Lapatinib + Vinorelbine in ErbB2 overexpressing, First or Second Line Metastatic Breast Cancer Subjects

A subject will be eligible for inclusion in this study only if all of the following criteria apply: 1. Signed informed consent prior to registration. 2. Considered by the Investigator to have a life expectancy of ≥12 weeks. 3. Subjects must have histologically confirmed invasive breast cancer with Stage IV disease at primary diagnosis or at relapse after curative-intent surgery.

• Where the disease is restricted to a solitary lesion, the neoplastic nature of the lesion should be confirmed by cytology or histology. 4. Documented amplification of ErbB2 3+ by immunohistochemistry or a positive score (>2.2) by fluorescence in situ hybridization (FISH) using a local laboratory result (which will be considered sufficient in this study with no further verification by a central laboratory). NOTE: If both IHC and FISH results available, FISH results must be used for eligibility. 5. Subjects must not have received more than 1 prior chemotherapeutic regimen in the metastatic setting. 6. All prior chemotherapy, immunotherapy, biologic therapy, or surgery (except for minor surgical procedures) must be discontinued at least 4 weeks prior to first dose of investigational product. Hormonal therapy must be discontinued at least 1 week prior to first dose. 7. Prior diagnosis of cancer is allowed as long as the subject is free of disease and has been off treatment for prior malignancies for 5 years. Subjects with completely resected basal or squamous cell skin cancer or successfully treated cervical carcinoma in situ will be allowed if it has been 1 year or longer since definitive surgery. 8. Subjects must have measurable disease, according to Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. 9. Females aged ≥18 years with any menopausal status:
• Non-child-bearing potential (i.e., women with functioning ovaries who have a current documented tubal ligation or hysterectomy, or women who are postmenopausal)
• Child-bearing potential (i.e., women with functioning ovaries and no documented impairment of oviductal or uterine function that would cause sterility): This category includes women with oligomenorrhea (severe), women who are perimenopausal, and young women who have begun to menstruate. These subjects must have a negative serum pregnancy test at screening and agree to one of the following:
• Complete abstinence from intercourse from 2 weeks prior to administration of the first dose of study medication until 28 days after the final dose of study medication; or
• Consistent and correct use of one of the following acceptable methods of birth control: male partner who is sterile prior to the female subject's entry into the study and is the sole sexual partner for that female subject; any intrauterine device with a documented failure rate of less than 1% per year; oral contraceptives (either combined or progestogen only) where not contraindicated for this subject population or per local practice.; or barrier methods, including diaphragm or condom with a spermicide. 10. ECOG performance status (PS) of 0 to 2 [Oken, 1982] (Appendix 1). 11. Subjects must have normal organ and marrow function as defined in Table 1. Table 1 Baseline Laboratory Values for Adequate Organ Function System Laboratory Value Hematologic Absolute neutrophil count ≥1.5 × 10^9/L Hemoglobin ≥9 g/dL Platelets ≥100 × 10^9/L Hepatic Serum bilirubin ≤1.25 × upper limit of normal (ULN) Aspartate aminotransferase and alanine aminotransferase ≤3 × ULN without liver metastases ≤5 × ULN if documented liver metastases Renal Serum creatinine ≤1.5 mg/dL

Calculated creatinine clearance ≥40 mL/min 12. Subjects must have a cardiac ejection fraction of at least 50% (as measured by echocardiogram [ECHO] or multigated acquisition scan [MUGA]) and within the institutional range of normal. Subjects who require cardiac medications (e.g. positive inotropic agents or afterload reducers) for abnormal ejection fraction are ineligible. MUGA scans will be accepted in cases where an ECHO cannot be performed or is inconclusive. The same modality to assess cardiac ejection fraction must be used consistently throughout the study. 13. Radiotherapy prior to initiation of study medication is allowed to a limited area (e.g., palliative therapy), if it is not the sole site of disease. Subjects must have completed radiation treatment and recovered from all acute radiation treatment-related toxicities (e.g., bone marrow suppression) prior to commencement of combination treatment. 14. Subjects with stable central nervous system (CNS) metastases. Subjects with stable CNS metastases are defined as follows: subject is asymptomatic with CNS metastases that have been stable for at least 3 months as confirmed by computed tomography (CT)/magnetic resonance imaging (MRI). Subjects with evidence of leptomeningeal/parenchymal involvement are eligible only if they are not taking steroids or enzyme-inducing anticonvulsants within 4 weeks of commencement of the study. Treatment with prophylactic anticonvulsants is permitted, unless listed as a prohibited medication. 15. Subject must be free of gastrointestinal diseases that impede swallowing and retaining of oral medications. 16. Able to swallow and retain oral medication (intact pill). 17. Bisphosphonate therapy for bone metastases is allowed; however, treatment must be initiated prior to the first dose of study medication. Prophylactic use of bisphosphonates in subjects without bone disease, except for the treatment of osteoporosis, is not permitted. 18. Subjects whose disease is estrogen receptor + and/or progesterone receptor + or unknown status will only be included in the study if they meet the following criteria:

• They have symptomatic visceral disease that requires chemotherapy.
• The disease is considered by the Investigator to be progressing rapidly or is life threatening.
• Subjects who have received endocrine therapy and who are no longer benefiting from this therapy.