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Background: A phase 1b trial was conducted to evaluate the duration of interferon-alpha (IFNα) production after intravesical administration of recombinant adenovirus-mediated interferon α2b (Ad-IFN) formulated with the excipient Syn3. The primary aim was to determine whether a second instillation 3 days after initial treatment produced prolonged urinary IFN production., Methods: The study enrolled seven patients who experienced recurrent non-muscle invasive bladder cancer after bacillus Calmette-Guerin therapy. Each treatment consisted of intravesical instillation of SCH721015 (Syn3) and Ad-IFN at a concentration of 3 × 10 11 particles/mL to a total volume of 75 mL given on days 1 and 4. The patients were followed for 12 weeks, during which the magnitude and duration of gene transfer were determined by urine INFα levels. Drug efficacy was determined by cystoscopy and biopsy, and patients who had no recurrence at 12 weeks were eligible for a second course of treatment., Results: Seven patients were treated with an initial course (instillation on days 1 and 4). Two of the patients had a complete response at 12 weeks and received a second course of treatment. One patient remained without evidence of recurrence after a second course (total 24 weeks). One patient experienced a non-treatment-associated adverse event. Despite a transient rise in IFNα levels, sustained production was not demonstrated., Conclusion: Previously, Ad-IFNα intravesical therapy has shown promising drug efficacy. A prior phase 1 trial with a single instillation compared similarly with the current study, suggesting that a second instillation is not necessary to achieve sufficient urinary IFNα levels.