Introduction:

The standard of care for patients with high-risk non-muscle invasive bladder cancer (NMIBC) after exposure to induction only Bacillus Calmette-Guérin (BCG) or relapse > 12 months after “adequate” BCG is re-treatment with BCG. The proportion of patients expected to be relapse-free at 6 months is 50%.  Studies testing BCG plus intravesical mitomycin-C (MMC) have reported improved response rates but bladder toxicity is substantial.  Intravesical Gemcitabine (GEM), a common intravesical treatment for NMIBC, is well tolerated, enhances anti-tumor immune activity, and has better efficacy after BCG than MMC. Yet, GEM has not been systematically evaluated in combination with BCG.  This prospective trial investigated the safety, tolerability, and preliminary efficacy of intravesical chemoimmunotherapy using BCG plus GEM in patients with BCG-relapsed/BCG-exposed NMIBC.  

Methods:

This is the Phase I component of an open label Phase I/II trial (NCT04179162) of alternating intravesical GEM and BCG for patients with relapsing/exposed high-grade NMIBC within 24-months of prior BCG. Patients with BCG-unresponsive disease, contraindication to BCG, or prostatic/ureteral urothelial disease were excluded. Induction intravesical GEM was given twice weekly on weeks 1,4,7,10 and intravesical BCG was given weekly on weeks 2,3,5,6,8, and 9 followed by maintenance BCG (Figure). A fixed dose of BCG was given. GEM dose levels were 500mg, 1000mg, 1500mg, & 2000mg. Dose escalation used a modified continual reassessment method to determine the maximum tolerated dose (MTD) more accurately. Adverse events (AE) were recorded using Common Terminology Criteria for Adverse Events v5. Post-treatment cystoscopy and urine cytology were performed every 3-months for 1-year per protocol. Patients treated at the GEM MTD are carried forward in the ongoing Phase II trial examining efficacy. 

Results:

The phase I study enrolled 25 patients (median age 68[64-75] and 87% male) including 9(36%) with Tis, 7(28%) HGT1 + CIS, 6(24%) with HGTa +CIS, 2(8%) with HGTa only, and 1(4%) with HGT1 only. Toxicity data on induction treatment are currently available for 23 patients. Every patient completed the full 10 weeks of induction treatment and all patients reported at least one Grade 1 or 2 AE (Table). There were 3(13%) Grade 3 AEs all of which were unrelated or unlikely attributable to study drug. There were no dose-limiting toxicities or Grade 4/5 events. Based on the prospective biostatistical plan, the MTD/recommended phase II dose of GEM was 2000mg twice weekly. 19 (95%) of the 20 patients who completed the 6-month post-treatment evaluation were recurrence-free. Efficacy outcomes for all patients treated with the MTD will be reported as part of the ongoing Phase II trial.  

Conclusion:

A combination of intravesical GEM and BCG appears safe and well tolerated in patients with BCG-relapsed/BCG-exposed NMIBC. Toxicity for the combination was similar to that reported in studies of BCG and GEM given alone, supporting the safety of the combination therapy. Preliminary efficacy data are promising and will be formally assessed as part of the ongoing Phase II study that is currently enrolling patients (NCT04179162) 

Funding: This work was supported in part by the Sidney Kimmel Center for Prostate and Urologic Cancers at MSK, the National Institutes of Health/National Cancer Institute (NIH/NCI) with a Cancer Center Support Grant to Memorial Sloan Kettering Cancer Center (P30 CA008748), the Marie-Josée and Henry R. Kravis Center for Molecular Oncology, NCI Specialized Programs of Research Excellence (SPORE) in Bladder Cancer (P50 CA221745), NIH/NCI K12 Paul Calabresi Career Development Award for Clinical Oncology (K12 CA184746), Wofchuck Family Young Investigator Award, and the Bladder Cancer Advocacy Network Young Investigator Award