Gemcitabine Hydrochloride and Cisplatin With or Without Bevacizumab in Treating Patients With Advanced Urinary Tract Cancer

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Randomized Double-Blinded Phase III Study Comparing Gemcitabine, Cisplatin, and Bevacizumab to Gemcitabine, Cisplatin, and Placebo in Patients With Advanced Transitional Cell Carcinoma

Conditions
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Advanced Urothelial Carcinoma, Metastatic Bladder Urothelial Carcinoma, Metastatic Prostate Carcinoma, Metastatic Renal Pelvis Urothelial Carcinoma, Metastatic Ureter Urothelial Carcinoma, Metastatic Urethral Urothelial Carcinoma, Metastatic Urothelial Carcinoma, Stage IV Bladder Urothelial Carcinoma AJCC v7, Stage IV Prostate Cancer AJCC v7, Stage IV Renal Pelvis Cancer AJCC v7, Stage IV Ureter Cancer AJCC v7, Stage IV Urethral Cancer AJCC v7, Unresectable Urothelial Carcinoma

Intervention / Treatment
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* Biological: Bevacizumab
* Drug: Cisplatin
* Drug: Gemcitabine Hydrochloride
* Other: Laboratory Biomarker Analysis
* Other: Placebo Administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically or cytologically documented metastatic or unresectable transitional cell (urothelial) carcinoma of the urinary tract (renal pelvis, ureter, bladder, prostate, or urethra), with metastatic or locally advanced disease (T4b, N2, N3, or M1); patients must not be candidates for potentially curative surgery or radiotherapy For patients that have had surgical resection prior to study enrollment, residual or unresected disease (measurable and/or unmeasurable) must be evident on post-surgical scans Prior treatment for transitional cell carcinoma (TCC) Patients may not have received combination systemic chemotherapy for metastatic disease For the purposes of this study, radiosensitizing single agent chemotherapy is not considered prior systemic therapy Prior neoadjuvant or adjuvant systemic chemotherapy is permissible provided the interval from end of therapy to diagnosis of metastatic disease is at least 1 year >= 4 weeks since any prior radiation (including palliative) or major surgery and fully recovered >= 7 days since any minor surgery such as port placement >= 4 weeks since any intravesical therapy No prior treatment with bevacizumab or other angiogenesis inhibitors No known history of brain metastases; brain imaging (magnetic resonance imaging [MRI]/computed tomography [CT]) is not required No current congestive heart failure; New York Heart Association (NYHA) class II, III or IV Patients with history of hypertension must be well controlled (< 150/90) on a regimen of anti-hypertensive therapy Patients on full-dose anticoagulants must be on a stable dose of warfarin and have an in-range international normalized ratio (INR) (usually between 2 and 3) or be on a stable dose of low molecular weight (LMW) heparin; patients receiving anti-platelet agents are also eligible; in addition, patients who are on daily prophylactic aspirin or anticoagulation for atrial fibrillation are eligible No significant history of bleeding events or gastrointestinal (GI) perforation Patients with a history of a significant bleeding episode (e.g. hemoptysis, upper or lower GI bleeding, grade 3 or 4 gross hematuria unable to be controlled by trans-urethral resection of the bladder tumor) within 6 months of registration are not eligible Patients with a history of GI perforation within 12 months of registration are not eligible Patients with a history of peritoneal carcinomatosis are not eligible No arterial thrombotic events within 6 months of registration, including transient ischemic attack (TIA), cerebrovascular accident (CVA), peripheral arterial thrombus, unstable angina or angina requiring surgical or medical intervention in the past 6 months, or myocardial infarction (MI); patients with clinically significant peripheral artery disease (i.e., claudication on less than one block) are ineligible Patients who have experienced a deep venous thrombosis or pulmonary embolus within the past 6 months must be on stable therapeutic anticoagulation to be enrolled to this study No serious or non-healing wound, ulcer, or bone fracture No sensory or motor peripheral neuropathy >= grade 2 Patients with known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies are not eligible Patients that are pregnant or nursing are not eligible; women of child bearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 72 hours prior to registration For women of child-bearing potential with an elevated beta-HCG that is believed to be related to cancer and not pregnancy, a negative trans-vaginal ultrasound and gynecological examination are required Women of child-bearing potential include any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal [defined as amenorrhea >= 12 consecutive months; or women on hormone replacement therapy [HRT] with documented serum follicle stimulating hormone [FSH] level > 35 mIU/mL); even women who are using oral, implanted or injectable contraceptive hormones or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy or practicing abstinence or where partner is sterile (e.g., vasectomy), should be considered to be of child bearing potential Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (or Karnofsky performance status [KPS] >= 80) Absolute neutrophil count (ANC) >= 1,500/uL Platelet count >= 100,000/uL Calculated or measured creatinine clearance >= 50 mL/minute Bilirubin =< 1.25 times upper limits of normal; for patients with Gilbert's disease, =< 2.5 x upper limit of normal (ULN) is allowed Aspartate aminotransferase (AST) =< 2.0 x upper limits of normal Urine protein to creatinine ratio < 1.0 or urine protein =< 1+ or 24-hour urine protein =< 1 gram

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm I (gemcitabine hydrochloride, cisplatin, placebo)<br>Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and 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. | Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Drug: Gemcitabine Hydrochloride<br>* Given IV<br>* Other names: LY188011;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Placebo Administration<br>* Given IV<br>|
| Experimental: Arm II (gemcitabine hydrochloride, cisplatin, bevacizumab)<br>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. | Biological: Bevacizumab<br>* Given IV<br>* Other names: Zirabev;Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Drug: Gemcitabine Hydrochloride<br>* Given IV<br>* Other names: LY188011;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From date of randomization to date of death due to any cause, assessed up to 7 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | Up to 7 years |