Phase III Trial Comparing Capecitabine in Combination With Sorafenib or Placebo in the Treatment of Locally Advanced or Metastatic HER2-Negative Breast Cancer

Inclusion Criteria:

• Age is >=18 years
• Subject has histologically or cytologically confirmed HER2-negative adenocarcinoma of the breast. HER2 status should be determined by an accredited laboratory
• Subject has locally advanced or metastatic disease; locally advanced disease must not be amenable to resection with curative intent. Must have measurable or non-measurable disease (according to RECIST 1.1)
• All computer tomography (CT; with contrast) and magnetic resonance imaging (MRI) used to document disease must have been done <= 4 weeks before randomization. Bone scans (if clinically indicated) must have been done <= 12 weeks prior to randomization
• Subject must have received up to two prior chemotherapy regimens (adjuvant/neo-adjuvant treatments are considered one regimen), and no more than one prior regimen for advanced and/or metastatic disease. Chemotherapy regimens include both targeted and biologic therapy
• Prior regimens must have included an anthracycline (eg, doxorubicin, epirubicin) and a taxane (eg, paclitaxel, docetaxel), either in combination or in separate regimens, in either the neo-adjuvant/adjuvant or the metastatic setting or both, as either monotherapy or as part of a combination with another agent. Sequential regimens will count as a single regimen; multiple neo-adjuvant / adjuvant regimens will count as a single regimen
• Subjects are either resistant to or have failed prior taxane and anthracycline OR Resistant to or have failed prior taxane AND for whom further anthracycline therapy is not indicated (for example, intolerance or cumulative doses of doxorubicin or doxorubicin equivalents [for example, epirubicin)
• Subjects who relapse beyond 12 months after the last taxane or anthracycline dose given in the adjuvant, neo-adjuvant, or metastatic setting are eligible. Further therapy with the agent(s) for a subsequent regimen must have been considered and ruled out, for example due to prior toxicity or intolerance, or based on the local standard of practice
• Prior experimental chemotherapy treatment is allowed, provided it is given in combination with at least one drug approved for the treatment of breast cancer (excluding drugs that target VEGF or VEGFR, eg, bevacizumab, brivanib, sunitinib, vatalinib).
• Prior hormonal therapy for locally advanced or metastatic breast cancer is allowed. Subjects who are refractory to hormonal therapy are allowed.
• Prior neo-adjuvant or adjuvant chemotherapy is allowed.
• Subject must have discontinued prior chemotherapy (including both targeted and biologic therapies), prior therapeutic radiation therapy, or prior hormonal therapy for locally advanced or metastatic disease >= 4 weeks (28 days) before randomization. Start of study treatment is allowed within less than 28 days of the prior therapy provided that 5 half-lives of the prior treatment drug(s) have elapsed
• ECOG performance status 0 or 1
• Adequate bone marrow, liver and renal function within 7 days prior to randomization
• All acute toxic effects of any prior treatment have resolved to NCI-CTCAE v4.0 Grade 1 or less
• Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to randomization
• Subjects (men and women) of childbearing potential must agree to use adequate contraception beginning at the signing of the ICF until at least 30 days after the last dose of study drug.
• Subject must be able to swallow and retain oral medication

Exclusion Criteria:

• HER2 positive breast cancer
• Unknown hormone receptor status (estrogen and progesterone receptor).
• Subjects with bilateral breast cancer or a history of two distinct breast cancers.
• Subjects with inflammatory breast carcinoma.
• Subjects who have received no prior taxane and anthracycline for the treatment of breast cancer (either in adjuvant, neo-adjuvant or metastatic setting).
• Prior use of sorafenib or capecitabine
• Subjects considered by the treating investigator to be appropriate candidates for hormonal therapy as current treatment for locally advanced/metastatic breast cancer
• Subjects with locally advanced disease who are considered by the treating investigator to be appropriate candidates for radiation therapy as current treatment for locally advanced breast cancer
• Subjects with active brain metastases or leptomeningeal disease.
• Subjects with seizure disorder requiring medication.
• Radiation to any lesions <= 4 weeks prior to randomization. Palliative radiation to bone metastasis for pain control is permitted with provisions
• Major surgery, open biopsy, or significant traumatic injury <= 4 weeks
• Evidence or history of bleeding diathesis or coagulopathy. Uncontrolled hypertension, active or clinically significant cardiac disease. Subject with thrombotic, embolic, venus or arterial events
• Subjects with any hemorrhage/bleeding event of NCI-CTCAE v4.0 Grade 3 or higher within 4 weeks before randomization
• Subjects with an infection of NCI-CTCAE v4.0 > Grade 2
• Subjects with a history of human immunodeficiency virus infection or current chronic or active hepatitis B or C infection.
• Subjects who have used strong CYP3A4 inducers (eg, phenytoin, carbamazepine, phenobarbital, St. John's Wort [Hypericum perforatum], dexamethasone at a dose of greater than 16 mg daily, or rifampin [rifampicin], and/or rifabutin) within 28 days before randomization.
• Subjects with any previously untreated or concurrent cancer that is distinct in primary site or histology from breast cancer
• Subjects with a history DHPD reaction to fluropyrimidine or history of known or suspected allergy or hypersensitivity to any of the study drugs
• Presence of a non-healing wound, non-healing ulcer, or bone fracture
• Women pregnant or breast feeding
• Any condition which, in the investigator's opinion, makes the subject unsuitable for trial participation