Status:
Completed
Clinicaltrials.gov identifier:
Sponsor:
European Association of Urology Research Foundation
Enrollment:
345
Study Design:
BCG naïve patients with high grade Ta or T1, primary or recurrent, single or multiple papillary urothelial cancer with or without CIS after adequate resection of papillary component (with muscle present in the specimen) were randomized to standard BCG frequency (SF) or reduced BCG frequency (RF). The SF arm consisted of 15 total instillations: a) induction course of weekly BCG for 6 weeks followed by b) maintenance courses of weekly BCG for 3 weeks at month 3, 6, and 12. The RF arm consisted of 9 total instillations: a) induction course of BCG at week 1, 2, and 6 followed by b) maintenance courses of BCG at only weeks 1 and 3 at month 3, 6, and 12. Cystoscopy and cytology were performed every 3 months for the fi rst two years and every six months afterwards. Patients completed study at first recurrence or after occurrence of new CIS, upper tract urothelial carcinoma, prostatic urethral disease, distant metastases, or requiring systemic chemotherapy. The study was designed to establish therapeutic equivalence defined as the lower part of the confidence interval (CI) (using one-sided 2.5% level of significance) being higher than a hazard ratio of 0.75 for recurrence. The sample size was calculated to be 412 per arm after recruitment delay due to BCG shortage led to re-defi nition of statistical assumptions.
Rationale:
BCG is the standard treatment for high risk non-muscle invasive bladder cancer (NMIBC) and given recent data suggesting comparable efficacy and improved tolerability with reduced dosing as well as recent challenges in administration given BCG shortages, this trial evaluated whether a reduced number of standard dose BCG instillations were non-inferior to the standard number and dose of BCG instillations for patients with high grade NMIBC.
Endpoints:
The primary endpoint was time to first recurrence. Secondary endpoints included progression to muscle-invasion, number and grade of recurrent tumors, and side effects.
Comments:
NIMBUS was designed based on animal data demonstrating profound Th1-mediated cytokine responses at weeks 1 and 6 of induction BCG equivalent to an entire 6-week induction phase. The maintenance course was also shortened in the RF arm based on data from CUETO 98013 demonstrating that one maintenance instillation is sufficient. However, the results in this randomized trial demonstrated an increased recurrence rate in the RF arm. There are obvious limitations to this trial (lack of central pathology review, stopping maintenance at 1 year) but the trial did factor in BCG shortages and 90% of patients had a re-TUR. Despite data in animal models, current SF BCG protocols result in lower recurrence rates and should remain the standard of care. This trial does not address the common practice of maintaining standard frequency BCG administration but with reduced dosing (e.g. one-half to one-third dose) for maintenance instillations.
Results:
As of November 2021, 359 patients were randomized with 177 to the RF arm and 182 to the SF arm. Majority of tumors were T1 and concomitant CIS seen in 28% of the RF arm and 29% of the SF arm. After fourteen months of median follow-up for all patients, ITT analysis demonstrated disease recurrence in 85 (24%) of the 359 patients: 55 (31%) of the 177 RF patients and 30 (16%) of the 182 SF patients. Univariate Cox regression demonstrated a HR of 0.47 (95% CI: 0.30-0.74) for first recurrence favoring the SF arm. The trial closed early due to inferiority of the RF arm. Interestingly, seven patients progressed to muscle invasive bladder cancer with one in the RF arm and six in the SF arm.
