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

Study Overview
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Brief Summary
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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.

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

Conditions
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Bladder Cancer

Intervention / Treatment
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* Drug: Gemcitabine
* Drug: Carboplatin
* Drug: Sorafenib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Chemotherapy plus sorafenib<br>Gemcitabine 1000 mg/m2 weekly x 2 weeks plus carboplatin AUC (Area under curve) 5 every 3 weeks plus sorafenib x 6 cycles then maintenance sorafenib alone | Drug: Gemcitabine<br>* Gemcitabine will be given at a standard dose schedule of 1000 mg/m² on day 1 and 8.<br>* Other names: Gemzar;Drug: Carboplatin<br>* Carboplatin will be given on day 1 to an AUC of 5.<br>Drug: Sorafenib<br>* Sorafenib will be administered orally daily on days 2-19 at 400 mg bid<br>* Other names: BAY 43-9006;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | The primary outcome was the proportion of patients who achieved progression free survival (PFS) of five months. PFS was defined as time to progression or any-cause mortality, whichever came first. | Upon completion of study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Ruction (Toxicity) | To determine the toxicity of combination therapy with sorafenib, gemcitabine and carboplatin, dose reductions by drug are reported. The number of patients that were reduced in dosage are reported here. | Upon completion of study | 
| Best Reported Response | The best reported response captures 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. | Upon completion of study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced/Metastatic Bladder Carcinoma