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