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.
PRIMARY OBJECTIVE: I. To compare high-grade recurrence-free-survival between treated with gemcitabine with BCG (GemBCG) compared to those treated with BCG alone. SECONDARY OBJECTIVES: I. To compare the proportion of patients who remain high grade cancer free on initial post-treatment cystoscopic biopsies/transurethral resection of bladder tumor (TURBT) (week 13/month 3) between those treated with GemBCG compared to those treated with BCG alone. II. To compare the 6-month (Week 25) complete response rate and the complete response durability between patients treated with GemBCG compared to those treated with BCG alone among patients with pre-treatment CIS. III. To compare the time to recurrence of any-grade bladder cancer between patients treated with GemBCG compared those treated with BCG alone. IV. To compare the progression-free-survival between patients treated with GemBCG compared to those treated with BCG alone. V. To compare the cystectomy-free-survival between patients treated with GemBCG compared to those treated with BCG alone. VI. To compare the proportion of patients free from BCG-unresponsive NMIBC between those treated with GemBCG compared to those treated with BCG alone. VII. To determine the safety of and toxicity associated with GemBCG treatment relative to that of BCG treatment alone. EXPLORATORY OBJECTIVE: I. To collect tumor tissue/bladder biopsies, blood, and urine samples for biobanking that will enable future correlative studies. OUTLINE: Patients are randomized to 1 of 2 arms. ARM A: Patients receive BCG intravesically over 2 hours once per week (QW) for 6 weeks. 2-6 weeks after completing endoscopic assessment, patients receive BCG over 2 hours QW for 3 weeks at month 3, 6 and 12 in the absence of disease progression or unacceptable toxicity. Patients undergo bladder biopsy, TURBT, cystoscopy, computed tomography (CT) scan/ magnetic resonance imaging (MRI) and blood and urine sample collection throughout the study. ARM B: Patients receive gemcitabe intravesically over 1 hour twice weekly on weeks 1 and 10 and once weekly on weeks 4 and 7. Patients also receive BCG intravesically over 2 hours QW on weeks 2, 3, 6, 8 and 9. 2-6 weeks after completing endoscopic assessment, patients receive gemcitable intravesically over 1 hour on week 1 and BCG intravesically over 2 hours on week 2-4 at month 3, 6 and 12 in the absence of disease progression or unacceptable toxicity. Patients undergo bladder biopsy, TURBT, cystoscopy, CT scan/MRI and blood and urine sample collection throughout the study. After completion of study treatment, patients are followed every 3 months for 2 years, then every 6 months for 3 years up to 5 years from randomization.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
330
Given intravesically
Undergo bladder biopsy
Undergo cystoscopy
Undergo CT Scan
Undergo MRI
Undergo blood and urine sample collection
Undergo TURBT
Given intravesically
University of Alabama at Birmingham Cancer Center
Birmingham, Alabama, United States
RECRUITINGBanner MD Anderson Cancer Center
Gilbert, Arizona, United States
RECRUITINGMayo Clinic Hospital in Arizona
Phoenix, Arizona, United States
RECRUITINGUCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care
Irvine, California, United States
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 (
Time frame: Up to 5 years
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.
Time frame: at 3 months
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.
Time frame: At 6 months
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.
Time frame: Up to 5 years
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.
Time frame: Up to 5 years
Progression-free survival
Progression-free survival will be calculated as the time from randomization until disease progression, defined as development of muscle invasive disease (stage greater than or equal to T2), lymph node or distant metastasis, or death without documented disease progression. 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.
Time frame: up to 5 years
Cystectomy-free survival
Cystectomy-free survival will be defined as the time from randomization until the patient undergoes a cystectomy, censoring patients without a cystectomy at last follow-up or death, whichever is 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 generated by a stratified Cox model.
Time frame: up to 5 years
• Bacille Calmette Guerin (BCG)-unresponsive non muscle invasive bladder cancer free survival
BCG unresponsive NMIBC free survival will be defined as time from randomization until the patient develops BCG unresponsive NMIBC, defined as persistent or recurrent high-grade papillary NMIBC (Ta/T1) \<6 months of "adequate" BCG (≥5 of 6 plus an additional ≥2 doses of BCG) or CIS (with or without Ta/T1 papillary disease) recurrence \<12 months of "adequate" BCG (≥5 of 6 plus an additional ≥2 doses of BCG) or High Grade T1 at week 13 (month 3) assessment. Patients who do not develop BCG-unresponsive NMIBC will be censored at the time of their last follow-up or death, whichever is 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.
Time frame: up to 5 years
Rate of Grade 3+ Adverse Events
o Adverse events will be collected and graded according to the NCI Common Terminology Criteria for Adverse Events version 5.0. The number (percent) of patients that experience each grade 3+ adverse event will be summarized by treatment arm. In addition, the number (percent) of patients that experience a grade 3+, grade 4+, and grade 5 adverse event will be summarized by treatment arm.
Time frame: Up to 5 years
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UC Irvine Health/Chao Family Comprehensive Cancer Center
Orange, California, United States
RECRUITINGSibley Memorial Hospital
Washington D.C., District of Columbia, United States
RECRUITINGUF Health Cancer Institute - Gainesville
Gainesville, Florida, United States
RECRUITINGMayo Clinic in Florida
Jacksonville, Florida, United States
RECRUITINGKootenai Health - Coeur d'Alene
Coeur d'Alene, Idaho, United States
RECRUITINGKootenai Clinic Cancer Services - Post Falls
Post Falls, Idaho, United States
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