CALGB 90601: A Randomized, Double-blinded Phase III Study Comparing Gemcitabine, Cisplatin, and Bevacizumab to Gemcitabine, Cisplatin and Placebo in Patients with Advanced Transitional Cell Carcinoma


Patients will be randomized in a 1:1 allocation ratio between gemcitabine, cisplatin, and bevacizumab and gemcitabine, cisplatin, and placebo. in the absence of unacceptable toxicity or progression, patients will receive a maximum of 6 cycles of chemotherapy. if patients do not have disease progression after six cycles, then
patients will continue on bevacizumab/placebo until disease progression or until patients experience unacceptable toxicity. Study participants will remain blinded at progression with no crossover permitted.

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 or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. others find tumor cells and help kill them or carry tumor-killing substances to them. it is not yet known whether gemcitabine hydrochloride and cisplatin are more effective when given together with or without bevacizumab in treating patients with urinary tract cancer.

This randomized phase iii study will compare standard gemcitabine/cisplatin (GC) chemotherapy to gemcitabine/cisplatin/bevacizumab (GCB) chemotherapy with overall survival as the primary endpoint. This study will have early stopping rules for futility of the experimental arm to ensure that excessive numbers of patients are not exposed to an obviously inferior regimen. in addition, real-time toxicity monitoring with monthly conference calls will be incorporated into the protocol to monitor for excess toxicity in the GCB arm.

Progression free survival is a secondary endpoint of this study. a non-biased assessment of this endpoint necessitates that this trial be a placebo-controlled, double-blinded study. Previous randomized clinical trials of advanced TCC have treated patients for a maximum of six chemotherapy cycles. Therefore, this trial will allow administration of up to six cycles of chemotherapy. Bevacizumab/placebo as maintenance therapy may be administered until progression.

There is increasing evidence suggesting that germline polymorphisms related to anticancer drug metabolism, transport, and resistance correlate with drug response. Furthermore, germline polymorphisms related to therapeutic targets and/or therapeutic pathways might also help predict therapeutic outcome. assays for genetic variants will be performed for VeGF (Bevacizumab) and CDa, DCK, DCTD,SLC29a1, SLC28a1, SLC29a2 (gemcitabine) and GST P1, GST M1, XRCC1 (cisplatin). These candidate genes have been chosen based on their potential influence on
activation, degradation, transport disposition or cytotoxicity of gemcitabine, cisplatin, and bevacizumab. additional genes or variants of interest might also be explored as new information relevant to the study emerges. The primary hypothesis of the pharmacogenomic substudy is that patients with the VeGF CC genotype will receive significantly greater benefit (oS, PFS) from anti-VeGF therapy.

Participant Eligibility

1. 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 metastatic or locally advanced disease (T4b, N2, N3, or M1). Patients must not be candidates for potentially curative surgery or radiotherapy.
2. Prior Treatment:

* For the purposes of this study, radio-sensitizing 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
3. No known brain metastases, Brain imaging (MRI/CT) is not required.
4. No current congestive heart failure: New York Heart Association Class II, III or IV.
5. Patients with history of hypertension must be well controlled (< 150/90) on a regimen of anti- hypertensive therapy.
6. 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.
7. No significant history of bleeding events or GI perforation.
8. 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 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.
9. No serious or non-healing wound, ulcer or bone fracture.
10. No sensory or motor peripheral neuropathy >= grade 2.
11. 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.
13. ECOG performance status 0-1 (or KPS >= 80)
14. Age >= 18.
15. Required Initial Laboratory Values (other tests are required; see Protocol Section 6.0):
Platelet count >= 100,000/[MICRO-SYMBOL]L
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 Protocol Appendix III for information regarding the calculation of UPC ratio.
** For patients with Gilbert's Disease, <= 2.5 X ULN is allowed.
*** Modified Cockroft and Gault formula; see below
Modified Cockcroft and Gault Formula for Estimated Creatinine Clearance (CLcr)
For Serum Creatinine Concentration (Sr Cr) in mg/dL:
Clcr (mL/min) = (140 – age (yrs)) (actual weight (kg)) / (72) (Sr Cr)
For females, use 85% of calculated Clcr value