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The Dutch Cancer Society.

INTRODUCTION AND OBJECTIVES: Patients with high-grade NMIBC who fail BCG can experience high rates of disease progression and subsequent mortality. Those who refuse radical cystectomy in this setting have limited effective bladder-sparing options. CG0070 is an oncolytic adenovirus that preferentially destroys bladder tumor cells through their defective retinoblastoma (Rb) pathway. We evaluated the safety and efficacy of intravesical CG0070 in patients with BCG-refractory NMIBC who refused cystectomy.METHODS: Twenty-two patients with unresectable carcinoma in situ (CIS) or residual high grade disease (Ta/T1 with CIS, or CIS alone) enrolled in this open label, randomized, parallel and controlled trial (NCT01438112). Inclusion criteria mandated receipt of at least 2 prior courses of intravesical therapy for CIS, with at least 1 of them being a course of BCG. Patients had either failed BCG induction therapy within 6 months or had been successfully treated with BCG with subsequent recurrence. Available baseline Rb pathway data was characterized. Initial complete response (CR) was defined as absence of disease on biopsy or cytology at 3 months. Primary endpoints were durable CR at 6 and 12 months.RESULTS: Fifteen patients received CG0070 and 7 control patients received other standard intravesical therapies (4 Valrubicin, 2 Mitomycin C, 1 Gemcitabine). Eight (53%) patients receiving CG0070 and 4 (57%) control patients had an initial CR. Of the 8 CG0070 patients with initial CR, 6 patients had durable CR at 6 and 9 months. Four of 9 (44%) patients who received CG0070 and possessed defective Rb pathways had an initial CR, compared with 1 of 3 (33%) patients who received CG0070 with normal Rb expression. The safety profile of CG0070 was similar to the control arm. Grade 1/2 adverse events (AEs) occurred in 40% and 39% of CG0070 and control patients, respectively. One control patient experienced Grade 3 lumbago. No patients had Grade 4/5 AEs. The most frequent AEs in the CG0070 and control arms were local bladder toxicities (82% and 79%), followed by systemic (13% and 19%) and immunologic (4% and 2%) toxicities. Both patients with immunologic toxicity had self-limited influenza-like symptoms.CONCLUSIONS: This phase II/III study shows that intravesical CG0070 yields a durable response in a subset of high-risk patients and has an attractive toxicity profile. The correlation of defective Rb pathways and clinical response in the CG0070 cohort is unclear. Ongoing follow-up will clarify the utility of this agent in the BCG-refractory NMIBC population.

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