A Randomized, Double Blind, Placebo-Controlled, Multicenter, Phase III Study Comparing the Activity of Paclitaxel Plus Trastuzumab Plus Lapatinib to Paclitaxel Plus Trastuzumab Plus Placebo in Women With ErbB2 Overexpressing Metastatic Breast Cancer

Inclusion Criteria

Inclusion criteria:

- Histologically confirmed invasive breast cancer with stage IV disease If trastuzumab
was administered in the adjuvant setting, >12 months must have elapsed since
discontinuation of trastuzumab therapy

- If a taxane was administered in the neoadjuvant or adjuvant setting, progression must
have occurred 12 months after completion of this treatment

- Had tumors that overexpress ErbB2 (Immunohistochemistry 3+ or Fluorescent in-situ
hybridisation gene amplification)

- Patients must have tumor tissue available for central testing Measurable lesion(s)

- Subjects must be females of at least 18 years Non-childbearing potential or
Childbearing potential but using adequate contraception

- Radiotherapy to a limited area other than the sole site of measurable and assessable
disease is allowed; however, patients must have completed treatment and recovered
from all acute treatment-related toxicities prior to administration of the first dose
of study medication

- Bisphosphonate therapy for bone metastases is allowed; however, treatment must be
initiated prior to the first dose of randomized therapy. Prophylactic use of
bisphosphonates in patients without bone disease is not permitted, except for the
treatment of osteoporosis

- Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 1

- For those patients whose disease is estrogen receptor positive+ and/or progesterone
receptor + one the following criteria should be met: Patients with visceral disease
that requires chemotherapy (eg., patients with liver or lung metastases) or Rapidly
progressing/life threatening disease, as determined by the investigator or Patients
who received hormonal therapy and are no longer benefiting from this therapy;

- Able to swallow and retain oral medication

- Cardiac ejection fraction within institutional range of normal

- Patient must have adequate organ function

Exclusion criteria:

- Pregnant or lactating females;

- Received prior chemotherapy, immunotherapy, biologic therapy, or anti-ErbB1/ErbB2
therapy for metastatic disease, prior hormonal therapy is permitted but must be
discontinued a minimum of 7 days prior to randomization; Malabsorption syndrome,
disease significantly affecting gastrointestinal function, or resection of the
stomach or small bowel.

- Patients with ulcerative colitis are also excluded;

- History of other malignancy; however, patients who have been disease-free for five
years, or patients with a history of completely resected non-melanoma skin cancer or
successfully treated in situ carcinoma are eligible;

- Concurrent disease or condition that would make the patient inappropriate for study
participation, or any serious medical disorder that would interfere with the
patient's safety;

- Unresolved or unstable, serious toxicity from prior administration of another
investigational drug and/or of prior cancer treatment;

- Peripheral neuropathy of Grade 2 or greater;

- Active or uncontrolled infection;

- Dementia, altered mental status, or any psychiatric condition that would prohibit the
understanding or rendering of informed consent;

- Known history of uncontrolled or symptomatic angina, arrhythmias, conduction
abnormalities or congestive heart failure;

- Known history or clinical evidence of central nervous system (CNS) metastases or
leptomeningeal carcinomatosis;

- Concurrent cancer therapy (chemotherapy, radiation therapy, immunotherapy, biologic
therapy, hormonal therapy); Concurrent treatment with an investigational agent or
participation in another clinical trial;

- Concurrent treatment with any medication on the prohibited medications list.

- Used an investigational drug within 30 days or 5 half-lives, whichever is longer,
preceding the first dose of treatment. Hormonal therapy needs to be discontinued at
least 7 days before the first dose of treatment.

- Prior therapy with an ErbB2 inhibitor, other than trastuzumab in the adjuvant
setting;

- A known immediate or delayed hypersensitivity reaction to drugs chemically related to
lapatinib or excipients;

- A known immediate or delayed hypersensitivity reaction to drugs chemically related to
paclitaxel or excipients;

- A known immediate or delayed hypersensitivity reaction to drugs chemically related to
trastuzumab or excipients;

- Non compliance with any of the screening procedures