A Phase I Trial of Intravesical Nanoparticle Albumin-Bound Paclitaxel in the Treatment of Bacillus Calmette-Guérin Refractory Nonmuscle Invasive Bladder Cancer James M. McKiernan, LaMont J. Barlow,* Melissa A. Laudano, Mark J. Mann, Daniel P. Petrylak and Mitchell C. Benson From the Department of Urology (JMM, LJB, MAL, MJM, MCB) and Oncology (DPP), Columbia University Medical Center, New York, New York Abbreviations and Acronyms BCG = bacillus Calmette-Guérin CR = complete response DLT = dose limiting toxicity MDD = maximum deliverable dose nab-paclitaxel = nanoparticle albumin-bound paclitaxel NMIBC = nonmuscle invasive bladder cancer NR = no response NS = normal saline TUR = transurethral resection Submitted for publication January 13, 2011. Study received institutional review board ap- proval. Supported by Abraxis Oncology and the Doris Duke Charitable Research Foundation. * Correspondence: Department of Urology, Herbert Irving Pavilion–11th Floor, 161 Fort Washington Ave., New York, New York 10032 (telephone: 617-538-2648; FAX: 212-305-6813; e-mail: ljb2119@columbia.edu). For another article on a related topic see page 702. Purpose: Up to 50% of patients treated with intravesical agents for high grade nonmuscle invasive bladder cancer will have disease recurrence. Response rates to current second line intravesical therapies are low and for these high risk patients novel agents are necessary. Our previously completed phase I trial showed docetaxel was a safe agent for intravesical use. Nanoparticle albumin- bound paclitaxel (Abraxane®, ABI-007) has been shown to have increased solu- bility and lower toxicity compared to docetaxel in systemic therapy. Thus, we assessed the dose limiting toxicity and maximum deliverable dose of intravesical nanoparticle albumin-bound paclitaxel. Materials and Methods: Inclusion criteria for this institutional review board approved phase I trial were recurrent high grade Ta, T1 and Tis transitional cell carcinoma of the bladder for which at least 1 prior standard intravesical regimen failed. Six weekly instillations of nanoparticle albumin-bound paclitaxel were administered with a modified Fibonacci dose escalation model used until the maximum deliverable dose was achieved. The primary end point was dose lim- iting toxicity and the secondary end point was response rate. Results: A total of 18 patients were enrolled in the study. One patient demon- strated measurable systemic absorption after 1 infusion. Grade 1 local toxicities were experienced by 10 (56%) patients with dysuria being the most common, and no grade 2, 3 or 4 drug related local toxicities were encountered. Of the 18 patients 5 (28%) had no evidence of disease at posttreatment evaluation. Conclusions: Intravesical nanoparticle albumin-bound paclitaxel exhibited mini- mal toxicity and systemic absorption in the first human intravesical phase I trial to our knowledge. A larger phase II study has begun to formally evaluate the activity of this regimen. Key Words: urinary bladder neoplasms; administration, intravesical; paclitaxel; nanotechnology IN 2009 more than 70,000 new cases of bladder cancer were diagnosed in the United States and more than 14,000 deaths occurred due to the dis- ease. 1 NMIBC, including carcinoma in situ (Tis) as well as stages Ta and T1, accounts for approximately 70% of cases. 2 While the primary method of nonmuscle invasive bladder tumor di- agnosis and treatment continues to be TUR, intravesical therapy has be- come an integral component in the management of NMIBC. 3 Intravesical BCG is considered the gold standard 448 www.jurology.com 0022-5347/11/1862-0448/0 Vol. 186, 448-451, August 2011 THE JOURNAL OF UROLOGY ® Printed in U.S.A. © 2011 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH,INC. DOI:10.1016/j.juro.2011.03.129