1st or 2nd Line MBC (Metastatic Breast Cancer) With Previous Avastin (Bevacizumab) Therapy

• Overall Survival [ Time Frame: From the date of randomization to date of death due to any cause. ] [ Designated as safety issue: No ]
• Time to Progression [ Time Frame: Calculated as the time (days) from date of randomization to date of first observed disease progression (radiological or clinical, whichever is earlier). ] [ Designated as safety issue: No ]
• Overall Response Rate [ Time Frame: The overall tumor burden at baseline will be compared with subsequent measurements up to the date of first documented disease progression or the date of death due to any cause, if before progression. ] [ Designated as safety issue: No ]
• Duration of Overall Response [ Time Frame: Period measured from the first documentation of complete or partial response (whichever status is recorded first) until the first date that recurrent or progressive disease or death is objectively documented. ] [ Designated as safety issue: No ]
• Treatment-Emergent AEs, Laboratory Parameters, and Vital Signs [ Time Frame: An AE is treatment emergent if it starts or worsens in severity after the first dose of study treatment. Reported AEs will be coded by MedDRA dictionary. The toxicity grade of selected lab parameters will be determined using the NCI-CTCAE, Version 3.0. ] [ Designated as safety issue: Yes ]

• Overall Survival
• Time to progression
• Overall response rate
• Duration of overall response
• Treatment-emergent AEs, laboratory parameters, and vital signs

The study is being conducted to compare progression-free survival in patients treated with sorafenib and gemcitabine/capecitabine versus patients treated with placebo and gemcitabine/capecitabine for locally advanced or metastatic breast cancer that has progressed during or following treatment with a bevacizumab-containing regimen.

• Drug: Gemcitabine
  Gemcitabine will be administered 1000 mg/m2 pm Days 1 and 8 of a 21 day cycle;
• Drug: Sorafenib
  Sorafenib will be administered (400 mg; 2 tablets x 200 mg) orally twice daily (approximately every 12 hours)
• Drug: Placebo
  Placebo will be administered (400 mg; 2 tablets x 200 mg) orally twice daily (approximately every 12 hours)
• Drug: Capecitabine
  Capecitabine will be administered orally at a dose of 1,000 mg/m2 twice daily, within 30 minutes after a meal, for 14 days followed by a 7 day rest period (without capecitabine).

• Active Comparator: A
  Gemcitabine will be administered 1000 mg/m2 pm Days 1 and 8 of a 21 day cycle; Sorafenib will be administered (400 mg; 2 tablets x 200 mg) orally twice daily (approximately every 12 hours)
  Interventions:

  • Drug: Gemcitabine
  • Drug: Sorafenib
• Placebo Comparator: B
  Gemcitabine will be administered 1000 mg/m2 pm Days 1 and 8 of a 21 day cycle; Placebo will be administered ( 2 tablets ) orally twice daily (approximately every 12 hours)
  Interventions:

  • Drug: Gemcitabine
  • Drug: Placebo
• Active Comparator: C
  Capecitabine will be administered orally at a dose of 1,000 mg/m2 twice daily, within 30 minutes after a meal, for 14 days followed by a 7 day rest period (without capecitabine); Sorafenib will be administered (400 mg; 2 tablets x 200 mg) orally twice daily (approximately every 12 hours)
  Interventions:

  • Drug: Sorafenib
  • Drug: Capecitabine
• Placebo Comparator: D
  Capecitabine will be administered orally at a dose of 1,000 mg/m2 twice daily, within 30 minutes after a meal, for 14 days followed by a 7 day rest period (without capecitabine); Placebo will be administered (2 tablets) orally twice daily (approximately every 12 hours).
  Interventions:

  • Drug: Placebo
  • Drug: Capecitabine

Inclusion Criteria:

• Histologically or cytologically confirmed adenocarcinoma of the breast.
• Measurable or evaluable locally advanced or metastatic disease.
• Age ≥18 years.
• 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 allowed provided it has 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
• 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 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.
• Patients must be able to swallow and retain oral medication.

Exclusion Criteria:

• Patients with breast cancer over-expressing human epidermal growth factor receptor 2 (HER-2) (gene amplification by FISH or 3+ over-expression by immunohistochemistry). Patients with unknown HER-2 status are not eligible.
• Patients with active brain metastases.
• Major surgery, open biopsy, or significant traumatic injury within 4 weeks of randomization.
• Prior use of gemcitabine/capecitabine 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 is not allowed.
• Clinically significant cardiac disease
• Uncontrolled hypertension
• Thrombolic, embolic, venous, or arterial events such as a cerebrovascular accident including transient ischemic attacks within the past 6 months.
• Pulmonary hemorrhage/bleeding event > 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 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/capecitabine.
• Prior or concurrent use of St. John's Wort or rifampin (rifampicin) within 3 weeks of randomization.
• Concurrent anti-cancer therapy other than gemcitabine/capecitabine and sorafenib/placebo.
• Prior treatment with any agent that targets VEGF or 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.
• Inability to comply with protocol and/or not willing or not available for follow-up assessments.
• Any condition which in the investigator's opinion makes the patient unsuitable for the study participation.