This is a phase IB/II trial of sorafenib, a new tyrosine kinase inhibition of multiple genes that is active against renal cancer, plus vinorelbine, a chemotherapy agent active in breast cancer.

The investigators are combining these 2 drugs in order to determine if the investigators can increase the activity of vinorelbine in metastatic breast cancer patients.

Patients with measurable metastatic breast cancer without previous chemotherapy for metastatic disease are eligible for the protocol. They will be treated with 2 different dose levels of sorafenib in order to determine the most tolerable dose.

Inclusion Criteria:

• Women affected by histologically proven metastatic breast cancer.

• Tumor not susceptible to therapy with trastuzumab, defined as FISH negative for HER-2 amplification or immunohistochemistry 0-1+ for HER-2 expression.

• Female, age ≥ 18.

• Documented measurable disease by appropriate radiologic imaging according to RECIST criteria (see Appendix E). Lesions in previously irradiated areas are not considered measurable disease, unless progression has been documented post-radiation.

• ECOG performance status 0-1 (see Appendix B)

• Life expectancy > 6 months.

• Adequate bone marrow function, as indicated by:

  • Hemoglobin ≥ 90 g/L
  • Neutrophils ≥ 1.5 x 109/L
  • Platelets ≥ 100 x 109/L

• Adequate renal function, as indicated by serum creatinine ≤1.5 times the upper limit of normal and/or Creatinine Clearance calculated as >50% lower normal limit, or estimated as ≥ 50 ml/min (Appendix C).

• Adequate liver function, as indicated by:

  • bilirubin ≤ 1.5 times upper normal limit;
  • AST and ALT ≤ 2 times upper normal limit.

• Left ventricular ejection fraction (LVEF) ≥50% as measured by either multigated acquisition (MUGA) scan or echocardiogram (ECHO).

• No therapy for breast cancer in the 4 weeks preceding the therapy start.

• Women of childbearing potential must be using adequate contraception and have a negative pregnancy test at the time of enrollment.

• Patient able to understand and give written informed consent.

Exclusion Criteria:

• Patients with locally advanced breast cancer or stage IIIb only.
• Presence of only non-measurable disease.
• Previous (neo)adjuvant chemotherapy with vinorelbine.
• Any previous anti-angiogenic therapy.
• Any previous chemotherapy for metastatic breast cancer. Previous hormonal treatments or radiotherapy for metastatic disease are allowed.
• Radiotherapy, chemotherapy or hormonal therapy for breast cancer in the last 4 weeks prior to starting the study treatment.
• Major surgery within 4 weeks of first study treatment, or minor surgery (including placement of an access device) within 7 days of therapy start.
• Presence of life-threatening disease or central nervous system localizations.
• Evidence of HER-2 positive breast cancer, defined as FISH-positive for amplification or score 3+ by immunohistochemistry.
• Any other possibly active primary tumor, except basal cell carcinoma of the skin, or carcinoma in situ of the cervix.
• Clinically significant hepatic disease with respect to hepatitis B, hepatitis C, cirrhosis or other liver diseases.
• Uncontrolled bacterial, viral or fungal infection.
• Previous history of ischemic disease.
• Patients with previous history of thrombo-embolic events, or with documented risk factors for thrombotic disease other than cancer.
• History of gross hemorrhage within the past 6 months (e.g., hemoptysis or hematuria requiring medical intervention).
• Uncontrolled hypertension.
• Other serious medical conditions, such as uncontrolled cardiac disease, severe pulmonary disease, uncontrolled diabetes.
• Patient exhibiting confusion or disorientation.
• Any condition (medical, social, psychological, geographical) that would prevent adequate follow-up.
• Patient is pregnant, or is breast-feeding, or is unwilling to use adequate contraception.
• Failure to give informed consent.