This phase III trial compares the effect of adding gemcitabine to intravesical Bacillus Calmette Guerin (BCG) versus intravesical BCG alone in patients with non-muscle invasive bladder cancer that has come back after a period of improvement (recurrent). Gemcitabine is a chemotherapy drug that blocks the cells from making deoxyribonucleic acid (DNA) and may kill cancer cells. Intravesical BCG is a solution containing the live BCG bacteria that is placed in the bladder via a catheter (intravesical). When the solution comes into direct contact with the bladder wall, it stimulates the body's immune system which kills tumor cells. Giving gemcitabine with intravesical BCG may kill more tumor cells in patients with recurrent non-muscle invasive bladder cancer.
Documentation of Disease: Histologic confirmation of urothelial carcinoma that is high grade Ta, high grade T1, or Tis (Tis/carcinoma in situ [CIS] only disease) within 120 days prior to randomization
Any component of neuroendocrine carcinoma (i.e., small cell or large cell) is not allowed. Other histologic subtypes/variant histologies are allowed so long as there is a predominantly urothelial component.
All visible papillary lesions must be macroscopically resected by TURBT within 90 days of randomization. (Residual CIS is permitted).
All patients with high grade T1 must undergo a restaging TURBT within 90 days of randomization. Patients who undergo a restaging TURBT that shows no residual cancer in the specimen are still eligible for trial based on prior TURBT
None
Parallel
BCG Solution
Biological/VaccineGiven intravesically
Biopsy of Bladder
Procedure/SurgeryUndergo bladder biopsy
Cystoscopy
Procedure/SurgeryUndergo cystoscopy
Computed Tomography
Procedure/SurgeryUndergo CT Scan
Magnetic Resonance Imaging
Procedure/SurgeryUndergo MRI
Biospecimen Collection
Procedure/SurgeryUndergo blood and urine sample collection
Transurethral Resection of Bladder Tumor
Procedure/SurgeryUndergo TURBT
Gemcitabine
DrugGiven intravesically
High Grade Recurrence-free survival (HG-RFS)
HG-RFS will be calculated from randomization until the detection of a high-grade bladder cancer recurrence (biopsy proven intravesical recurrence or distant metastasis), cystectomy, or death, whichever occurs first. Patients who are alive and without documented high-grade recurrence will be censored at the time of last disease evaluation. HG-RFS will be compared between the two study arms using a stratified log-rank test. The treatment effect will be estimated with a hazard ratio (HR) and corresponding 95% confidence interval obtained from a stratified Cox model with treatment group (
High-grade cancer free at 3 months
A patient will be classified as being cancer free if no high-grade bladder cancer is detected upon a cystoscopic biopsy (± transurethral resection of bladder tumor \[TURBT\]). This will be calculated as the number of patients who underwent cystoscopic biopsy with or without TURBT at 3 months and no high-grade cancer was detected, divided by the total number of patients.
6-month Complete Response
Complete response rate will be determined among patients who had carcinoma in situ (CIS) at baseline. Patients will be classified as having a complete response at 6 months if there is no biopsy-proven high grade bladder cancer detected based on a cystoscopy and urinary cytology (± biopsy/TURBT). This will be calculated as the number of patients who had CIS at baseline and who had no evidence of disease at 6-months, divided by the total number of patients who had CIS at baseline. The proportion of patients who remain with a complete response will be compared between the two arms with a chi-square test or Fisher's exact test.
Durability of Response
o Durability of the response will be determined only in the patients who had CIS at baseline and had a complete response at 6 months. This will be measured as time from the 6-month evaluation until documented disease recurrence, censoring patients without disease recurrence at time of death or at last disease evaluation, whichever is last. The durability of response will be compared between the two treatment groups using a log-rank test, and Kaplan-Meier estimators will be used to determine the median durability.
Recurrence-free survival
Recurrence-free survival will be calculated as the time from randomization until the detection of any grade bladder cancer, censoring those without documented disease recurrence at time of last disease evaluation or death, whichever occurs last. This will be compared between the two treatment arms using a stratified log-rank test. An estimate of the outcome differences between the arms will be made with a HR and 95% confidence interval generated by a stratified Cox model.
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Alliance for Clinical Trials in Oncology
Lead sponsor
National Cancer Institute (NCI)
Collaborator
