Double-Blind, Randomized, Placebo-controlled Studies Evaluating Apaziquone (E09, Qapzola™) Intravesical Instillation Post Transurethral Resection of Bladder Tumors for the Treatment of Low-risk Non-Muscle Invasive Bladder Cancer.

Background: Guidelines recommend a single postoperative instillation of intravesical chemotherapy within 24 hours of transurethral resection of bladder tumors (TURBT) in patients with low-and intermediate-risk non-muscle invasive bladder cancer (NMIBC) to reduce recurrence risk. Objective: To evaluate the 2-year recurrence rate (2-YRR) of bladder cancer in randomized patients with Ta, G1-G2 histology who receive TURBT plus apaziquone versus TURBT plus placebo. Methods: Two nearly identical Phase 3, multinational, randomized, double-blind, placebo-controlled trials were conducted in patients with histologically confirmed Ta, G1-G2 NMIBC (Target Population) to evaluate the efficacy/safety of a single instillation of apaziquone post-TURBT. A single intravesical instillation of apaziquone (4 mg/40 mL) or placebo was administered within 6 hours post-TURBT. The primary and secondary efficacy endpoints were 2-YRR and time to recurrence (TTR) respectively. Results: Overall, 1614 patients were enrolled, including 1146 patients in the Target Population. Individually, the two studies did not meet statistical significance for 2-YRR(38.0% vs 44.6%; 39.7% vs. 46.3%). Because apaziquone is rapidly metabolized in blood, a post hoc subgroup analysis was performed by time window of drug instillation post-TURBT. Patients who had drug instilled in the time window 60 +/- 30 minutes post-TURBT demonstrated 20.3% and 20.8% reduction in 2-YRR and 56% (HR = 0.44) and 45% (HR = 0.55) reduction in hazards for TTR in two studies respectively. Apaziquone was well tolerated with minimal toxicity. Conclusions: Two identical Phase 3 studies supported the safety of apaziquone (4 mg/40 mL) administered as a single intravesical instillation post-TURBT and identified efficacy when instilled within 60 +/- 30-minutes time interval which requires further study.