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

• Published in: Urologic oncology 2016-01, Vol.34 (1), p.4.e11-4.e17
• Main Authors: Hahn, Noah M., M.D, Knudsen, Beatrice S., M.D., Ph.D, Daneshmand, Siamak, M.D, Koch, Michael O., M.D, Bihrle, Richard, M.D, Foster, Richard S., M.D, Gardner, Thomas A., M.D, Cheng, Liang, M.D, Liu, Ziyue, Ph.D, Breen, Timothy, Ph.D, Fleming, Mark T., M.D, Lance, Raymond, M.D, Corless, Christopher L., M.D., Ph.D, Alva, Ajjai S., M.D, Shen, Steven S., M.D., Ph.D, Huang, Fangjin, M.S, Gertych, Arkadiusz, Ph.D, Gallick, Gary E., Ph.D, Mallick, Jayati, M.D, Ryan, Christopher, M.D, Galsky, Matthew D., M.D, Lerner, Seth P., M.D, Posadas, Edwin M., M.D, Sonpavde, Guru, M.D
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Antineoplastic Agents - therapeutic use; Biomarkers, Tumor - metabolism; Bladder; Dasatinib; Dasatinib - therapeutic use; Feasibility Studies; Female; Follow-Up Studies; Humans; Immunoenzyme Techniques; Male; Middle Aged; Muscle Neoplasms - drug therapy; Muscle Neoplasms - metabolism; Muscle Neoplasms - pathology; Neoadjuvant Therapy; Neoplasm Invasiveness; Neoplasm Staging; Prognosis; Prospective Studies; Protein kinase inhibitors; Src-family kinases; Translational medical research; Urinary Bladder Neoplasms - drug therapy; Urinary Bladder Neoplasms - metabolism; Urinary Bladder Neoplasms - pathology; Urology; Urothelial carcinoma
• ISSN: 1078-1439; 1873-2496
• DOI: 10.1016/j.urolonc.2015.08.005

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 100 mg 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