Trial Information
Indication: Breast Cancer
Study Summary: This is a multi-national, double-blind, placebo controlled study in patients with locally advanced or metastatic breast cancer.
The primary objective is to compare progression-free survival (PFS) in patients treated with sorafenib and capecitabine versus patients treated with placebo and capecitabine for locally advanced or metastatic breast cancer.
Subjects will receive capecitabine daily 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.
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.
- Failed taxane and an anthracycline-containing chemotherapy regimen or for whom anthracycline therapy is not indicated.
- No more than one prior chemotherapy for locally advanced or metastatic breast cancer.
- Patients must have discontinued chemotherapy at least 3 weeks prior to randomization.
- Prior hormonal therapy for locally advanced or metastatic disease is allowed.
- 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 (See Appendix A).
- 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 ≤2.0 times the upper limit of normal (ULN)
- Alanine aminotransferase (ALT) and aspartate aminotransferase) (AST ≤2.5 x ULN (≤5 x ULN for patients with liver involvement)
- International Normalized Ratio for Prothrombin Time (PT-INR) ≤1.5 and activated partial thromboplastin 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 ≤2.0 times the 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 prior to randomization and for the duration of study participation.
- 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.
- Patients must be willing and able to fill out patient-reported outcome questionnaires. In the event that the patient is unable to hold a pen or pencil, an accompanying family member/friend or a nurse coordinator may fill in the questionnaire with the answers that the patient provides to him or her.
Exclusion Criteria
- 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 brain disease and are off definitive therapy (including steroids) at least 3 months prior to randomization.
- Patients who received prior capecitabine therapy.
- Major surgery, open biopsy, or significant traumatic injury within 4 weeks of randomization.
- 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 Health Association (NYHA) (see Appendix D), or
- Unstable angina (anginal symptoms at rest), or new-onset angina (begun 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 mm Hg or diastolic pressure >90 mm Hg) 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 > Grade 2 National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) within 4 weeks of randomization.
- Any other hemorrhage/bleeding event ≥ Grade 3 NCI-CTCAE within 4 weeks of randomization.
- Active clinically serious infection > Grade 2 NCI-CTCAE.
- Known human immunodeficiency virus (HIV) infection or chronic hepatitis B or C.
- Previous or concurrent cancer that is distinct in primary site or histology from breast cancer within 5 years prior to randomization EXCEPT cervical cancer in situ, treated basal cell carcinoma, superficial bladder tumors [Ta and Tis].
- Known or suspected allergy to sorafenib, or hypersensitivity to capecitabine or to any of the excipients or fluorouracil.
- History of severe and unexpected reactions to fluoropyrimidine therapy or patients with known dihydropyrimidine dehydrogenase deficiency.
- Prior or concurrent treatment with sorivudine or its chemically related analogues, such as brivudine.
- Concurrent or use of St. John’s Wort or rifampin (rifampicin) within 1 week of randomization.
- Prior treatment with bevacizumab or any other drugs (licensed or investigational) that target vascular endothelial growth factor (VEGF) or VEGF receptors (VEGFR).
- Concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery, immunotherapy, biologic therapy, or tumor embolization) other than capecitabine and sorafenib/placebo. This includes agents such as Dasatinib, Sunitinib, pazopanib, motesanib, SU-14813, AZD2171, Zactima (DZ6474), ABT-869, and XL647.
- Women who are pregnant or breast feeding.
- Use of any investigational drug within 30 days or 5 half-lives, whichever is longer, preceding randomization.
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