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

• To determine the overall safety and tolerability of combination therapy with sorafenib, gemcitabine and carboplatin [ Time Frame: Upon completion of study ] [ Designated as safety issue: Yes ]
• To define the proportion of patients with advanced or metastatic transitional cell carcinoma of the bladder that achieve a complete or partial response to the combination therapy with sorafenib, gemcitabine, and carboplatin. [ Time Frame: Upon completion of study ] [ Designated as safety issue: No ]

• To determine the overall safety and tolerability of combination therapy with sorafenib, gemcitabine and carboplatin
• To define the proportion of patients with advanced or metastatic transitional cell carcinoma of the bladder that achieve a complete or partial response to the combination therapy with sorafenib, gemcitabine, and carboplatin.

This is a Phase II, nonrandomized multicenter study designed to evaluate time to progression and response proportion of patients with advanced or metastatic transitional cell carcinoma of bladder receiving 6 cycles of gemcitabine, carboplatin and sorafenib and then maintenance sorafenib.

• Drug: Gemcitabine
  Gemcitabine will be given at a standard dose schedule of 1000 mg/m² on day 1 and 8.
  Other Name: Gemzar
• Drug: Carboplatin
  Carboplatin will be given on day 1 to an AUC of 5.
• Drug: Sorafenib
  Sorafenib will be administered orally daily on days 2-19 at 400 mg bid
  Other Name: BAY 43-9006

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