This open label study is designed to evaluate Lapatinib effect on incidence of brain metastases in ErbB2 (HER2) positive metastatic breast cancer patients exposed to prior taxanes or anthracyclines.

• Drug: capecitabine
  oral medication; daily dose divided into morning and evening dose and taken for 14 days of 21 day cycle
• Drug: trastuzumab
  infusion therapy; loading dose of 8mg/kg, followed by 6mg/kg given every 3 weeks
• Drug: lapatinib
  oral medication; daily dose taken once a day

• Trastuzumab plus capecitabine: Active Comparator
  trastuzumab loading dose of 8mg/kg followed by 6mg/kg q3weekly infusions, and capecitabine 2500mg/m2/day, days 1-14, every 21 days
  Interventions:

  • Drug: capecitabine
  • Drug: trastuzumab
• Lapatinib plus capecitabine: Experimental
  Lapatinib 1250 mg once daily and capecitabine 2000mg/m2/day, days 1-14, every 21 days
  Interventions:

  • Drug: capecitabine
  • Drug: lapatinib

Inclusion Criteria:

• Females at least 18 years old;
• ECOG Performance Status 0-2;
• Histologically or cytologically confirmed HER2-positive invasive breast cancer, with Stage IV disease;
• Prior treatment with taxanes or anthracyclines is required;
• Prior treatment with other chemotherapeutic agents, trastuzumab, endocrine and radiation therapy is permitted;
• Baseline LVEF ≥ 50% and above the institutional lower limit of normal;
• Concurrent treatment with bisphosphonates is permitted, however treatment must be initiated prior to the first dose of study therapy;
• Able to swallow and retain oral medications;
• Women with potential to have children must be willing to practice acceptable methods of birth control during the study;
• Normal organ and marrow function.

Exclusion Criteria:

• History and/or current evidence of CNS metastases;
• Concurrent treatment with an investigational agent or participation in another treatment clinical trial;
• Prior therapy with lapatinib or an ErbB2 inhibitor other than trastuzumab and capecitabine;
• Known DPD deficiency;
• Concurrent chemotherapy, radiation therapy, immunotherapy, biologic therapy, or hormonal therapy for treatment of cancer;
• History of allergic reactions attributed to compounds chemically related to lapatinib (quinazolines), capecitabine, fluorouracil or any excipients;
• Concomitant use of CYP3A4 inhibitors or inducers;
• Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel;
• History of immediate or delayed hypersensitivity reaction to gadolinium contrast agents, or other contraindication to gadolinium contrast and other known contraindication to MRI;
• Concurrent disease or condition that would make the subject inappropriate for study participation or any serious medical or psychiatric disorder that would interfere with the patient's safety or compliance to study procedures;
• Current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases);
• Any on-going toxicity from prior anti cancer therapy;
• Active cardiac disease;
• Uncontrolled infection;
• History of other malignancy, except for curatively treated basal cell carcinoma or squamous cell carcinoma of the skin, or carcinoma in situ of the cervix; patients with other malignancies who have been disease-free for at least 5 years are eligible;
• Used an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of protocol treatment;
• Pregnant or lactating females.