This randomized phase III trial studies gemcitabine hydrochloride, cisplatin, and bevacizumab to see how well they work compared with gemcitabine hydrochloride and cisplatin in treating patients with urinary tract cancer that has spread to other places in the body. Drugs used in chemotherapy, such as gemcitabine hydrochloride and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with bevacizumab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. It is not yet known whether gemcitabine hydrochloride and cisplatin are more effective when given with or without bevacizumab in treating patients with urinary tract cancer.
PRIMARY OBJECTIVES: I. To determine if patients with advanced transitional cell carcinoma treated with bevacizumab, gemcitabine hydrochloride (gemcitabine) and cisplatin will have increased overall survival when compared to patients treated with gemcitabine, cisplatin, and placebo. SECONDARY OBJECTIVES: I. To compare the progression-free survival of these two regimens in patients with advanced transitional cell carcinoma. II. To compare the proportion of patients who experience an objective response on each regimen. III. To compare the grade 3 and greater toxicities in patients treated on the two regimens. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive gemcitabine hydrochloride intravenously (IV) over 30 minutes on days 1 and 8, cisplatin IV, and placebo IV over 30-90 minutes on day 1. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive placebo IV over 30-90 minutes every 21 days in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive gemcitabine hydrochloride and cisplatin as in arm I. Patients also receive bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive bevacizumab IV over 30-90 minutes every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up periodically for up to 7 years.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
506
University of Alabama at Birmingham Cancer Center
Birmingham, Alabama, United States
Providence Hospital
Mobile, Alabama, United States
Fairbanks Memorial Hospital
Fairbanks, Alaska, United States
University of Arizona Cancer Center-Orange Grove Campus
Tucson, Arizona, United States
Banner University Medical Center - Tucson
Tucson, Arizona, United States
Overall Survival (OS)
Overall survival time is defined as the time from randomization to death due to any cause. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator.The stratified log-rank statistic will be the primary analysis to compare the two treatment arms on OS with the stratification factors: presence of visceral metastases (no, yes) and prior chemotherapy (no, yes). In addition, the proportional hazards model will be used to assess the importance of the treatment arm adjusting on patient characteristics, stratification variables and other important covariates in predicting OS.
Time frame: From date of randomization to date of death due to any cause, assessed up to 7 years
Progression-free Survival (PFS)
The primary analysis of PFS will be a two-sided stratified log-rank test comparing arm A and arm B. The stratification factors will consist of the two stratification factors used for patient randomization: prior nephrectomy (yes vs. no) and Motzer score (0 vs. 1-2 vs. 3+). Results from unstratified log-rank tests will also be provided. Kaplan-Meier methodology will be used to estimate median PFS for each treatment arm.
Time frame: From the date of randomization to date of progression or death due to any cause, whichever occurs first, assessed up to 7 years
Objective Response
Objective response is defined as confirmed complete and partial responses using Response Evaluation Criteria in Solid Tumors criteria. A complete response (CR) is defined as a disappearance of all target lesions. A partial response (PR) is defined as having at least a 30% decrease in the sum of the longest diameter of target lesions taking as reference the baseline sum. In each arm, the number of patients reporting a CR or PR was divided by the number of patients evaluable in each arm to obtain the proportion.
Time frame: Up to 7 years
Number of Patients Experiencing Grade 3+ Toxicity
The number of patients experiencing grade 3 or higher toxicity (adverse events considered at least possibly related to treatment) is reported below.
Time frame: Up to 7 years
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University of Arizona Cancer Center-North Campus
Tucson, Arizona, United States
Baptist Memorial Hospital and Fowler Family Cancer Center - Jonesboro
Jonesboro, Arkansas, United States
John L McClellan Memorial Veterans Hospital
Little Rock, Arkansas, United States
University of Arkansas for Medical Sciences
Little Rock, Arkansas, United States
Alta Bates Summit Medical Center-Herrick Campus
Berkeley, California, United States
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