Phase I Trial of Intravesical Recombinant Adenovirus Mediated Interferon-α2b Formulated in Syn3 for Bacillus Calmette-Guerin Failures in Nonmuscle Invasive Bladder Cancer

Purpose: A phase I trial of intravesical recombinant adenovirus mediated interferon-alpha 2b gene therapy (rAd-IFN alpha) formulated with the excipient SCH Syn3 was conducted in patients with nonmuscle invasive bladder cancer who had disease recurrence after treatment with bacillus Calmette-Guerin. The primary objective was to determine the safety of rAd-IFN alpha/Syn3. Secondary end points were demonstrated effective rAd-IFN alpha gene expression and preliminary evidence of clinical activity at 3 months. Materials and Methods: A total of 17 patients with recurrent nonmuscle invasive bladder cancer after bacillus Calmette-Guerin treatment were enrolled in the study. A single treatment of rAd-IFN alpha (3 x 10(9) to 3 x 10(11) particles per ml) formulated with the excipient Syn3 was administered. Patient safety was evaluated for 12 or more weeks. Efficacy of gene transfer was determined by urine IFN alpha protein concentrations. Preliminary drug efficacy was determined at 3 months. Results: Intravesical rAd-IFN alpha/Syn3 was well tolerated as no dose limiting toxicity was encountered. Urgency was the most common adverse event and all cases were grade 1 or 2. rAd-IFN alpha DNA was not detected in the blood. However, transient low serum IFN alpha and Syn3 levels were measured. High and prolonged dose related urine IFN alpha levels were achieved with the initial treatment. Of the 14 patients treated at doses of 10(10) or more particles per ml with detectable urine IFN alpha, 6 (43%) experienced a complete response at 3 months and 2 remained disease-free at 29.0 and 39.2 months, respectively. Conclusions: Intravesical rAd-IFN alpha/Syn3 was well tolerated with no dose limiting toxicity encountered. Dose dependent urinary IFN alpha concentrations confirmed efficient gene transfer and expression. Intravesical rAd-IFN alpha/Syn3 demonstrated clinical activity in nonmuscle invasive bladder cancer recurring after bacillus Calmette-Guerin.