A Randomized, Multicenter, Open-Label, Phase III Study of Lapatinib in Combination With Trastuzumab Versus Lapatinib Monotherapy in Subjects With HER2-positive Metastatic Breast Cancer Whose Disease Has Progressed on Trastuzumab-Containing Regimens

Inclusion Criteria:

- Signed informed consent.

- Female ≥18 years. Women of childbearing potential must have a negative serum
pregnancy test at screening and must use an approved contraceptive method, if
appropriate (for example, intrauterine device [IUD], birth control pills, or barrier
device) beginning 2 weeks before the first dose of investigational product and for 28
days after the final dose of investigational product.

- Metastatic breast cancer, histologically/cytologically confirmed. If the disease is
restricted to a solitary lesion, its neoplastic nature must be confirmed by cytology
or histology.

- Subjects must have stage IV breast cancer whereby their disease has progressed in
either the adjuvant or metastatic setting. Prior therapies must include, but are not
limited to:

- Taxane-containing regimen for at least 4 cycles, or 2 cycles provided disease
progression occurred while on taxane.

- Anthracycline-containing regimen for at least 4 cycles, or 2 cycles provided disease
progression occurred while on anthracycline.

- Subjects must have documented progression following at least ONE trastuzumab plus
cytotoxic chemotherapy or anti-hormonal regimen in the metastatic setting.

- Note: The most recent treatment must have contained trastuzumab, either alone or in
combination with other therapy in the metastatic setting, and subjects must have
progressed while on this regimen. Progression is defined as either new lesions or a
≥20% increase in the sum of longest diameter (LD) on the progression radiologic scan.

- Subjects must have archived tumor tissue available for testing.

- Documented amplification of the ErbB2 gene by fluorescence in situ hybridization
(FISH) or documented overexpression of the ErbB2 protein by IHC in primary or
metastatic tumor tissue. The IHC or FISH amplification may be documented by a local
or central laboratory for randomization into the study. Subjects may be randomized
on the basis of ErbB2 positivity by IHC 3+ overexpression or FISH amplification.

- Lesion eligibility is as follows:

- at least one measurable lesion(s) according to Response Evaluation Criteria in Solid
Tumors [RECIST; Therasse, 2000], or

- bone-only disease.

- Note: Tumor lesions which are situated in a previously irradiated field, and have
well-defined margins which are located in soft tissue will be defined as measurable
disease.

- Subjects with stable CNS metastases defined as asymptomatic and off systemic steroids
and anticonvulsants for at least 1 month. Treatment with prophylactic
anticonvulsants is permitted, unless listed within the Prohibited Medications
(Section 8.2).

- Radiotherapy if received within 2 weeks prior to initiation of investigational
product to a limited area (e.g., palliative treatment for painful disease) other than
the sole site of measurable disease is allowed; however, subject must have completed
treatment and recovered from all treatment-related toxicities prior to administration
of the first dose of investigational product.

- With the single exception of prior trastuzumab treatment, all prior chemotherapy,
immunotherapy, biologic therapy, or surgery (except for minor surgical procedures)
must be discontinued at least 3 weeks prior to the first dose of investigational
product. Subjects must have recovered or stabilized sufficiently from
treatment-related toxicities prior to administration of the first dose of
investigational product.

- Bisphosphonate therapy for bone metastases is allowed; however, treatment must be
initiated prior to the first dose of investigational product. Prophylactic use of
bisphosphonates is permitted only for the treatment of osteoporosis.

- ECOG Performance Status of 0 to 2.

- Able to swallow and retain oral medication.

- Cardiac ejection fraction within institutional range of normal as measured by
echocardiogram. MUGA scans will be accepted in cases where an echocardiogram cannot
be performed or is inconclusive. Same modality used at baseline must be used for
repeat assessments throughout study.

- Subject must have adequate organ function as defined in Table 1 :

- Table 1 (Definitions for Adequate Hematologic and Hepatic Function)

- SYSTEM (LABORATORY VALUES)

- Hematologic:

- ANC (absolute neutrophil count) (≥ 1x10^9/ L)

- Hemoglobin (≥ 9 g / dL)

- Platelets (≥75x10^9/ L)

- Hepatic

- Albumin (≥ 2.5 g / dL)

- Serum bilirubin (≤ 2 mg / dL)

- AST and ALT (≤ 3 x ULN without liver metastases) (≤ 5 xULN if documented liver
metastases)

- Renal

- Serum Creatinine (≤1.5 mg / dL)

- OR -

- Calculated Creatinine Clearance1 (≥40 mL / min)

- Calculated by the Cockcroft and Gault Method.

- Subjects may continue anti-estrogen therapy only if treatment was initiated at least
1 month prior to the first dose of investigational product (IP). After
randomization, no anti-hormonal therapy may be initiated.

Exclusion Criteria:

- Pregnant or lactating females.

- Prior therapy with an ErbB1 and/or ErbB2 inhibitor other than trastuzumab.

- Malabsorption syndrome, disease significantly affecting gastrointestinal function, or
resection of the stomach or small bowel. Subjects with ulcerative colitis are also
excluded.

- History of other malignancy. However, subjects who have been disease-free for 5
years, or subjects 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 subject inappropriate for study
participation or any serious medical disorder that would interfere with the subject's
safety.

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

- 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, or congestive heart
failure.

- Known history or clinical evidence of leptomeningeal carcinomatosis.

- Concurrent cancer therapy (chemotherapy, radiation therapy, immunotherapy, biologic
therapy).

- Concurrent treatment with an investigational agent or participation in another
clinical trial.

- Used an investigational drug within 3 weeks or 5 half-lives, whichever is longer,
preceding the first dose of investigational product.

- Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to trastuzumab or lapatinib or their excipients.

- Have current active hepatic or biliary disease (with exception of patients with
Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver
disease per investigator assessment).