A Phase II, Multicenter Trial of Gemcitabine, Carboplatin, and Sorafenib in Chemotherapy-naive Patients With Advanced/Metastatic Bladder Carcinoma

Inclusion Criteria:

- Histologic documentation of diagnosis of transitional cell carcinoma of the bladder,
urethra, ureter, or renal pelvis

- Unresectable, locally advanced or metastatic disease

- CrCl ≥ 60 ml/min or serum creatinine < 1.5

- ≥ 4 weeks since prior RT

- ECOG Performance Status of 0 or 1 (Appendix I)

- Age ≥ 18 years of age

- Women of childbearing potential and men must agree to use adequate contraception
(barrier method of birth control) prior to study entry and for the duration of study
participation. Men and women should use adequate birth control for at least 2 weeks
after the last administration of sorafenib.

- Women of childbearing potential must have a negative serum pregnancy test performed
within 7 days prior to the start of treatment

- Ability to understand and the willingness to sign a written informed consent. A
signed informed consent must be obtained prior to any study specific procedures.

- Adequate bone marrow, liver and renal function as assessed by the following:

- Hemoglobin > 9.0 g/dl

- Absolute neutrophil count (ANC) ≥ 1,500/mm3

- Platelet count ≥ 100,000/mm3

- Total bilirubin ≤ 1.5 times ULN

- ALT and AST ≤ 2.5 times the ULN ( ≤ 5 x ULN for patients with liver involvement)

- INR < 1.5 or a PT/PTT within normal limits. Patients receiving anti-coagulation
treatment with an agent such as warfarin or heparin may be allowed to participate.
For patients on warfarin, the INR should be measured prior to initiation of sorafenib
and monitored at least weekly, or as defined by the local standard of care, until INR
is stable.

Exclusion Criteria:

- Prior treatment with systemic chemotherapy (prior intravesical chemotherapy is
permitted, and adjuvant therapy is permitted if > 12 months have lapsed)

- Current, recent (within 4 weeks of the first infusion of this study), or planned
participation in an experimental drug study

- Cardiac disease: Congestive heart failure > class II NYHA. Patients must not have
unstable angina (anginal symptoms at rest) or new onset angina (began within the last
3 months) or myocardial infarction within the past 6 months.

- History of stroke within six months

- Clinically significant peripheral vascular disease

- Known brain metastasis. Patients with neurological symptoms must undergo a CT
scan/MRI of the brain to exclude brain metastasis.

- Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.

- Uncontrolled hypertension defined as systolic blood pressure > 150 mmHg or diastolic
pressure > 90 mmHg, despite optimal medical management.

- Sorafenib is contraindicated in patients with known severe hypersensitivity to
sorafenib or any of the excipients.

- Known human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C.

- Active clinically serious infection > CTCAE Grade 2.

- Thrombolytic or embolic events such as a cerebrovascular accident including transient
ischemic attacks within the past 6 months

- Pulmonary hemorrhage/bleeding event ≥ CTCAE Grade 2 within 4 weeks of first dose of
study drug

- Any other hemorrhage/bleeding event ≥ CTCAE Grade 3 within 4 weeks of first dose of
study drug

- Evidence or history of bleeding diathesis or coagulopathy

- Major surgery, significant traumatic injury within 4 weeks of first study drug

- Use of St. John's Wort or rifampin (rifampicin)

- Known or suspected allergy to sorafenib or any agent given in the course of this
trial

- Any condition that impairs patient's ability to swallow whole pills

- Any malabsorption problem

- Anticipation of need for major surgical procedure during the course of the study

- Pregnant (positive pregnancy test) or lactating

- History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within 6 months prior to Day 0

- Serious, non-healing wound, ulcer, or bone fracture

- Inability to comply with study and/or follow-up procedures

- History of persistent gross hematuria