Lapatinib In Combination With Trastuzumab Versus Lapatinib Monotherapy In Subjects With HER2-positive Metastatic Breast Cancer

Inclusion Criteria:

• Signed informed consent.

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

• Metastatic breast cancer, histologically/cytologically confirmed. If the disease isrestricted to a solitary lesion, its neoplastic nature must be confirmed by cytologyor histology.

• Subjects must have stage IV breast cancer whereby their disease has progressed ineither the adjuvant or metastatic setting. Prior therapies must include, but are notlimited to:

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

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

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

• Note: The most recent treatment must have contained trastuzumab, either alone or incombination with other therapy in the metastatic setting, and subjects must haveprogressed 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 ormetastatic tumor tissue. The IHC or FISH amplification may be documented by a local orcentral laboratory for randomization into the study. Subjects may be randomized on thebasis 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 SolidTumors [RECIST; Therasse, 2000], or

• bone-only disease.

• Note: Tumor lesions which are situated in a previously irradiated field, and havewell-defined margins which are located in soft tissue will be defined as measurabledisease.

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

• Radiotherapy if received within 2 weeks prior to initiation of investigational productto a limited area (e.g., palliative treatment for painful disease) other than the solesite of measurable disease is allowed; however, subject must have completed treatmentand recovered from all treatment-related toxicities prior to administration of thefirst 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 investigationalproduct. Subjects must have recovered or stabilized sufficiently fromtreatment-related toxicities prior to administration of the first dose ofinvestigational product.

• Bisphosphonate therapy for bone metastases is allowed; however, treatment must beinitiated prior to the first dose of investigational product. Prophylactic use ofbisphosphonates 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 byechocardiogram. MUGA scans will be accepted in cases where an echocardiogram cannot beperformed or is inconclusive. Same modality used at baseline must be used for repeatassessments 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 livermetastases)

• 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 1month prior to the first dose of investigational product (IP). After randomization, noanti-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, orresection of the stomach or small bowel. Subjects with ulcerative colitis are alsoexcluded.

• 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 orsuccessfully treated in situ carcinoma are eligible.

• Concurrent disease or condition that would make the subject inappropriate for studyparticipation or any serious medical disorder that would interfere with the subject'ssafety.

• Unresolved or unstable, serious toxicity from prior administration of anotherinvestigational drug and/or of prior cancer treatment.

• Active or uncontrolled infection.

• Dementia, altered mental status, or any psychiatric condition that would prohibit theunderstanding or rendering of informed consent.

• Known history of uncontrolled or symptomatic angina, arrhythmias, or congestive heartfailure.

• Known history or clinical evidence of leptomeningeal carcinomatosis.

• Concurrent cancer therapy (chemotherapy, radiation therapy, immunotherapy, biologictherapy).

• Concurrent treatment with an investigational agent or participation in anotherclinical 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 drugschemically related to trastuzumab or lapatinib or their excipients.

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