Trial Information

Summary: First or Second Line Metastatic Breast Cancer with previous Avastin therapy

This is a multi-center, double-blind, placebo controlled study in patients with locally advanced or metastatic breast cancer that has progressed during or following treatment with bevacizumab (Avastin).

The primary objective is to compare progression-free survival (PFS) in patients treated with sorafenib and gemcitabine versus patients treated with placebo and gemcitabine for locally advanced or metastatic breast cancer that has progressed during or following treatment with a bevacizumab-containing regimen.

Subjects will receive gemcitabine weekly for 2 weeks (followed by a week of rest) in combination with sorafenib or placebo (twice a day, everyday) until it is determined that the cancer is not responding to the treatment.

Approximately 220 patients will participate in the study.

Study inclusion criteria:

• Histologically or cytologically confirmed adenocarcinoma of the breast.
• Measurable or evaluable locally advanced or metastatic disease. (Locally advanced disease must not be amenable to resection with curative intent.) All scans used to document measurable or evaluable disease must be done within 4 weeks prior to randomization.
• Age =18 years (the safety and effectiveness of sorafenib in patients less than 18 years of age have not been studied).
• Patients must have experienced disease progression during or after treatment with a bevacizumab-containing regimen in the adjuvant or first-line metastatic setting.
• Patients must have discontinued chemotherapy at least 3 weeks prior to randomization.
• No more than one prior chemotherapy regimen for locally advanced or metastatic disease.
• Prior hormonal therapy for locally advanced or metastatic disease is allowed but this must have been discontinued prior to randomization.
• Prior radiation therapy is allowed but must be completed at least 3 weeks prior to randomization. Previously radiated area(s) must not be the only site of disease.
• ECOG Performance Status of 0 or 1
• 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 the upper limit of normal
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =2.5 x upper limit of normal (=3 x ULN for patients with liver involvement)
  • International Normalized Ratio for Prothrombin Time (PT-INR) =1.5 and activated partial prothrombin time (aPTT) 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/placebo and monitored at least weekly, or as defined by the local standard of care, until INR is stable
  • Creatinine =1.5 times ULN.
• Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to randomization, and must agree to use adequate contraception (barrier method of birth control) prior to study entry, for the duration of study participation and 28 days after the last study drug dosing.
• Patients must be able and willing to sign a written informed consent. A signed informed consent must be appropriately obtained prior to any study specific procedures.
• Patients must be able to swallow and retain oral medication.

Exclusion criteria for the study include:

• Patients with breast cancer over-expressing human epidermal growth factor receptor 2 (HER-2) (gene amplification by fluorescence in situ hybridization (FISH) or 3+ over-expression by immunohistochemistry). Patients with unknown HER-2 status are not eligible.
• Patients with active brain metastases. Patients with neurological symptoms must undergo a contrast computed tomography (CT) scan or magnetic resonance imaging (MRI) of the brain to exclude active brain metastasis. Patients with treated brain metastases are eligible provided they have no evidence of active brain disease and are off definitive therapy (including steroids) within 3 months prior to randomization.
• Major surgery, open biopsy, or significant traumatic injury within 4 weeks of randomization.
• Prior use of gemcitabine or sorafenib.
• Evidence or history of bleeding diathesis or coagulopathy.
• Serious, non-healing wound, ulcer, or bone fracture.
• Substance abuse, or medical, psychological, or social condition that may interfere with the patient’s participation in the study or evaluation of the study results.
• Use of cytochrome P450 enzyme-inducing anti-epileptic drugs (such as phenytoin, carbamazepine, or phenobarbital) is not allowed.
• Cardiac disease:
  • Congestive heart failure >class II New York Heart Association (NYHA) (See Appendix D), or
  • Unstable angina (anginal symptoms at rest), or new-onset angina (began within the last 3 months), or myocardial infarction within the 6 months prior to randomization, or
  • Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.
• Uncontrolled hypertension (systolic blood pressure >150 mmHg or diastolic pressure >90 mmHg) despite optimal medical management.
• Thrombolic, embolic, venous, or arterial events such as a cerebrovascular accident including transient ischemic attacks within the past 6 months.
• Pulmonary hemorrhage/bleeding event >National Cancer Institute Common Terminology for Adverse Events (NCI-CTCAE) Grade 2 within 4 weeks of randomization.
• Any other hemorrhage/bleeding event =NCI-CTCAE Grade 3 within 4 weeks of randomization.
• Active clinically serious infection >NCI-CTCAE Grade 2.
• Known human immunodeficiency virus (HIV) infection or chronic hepatitis B or C (the safety and effectiveness of sorafenib in this patient population have not been studied).
• Previous or concurrent cancer that is distinct in primary site or histology from breast cancer EXCEPT cervical cancer in-situ, treated basal cell carcinoma, superficial bladder tumors [Ta and Tis] or any cancer curatively treated >5 years prior to randomization.
• Known or suspected allergy to sorafenib or gemcitabine.
• Prior or concurrent use of St. John’s Wort or rifampin (rifampicin) within 3 weeks of randomization.
• Concurrent anti-cancer therapy (chemotherapy, hormonal therapy, radiation therapy, surgery, immunotherapy, biologic therapy, or tumor embolization) other than gemcitabine and sorafenib/placebo.
• Prior treatment with any agent that targets vascular endothelial growth factor (VEGF) or VEGF receptors (VEGFR) (licensed or investigational), except bevacizumab.
• Women who are pregnant or breast-feeding.
• Use of any investigational drug within 30 days or 5 half-lives, whichever is longer, preceding randomization.

If you would like to learn more about participating in this study, please send an e-mail message using the form below.