Phase I trial of intravesical recombinant adenovirus mediated interferon-α2b formulated in Syn3 for Bacillus Calmette-Guérin failures in nonmuscle invasive bladder cancer

Abstract

Purpose: A phase I trial of intravesical recombinant adenovirus mediated interferon-α2b gene therapy (rAd-IFNα) formulated with the excipient SCH Syn3 was conducted in patients with nonmuscle invasive bladder cancer who had disease recurrence after treatment with bacillus Calmette-Guérin. The primary objective was to determine the safety of rAd-IFNα/Syn3. Secondary end points were demonstrated effective rAd-IFNα 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-Guérin treatment were enrolled in the study. A single treatment of rAd-IFNα (3 × 10(9) to 3 × 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 IFNα protein concentrations. Preliminary drug efficacy was determined at 3 months.

Results: Intravesical rAd-IFNα/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-IFNα DNA was not detected in the blood. However, transient low serum IFNα and Syn3 levels were measured. High and prolonged dose related urine IFNα 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 IFNα, 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-IFNα/Syn3 was well tolerated with no dose limiting toxicity encountered. Dose dependent urinary IFNα concentrations confirmed efficient gene transfer and expression. Intravesical rAd-IFNα/Syn3 demonstrated clinical activity in nonmuscle invasive bladder cancer recurring after bacillus Calmette-Guérin.

Keywords: AE; AWD; BCG; CR; DLT; IFN; LLOQ; NED; NMIBC; adverse event; alive with disease; bacillus Calmette-Guérin; complete response; dose limiting toxicity; genetic therapy; interferon; interferons; lower limit of quantitation; no evidence of disease; nonmuscle invasive bladder cancer; urinary bladder neoplasms.

Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1

Linear (A) and log-linear (B) mean plasma Syn3 concentration-time profiles for all patients after intravesical administration of rAd-IFNα/Syn3. Dose Level 1 = 3×109, Dose Level 2 = 1×1010, Dose Level 3 = 3×1010, Dose Level 4 = 1×1011, Dose Level 5 = 3×1011 particles/mL in 75mL.

Figure 1

Linear (A) and log-linear (B) mean plasma Syn3 concentration-time profiles for all patients after intravesical administration of rAd-IFNα/Syn3. Dose Level 1 = 3×109, Dose Level 2 = 1×1010, Dose Level 3 = 3×1010, Dose Level 4 = 1×1011, Dose Level 5 = 3×1011 particles/mL in 75mL.

Figure 2

Individual serum IFNα concentration detected in the hours following intravesical administration of rAd-IFNα/Syn3. Results are reported as IFN international units (IU) per mL. One IU is approximately equal to 4 pg.

Figure 3

Linear (A) and log-linear (B) mean IFNα concentrations in urine after intravesical administration of rAd-IFNα/Syn3. Dose Level 1 = 3×109, Dose Level 2 = 1×1010, Dose Level 3 = 3×1010, Dose Level 4 = 1×1011, Dose Level 5 = 3×1011 particles/mL in 75mL.

Figure 3

Linear (A) and log-linear (B) mean IFNα concentrations in urine after intravesical administration of rAd-IFNα/Syn3. Dose Level 1 = 3×109, Dose Level 2 = 1×1010, Dose Level 3 = 3×1010, Dose Level 4 = 1×1011, Dose Level 5 = 3×1011 particles/mL in 75mL.