A Phase I Clinical Trial of Chemoimmunotherapy with Alternating Intravesical Gemcitabine and Bacillus Calmette-Guérin (GemBCG) for BCG-Exposed High-Grade Non-Muscle-Invasive Bladder Cancer

PURPOSE: Retreatment with BCG alone is recommended for patients with Bacillus Calmette-Guérin (BCG)-exposed non-muscle-invasive bladder cancer (NMIBC), yet ∼50% recur and become "BCG-unresponsive." Strategies to improve the efficacy of BCG retreatment are urgently needed. MATERIALS AND METHODS: In this Phase I dose-escalation trial of intravesical chemoimmunotherapy with gemcitabine and BCG (GemBCG) in patients with BCG-exposed high-grade NMIBC (NCT04179162), Biweekly intravesical gemcitabine was given weeks 1, 4, 7, and 10 (8 doses total escalated from 500-2000 mg via a modified continual reassessment method) and weekly intravesical BCG (50 mg TICE) during weeks 2, 3, 5, 6, 8, and 9 (6 doses total). The primary objective was to define the maximally tolerated dose. Adverse events were assessed using CTCAE v5.0. The key secondary outcome was complete clinical response at 6-months. Analyses of tumor, urine, and blood samples were exploratory. RESULTS: 25 patients enrolled (median age 68 [IQR 64-75]) of whom 17 (68%) had CIS ± papillary disease. No treatment-related grade ≥3 AEs or dose-limiting toxicities occurred; 72% reported grade 1 and 20% reported grade 2 AEs. 24 of 25 patients (96%; 95%CI 80%-100%) achieved a complete clinical response at 6-months. T-cell recruitment chemokines (CXCL9, CXCL10, and CXCL11) increased and the immunosuppressive cytokine IL-6 decreased in the urine with treatment. CONCLUSION: GemBCG was safe, well-tolerated, and demonstrated promising early efficacy and modification of the tumor microenvironment. Based on these data, a randomized phase III trial is testing GemBCG vs. retreatment with BCG alone for BCG exposed high-grade NMIBC (Alliance A032303/NCT07000084).