Endocrine Therapy With or Without Inhibition of EGF and HER2 Growth Factor Receptors: A Randomized, Double-Blind, Placebo-Controlled Phase III Trial of Fulvestrant With or Without Lapatinib (GW572016) for Postmenopausal Women With Hormone Receptor Positive Advanced Breast Cancer

Inclusion Criteria:

- Histologically* or cytologically confirmed breast cancer, meeting 1 of the following
stage criteria:

- Stage III (locally advanced) disease not considered amenable to curative therapy

- Stage IV (primary or metastatic) disease

- Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 2.0 cm by
conventional techniques or ≥ 1.0 cm by spiral CT scan

- Lytic or blastic bone metastases as only site of disease allowed

- The following are not considered measurable disease:

- Bone lesions (except as above)

- Leptomeningeal disease

- Ascites

- Pleural/pericardial effusion

- Inflammatory breast cancer

- Lymphangitis cutis/pulmonitis

- Abdominal masses that are not confirmed and followed by imaging techniques

- Cystic lesions

- Must have received prior therapy with 1 or 2 endocrine treatments for breast cancer
in either the adjuvant or metastatic setting (not including treatment for ovarian
suppression or amenorrhea)

- Tumor must be potentially sensitive to endocrine therapy, defined as ≥ 3 months
of prior endocrine therapy without disease progression in the adjuvant or
metastatic setting

- Treatments must have been commercially-available third-generation aromatase
inhibitors (e.g., anastrozole, exemestane, or letrozole)*

- No symptomatic brain or other CNS metastases

- Previously treated brain metastases allowed provided patient is free of symptoms
AND > 3 months since prior treatment for brain metastases

- Hormone receptor status:

- Estrogen receptor- and/or progesterone receptor-positive tumor by IHC methods (≥
1% cells considered positive)

- Female

- Postmenopausal, meeting 1 of the following criteria:

- Age ≥ 60 years

- Age ≥ 45 years with an intact uterus and amenorrhea for ≥ 12 months

- History of bilateral oophorectomy

- Follicle-stimulating hormone levels within postmenopausal range

- Undergoing treatment with a gonadotropin-releasing hormone agonist for ovarian
suppression for ≥ 3 consecutive months prior to study entry, and remains on such
therapy throughout study treatment

- Life expectancy > 3 months

- ECOG performance status 0-2

- Granulocyte count ≥ 1,000/mm³

- Platelet count ≥ 100,000/mm³

- Total bilirubin ≤ 1.5 times upper limit of normal (ULN) (unless due to Gilbert's
syndrome)

- Creatinine ≤ 2.0 mg/dL

- AST and ALT ≤ 2.5 times ULN (5 times ULN for patients with liver metastases)

- INR ≤ 1.6

- LVEF normal

- Not pregnant or nursing

- Negative pregnancy test

- No pending visceral crisis

- No acquired or inherited bleeding disorder

- No other concurrent endocrine therapy, including systemic hormone-replacement therapy
or intravaginal estrogen

- Prior initiation of and concurrent bisphosphonate therapy allowed

- At least 2 weeks since prior chemotherapy and recovered

- Prior chemotherapy in the adjuvant and/or neoadjuvant setting allowed

- No more than 1 prior chemotherapy regimen for stage IV breast cancer

- At least 3 weeks since prior trastuzumab (Herceptin®) and recovered

- Prior trastuzumab in the adjuvant and/or neoadjuvant setting allowed

- No prior trastuzumab for stage IV breast cancer

- No prior fulvestrant

- No prior epidermal growth factor receptor (EGFR) inhibitors (e.g., gefitinib,
erlotinib hydrochloride, lapatinib ditosylate, or cetuximab)

- No other prior or concurrent experimental EGFR inhibitors

- No other concurrent chemotherapy

- No concurrent radiotherapy, including palliative radiotherapy

- No other concurrent hormonal therapy* except for the following:

- Steroids for adrenal failure

- Hormones for nondisease-related conditions (e.g., insulin for diabetes or
synthroid for hypothyroidism)

- Intermittent dexamethasone as an antiemetic

- No concurrent therapeutic systemic anticoagulation (defined as maintaining INR > 1.6)

- Low-dose warfarin or acetylsalicylic acid (or equivalent) for maintenance of
central venous catheter patency allowed