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

Authors :
Hahn, Noah M.
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
Source :
Urologic Oncology. Jan2016, Vol. 34 Issue 1, p4.e11-4.e17. 1p.
Publication Year :
2016

Abstract

<bold>Objectives: </bold>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).<bold>Materials and Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusions: </bold>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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
10781439
Volume :
34
Issue :
1
Database :
Academic Search Index
Journal :
Urologic Oncology
Publication Type :
Academic Journal
Accession number :
111420787
Full Text :
https://doi.org/10.1016/j.urolonc.2015.08.005