Title A Randomized Double-Blinded Phase III Study Comparing Gemcitabine, Cisplatin, and Bevacizumab to Gemcitabine, Cisplatin, and Placebo in Patients with Advanced Transitional Cell Carcinoma
IRB CALGB 90601
Hospital Beachwood, Fairview, Hillcrest, Independence, Main Campus, North Coast Cancer, Strongsville, Wooster
Phase Phase 3
Drug Bevacizumab , Cisplatin, Gemcitabine
- To determine if patients with advanced transitional cell carcinoma treated with bevacizumab, gemcitabine, and cisplatin will have increased overall survival when compared to patients treated with gemcitabine, cisplatin, and placebo.
- To compare the progression-free survival of these two regimens in patients with advanced transitional cell carcinoma.
- To compare the proportion of patients who experience an objective response on each regimen.
- To compare the grade 3 and greater toxicities in patients treated on the two regimens.
- Histologic Documentation and Stage: 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 progressive metastatic or locally advanced disease (T4b, N2, N3, or M1). Patients must not be candidates for potentially curative surgery or radiotherapy.
- Prior Treatment:
- 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 brain metastases: Brain imaging (MRI/CT) is not required.
- No current congestive heart failure: New York Heart Association 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 INR (usually between 2 and 3) or be on a stable dose of 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 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 transurethral 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 arterialthrombus, 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 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 HCG) within 72 hours prior to registration. This is because DNA alkylating agents are known to be teratogenic, and the effects of gemcitabine, cisplatin, and bevacizumab on a developing fetus at the recommended therapeutic doses are unknown.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 > 35mIU/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.
- Patients with known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies are not eligible.
- ECOG performance status 0-1 (or KPS ≥ 80)
- Age ≥ 18.
- Required Initial Laboratory Values (other tests are required; see Section 6.0):
- ANC ≥ 1500/μL
- Platelet count ≥ 100,000/μL
- Calculated or measured creatinine clearance ≥ 50 mL/minute
- Bilirubin ≤ 1.25 x upper limits of normal**
- 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
* See Appendix III for information regarding the calculation of UPC ratio.
** For patients with Gilbert’s Disease, ≤ 2.5 X ULN is allowed.
Modified Cockcroft and Gault Formula for Estimated Creatinine Clearance (CLcr)For Serum Creatinine Concentration (Sr Cr) in mg/dL:
Clcr (mL/min) = (140 - age) (actual weight)a / (72) (Sr Cr)
a Age in years and weight in kilograms
For females, use 85% of calculated Clcr value