received oral Neo-D 100mg once daily for 28±7 days followed by RC 8 to 24 hours after the last dose. The primary end point was feasibility, defined as≥60% of patients with miUCB completing therapy without treatment-related dose-limiting toxicity (DLT). Pre- and posttreatment tumor immunohistochemistry of phosphorylated SFK (pSFK), Ki-67, and cleaved caspase (Cas)-3 results were analyzed by paired t test.RESULTS: The study completed full accrual with enrollment of 25 patients of whom 23 were evaluable for feasibility. The study achieved its primary end point with 15 patients (65%) completing therapy without treatment-related DLTs. DLTs included: fatigue (n = 2), pulmonary embolism, abdominal pain, supraventricular tachycardia, enteric fistula, hematuria, and dyspnea (n = 1 each). At RC, 5 patients (23%) hadCONCLUSIONS: Neo-D in miUCB patients was feasible and safe. Overall, significant inhibition of pSFK was observed without overall reduction of cellular proliferation or increase of apoptosis, although biologic anti-tumor activity may exist in a small subset of patients. These results highlight the potential utility of the neoadjuvant trial paradigm and suggest that clinical benefit of single-agent SFK inhibition in unselected patients with miUCB is unlikely.

KW - Bladder

KW - Dasatinib

KW - Neoadjuvant therapy

KW - Protein kinase inhibitors

KW - Src-family kinases

KW - Translational medical research

KW - Urothelial carcinoma

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