A Randomized, Double-blind, Multicenter, Placebo-controlled Study of Adjuvant Lapatinib (GW572016) in Women With Early-Stage ErbB2 Overexpressing Breast Cancer

Inclusion Criteria:

- Have histologically or cytologically confirmed ErbB2-overexpressing invasive
carcinoma (TX or T1-4) of the breast at the time of the initial diagnosis and have
undergone adequate excision of tumor;

- Had tumors that overexpress ErbB2 defined as 3+ by IHC or c-erbB2 gene amplification
by FISH (ErbB2 expression/amplification must be documented prior to study entry;
however, a tumor tissue sample must be sent to a central laboratory for subsequent
re-analysis of ErbB2 status);

- Have Stage I through Stage IIIc disease according to the American Joint Committee on
Cancer (6th edition) staging criteria for breast cancer and meet one of the following
criteria:

node-positive disease defined as: one positive lymph node by sentinel node biopsy OR at
least 1 positive lymph node found among at least 6 axillary nodes examined on axillary
node dissection OR status post axillary radiotherapy for sterilization if clinically
evaluated as cN1 or cN2 (if sentinel node biopsy is positive, subject may either undergo
an axillary node dissection or radiotherapy to the axilla).

node-positive disease evaluated as: ipsilateral axillary lymph nodes cN0-2 by clinical
evaluation and axillary lymph nodes pNX, pN0(i+), or pN1-3 by pathological evaluation
[patients with pN3 (Stage IIIc disease) must be disease free following completion of
neoadjuvant or adjuvant chemotherapy for at least 12 months and must not have been lost to
follow up].

OR node-negative disease defined as: negative sentinel node biopsy OR no positive lymph
nodes found among at least 6 axillary nodes examined on axillary node dissection OR status
post axillary radiotherapy for sterilization if clinically evaluated as cN0.

node-negative disease categorized as: high-risk disease (tumor >2.0 cm if ER and/or
progesterone receptor (PgR) positive disease is present or tumor >1.0 cm if ER and PgR
negative disease) OR intermediate-risk disease (tumor 1.0-2.0 cm and ER and/or PgR
positive disease).

- Women with synchronous bilateral invasive breast cancer or synchronous DCIS of either
the contralateral or ipsilateral breast at the time of the initial diagnosis are also
eligible;

- Have undergone either mastectomy OR lumpectomy;

- Have received and completed treatment with a neoadjuvant or adjuvant chemotherapy
regimen containing either an anthracycline or a taxane; or any cyclophosphamide,
methotrexate and 5-fluorouracil (CMF) regimen;

- May continue to receive endocrine therapy while taking study medication, if endocrine
therapy was initiated as either adjuvant therapy for treatment of the initial
diagnosis of invasive breast cancer or for ovarian function suppression; however,
endocrine therapy may not be initiated while taking study medication. Endocrine
therapy agents may be switched while participating in this study (e.g., stop
tamoxifen and start letrozole);

- May have received prior radiotherapy as treatment for primary tumor; however, is not
required for study entry;

- May continue to receive radiotherapy while taking study medication, if radiotherapy
was initiated as adjuvant therapy for treatment of the initial diagnosis of invasive
breast cancer;

- May continue to receive bisphosphonates only for treatment of documented
osteoporosis, but not as treatment or prophylaxis of bone metastases;

- All women eligible for adjuvant treatment with trastuzumab, including those diagnosed
and treated within the last six months, must be considered for such treatment prior
to being offered participation in this study. Participation in this study will be
allowed only if the physician and patient have considered and discussed at length the
advantages of trastuzumab, but have mutually decided against initiating trastuzumab
therapy.

- Have clinical and radiologic assessments that are negative for local or regional
recurrence of disease or metastatic disease at the time of study entry;

- if signs or symptoms suggestive of either recurrence of disease or metastatic disease
are present, the appropriate radiological imaging must be performed

- if the following laboratory results are present, the appropriate radiological imaging
must be performed:

- for AST/ALT ≥2×ULN or ALP ≥2×ULN (not in the bone fraction), an abdominal CT or MRI
must be done

- for ALP≥2×ULN in the bone fraction, a bone scan must be done; a confirmatory x-ray,
CT scan or MRI scan or biopsy is required if the results of the bone scan are
inconclusive

- Have a unilateral/bilateral mammogram within 12 months prior to study entry;

- Have an analysis of both ER and PgR on the primary tumor prior to study entry;

- Have a cardiac ejection fraction within institutional range of normal as measured by
either echocardiogram or multigated acquisition scans;

- Have an Eastern Cooperative Oncology Group Performance Status of 0 to 1;

- Women with a history of non-breast malignancies are eligible if they have been
disease-free for at least 5 years and are deemed by the investigator to be at low
risk for recurrence. Women with the following cancers are eligible if diagnosed and
treated within the past 5 years: cervical carcinoma in situ, melanoma in situ, and
basal cell or squamous cell carcinoma of the skin;

- Are able to swallow and retain oral medication;

- Have a paraffin-embedded tissue block from an archived tumor tissue from the primary
tumor or twenty (20) slides of paraffin-embedded tissue available for biomarker
analysis;

- Have adequate organ function defined as: absolute neutrophil count ≥1.5× 10^9/L;
hemoglobin ≥9 g/dL; platelets ≥75 × 10^9/L; albumin ≥2.5 g/dL; serum bilirubin ≤1.25
×ULN; aspartate aminotransferase and alanine aminotransferase ≤3 × ULN and serum
creatinine ≤2.0 mg/dL or calculated creatinine clearance ≥40 mL/min

- Have signed the informed consent form (ICF);

- Women of child-bearing potential must have a negative serum pregnancy test at
screening and agree to complete abstinence from intercourse or consistent and correct
use of an acceptable methods of birth control from 2 weeks prior to administration of
the first dose of study medication until 28 days after the final dose of study
medication:

Exclusion Criteria:

- Have clinical and radiologic evidence of local or regional recurrence of disease or
metastatic disease at the time of study entry;

- Had metachronous invasive breast cancer (breast cancers diagnosed at different
times);

- Have a prior history of other breast cancer malignancies, including DCIS;

- Are unable to provide archived tumor tissue samples for assay;

- Had prior therapy with an ErbB1 and/or ErbB2 inhibitor; women who experienced a
hypersensitivity or allergic reaction to trastuzumab during the first infusion and
were unable to complete this infusion are eligible;

- Receive concurrent anti-cancer therapy (chemotherapy, immunotherapy, and biologic
therapy) while taking study medication;

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

- Have malabsorption syndrome, disease significantly affecting gastrointestinal
function, or resection of the stomach or small bowel. Women with ulcerative colitis
are also excluded;

- Have a concurrent disease or condition that would make the woman inappropriate for
study participation, or any serious medical disorder that would interfere with the
woman's safety;

- Have an active or uncontrolled infection;

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

- Have a known history of uncontrolled or symptomatic angina, arrhythmias, or CHF;

- Are pregnant or breastfeeding;

- Receive concurrent treatment with an investigational agent; women, who are in
follow-up in another clinical trial where the primary endpoint has been met and the
interval between assessments is ≥12 months and radiological imaging is not required
at these assessments, are eligible;

- Receive concurrent treatment with a selected list of strong inducers and inhibitors
of CYP3A4;

- Used an investigational drug within 30 days or 5 half-lives, whichever is longer,
preceding the first dose of study medication;

- Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to lapatinib or excipients;