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

Phase 2

Completed

Conditions: Bladder Cancer

Interventions: Drug: Gemcitabine
Drug: Carboplatin
Drug: Sorafenib

Registration Number: NCT00461851

Lead Sponsor: Yale University

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 17

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Chemotherapy plus sorafenib	Sorafenib	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
Chemotherapy plus sorafenib	Carboplatin	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
Chemotherapy plus sorafenib	Gemcitabine	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

Primary Outcome Measures

Name	Time	Method
Progression Free Survival (PFS)	Upon completion of study	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.

Secondary Outcome Measures

Name	Time	Method
Dose Ruction (Toxicity)	Upon completion of study	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.
Best Reported Response	Upon completion of study	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.