Phase IB/II Trial Combining Vinorelbine With Sorafenib as First-Line Treatment in Patients With Metastatic Breast Cancer

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.