Gemcitabine Hydrochloride and Cisplatin With or Without Bevacizumab in Treating Patients With Advanced 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.

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