- Compare the overall survival of patients with advanced transitional cell carcinoma of the urinary tract treated with gemcitabine hydrochloride, cisplatin, and bevacizumab vs gemcitabine hydrochloride, cisplatin, and placebo.
- Compare the progression-free survival of patients treated with these regimens.
- Compare the objective response rate in patients treated with these regimens.
- Compare the grade 3 and greater toxicities of these regimens in these patients.
OUTLINE: This is a multicenter study. Patients are stratified according to presence of visceral (lung, liver, bone, splenic, or intra-abdominal) metastases (no vs yes) and prior chemotherapy (including adjuvant therapy, neoadjuvant therapy, and single-agent radiosensitizers) (no vs yes). Patients are randomized to 1 of 2 treatment arms.
- Arm I: Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and cisplatin IV over 1 hour and placebo IV over 30-90 minutes on day 1. Treatment repeats every 21 days for 6 courses 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 courses 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 therapy, patients are followed up periodically for up to 7 years.
- Histologically or cytologically confirmed transitional (urothelial) cell carcinoma of the urinary tract (renal pelvis, ureter, bladder, prostate, or urethra)
- Unresectable or progressive metastatic or locally advanced disease (T4b, N2, N3 or M1)
- Not a candidate for potentially curative surgery or radiotherapy
- No history of peritoneal carcinomatosis
- No known brain metastases
- ECOG performance status (PS) 0-1 OR Karnofsky PS 80-100%
- ANC ≥ 1,500/mm^3
- Platelet count ≥ 100,000/mm^3
- Bilirubin ≤ 1.25 times upper limit of normal (ULN) (≤ 2.5 times ULN for patient's with Gilbert's disease)
- AST ≤ 2.0 times ULN
- Creatinine clearance ≥ 50 mL/min
- Urine protein:creatinine ratio < 1.0 OR urine protein ≤ 1+ OR 24-hour urine protein ≤ 1 gram
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception during and for up to 3 months after completion of study treatment
- No NYHA class II-IV congestive heart failure
- History of hypertension allowed provided it is well controlled (i.e., BP < 150/90 mm Hg) on a regimen of anti-hypertensive therapy
- No arterial thrombotic events within the past 6 months, including any of the following:
- Transient ischemic attack
- Cerebrovascular accident
- Peripheral arterial thrombus
- Unstable angina or angina requiring surgical or medical intervention
- Myocardial infarction
- No clinically significant peripheral artery disease (i.e., claudication on < one block)
- Deep venous thrombosis or pulmonary embolus within the past 6 months allowed provided patient is on stable therapeutic anticoagulation
- No significant bleeding events (e.g., hemoptysis, upper or lower gastrointestinal [GI] bleeding, or grade 3 or 4 gross hematuria uncontrolled by transurethral resection of the bladder tumor) within the past 6 months
- No GI perforation within the past 12 months
- No serious or non-healing wound, ulcer, or bone fracture
- No sensory or motor peripheral neuropathy ≥ grade 2
- No known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
PRIOR CONCURRENT THERAPY:
- At least 4 weeks since prior radiotherapy (including palliative radiotherapy) or major surgery and recovered
- At least 4 weeks since prior intravesical therapy
- At least 7 days since any minor surgery such as port placement
- No prior combination systemic chemotherapy for metastatic disease
- Single-agent radiosensitizing chemotherapy is not considered prior systemic therapy
- Prior neoadjuvant or adjuvant systemic chemotherapy allowed provided it was completed ≥ 1 year prior to the diagnosis of metastatic disease
- No prior bevacizumab or other angiogenesis inhibitors
- No concurrent radiotherapy (including palliative radiotherapy)
- Concurrent full-dose anticoagulants allowed provided patient is on a stable dose of warfarin and has an in-range INR (between 2 and 3) OR is on a stable dose of low molecular weight heparin
- Concurrent anti-platelet agents, daily prophylactic aspirin, or anticoagulation agents for atrial fibrillation allowed
Last updated: 03/26/2012
NCT ID: NCT00942331