Phase 2 Neoadjuvant Doxorubicin and Cyclophosphamide -> Docetaxel With Lapatinib in Stage II/III Her2Neu+ Breast Cancer

Lapatinib acts as a dual inhibitor of both epidermal growth factor receptor (EGFR) and ErbB-2
(Her2/neu) tyrosine kinase activity. EGFR and ErbB2 receptors are frequently over-expressed
or altered in human cancers including breast cancer. This study plans to determine the
antitumor activity of this regimen and its effectiveness preventing tumor growth and spread.

Neoadjuvant chemotherapy which achieves pathologic complete responses (pCR) has been shown to
predict improved long-term survival and serves as a surrogate for clinical outcome. By using
this primary endpoint we can obtain statistical data with smaller patient numbers and at a
lower overall cost. Additionally, we hope to correlate clinical and radiologic outcomes with
gene expression data.

INCLUSION CRITERIA

- Female

- Histologically-confirmed Her2neu positive breast cancer, by either
Immunohistochemistry (IHC) 3+ or Fluorescence In Situ Hybridization (FISH)+

- Stage II/III breast cancer including any large primary tumor (> 2 cm), tumors of any
size associated with skin or chest wall involvement, tumors of any size with axillary
lymph node involvement, (T2-T4, N0-N2) and those with ipsilateral subclavicular or
supraclavicular lymph nodes).

- At least one bi-dimensional, measurable indicator lesion.

- Between 18 and 70 years of age

- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 / Karnofsky ≥ 60% at
screening and on the first day of treatment.

- Informed consent must be obtained prior to registration.

- Cardiac ejection fraction within the institutional range of normal as measured by
multigated acquisition (MUGA) or echocardiography (ECHO) scan.

- Absolute neutrophil count > 1,500/mm³

- Hemoglobin > 8.0 g/dL

- Platelet count > 100,000/mm³

- Creatinine within normal institutional limits

- Total Bilirubin equal to or less than institutional upper limit of normal (ULN)

- Aspartate aminotransferase (AST); alanine aminotransferase (ALT); and alkaline
phosphatase must be within the range allowing for eligibility. In determining
eligibility the more abnormal of the two values (AST or ALT) should be used.

- Eligibility of patients receiving medications or substances known to affect, or with
the potential to affect the activity or pharmacokinetics of GW572016 will be
determined following review of their use by the Principal Investigator

- Antacid use is prohibited 1 hour before and 1 hour after GW572016 dosing.

- All herbal (alternative) medicines are prohibited.

- Medications prohibited during the administration of lapatinib .

- Women of child-bearing potential must have negative pregnancy test and must agree to
use adequate contraception (hormonal or barrier method of birth control or abstinence)
prior to study entry and for the duration of study participation.

- Peripheral neuropathy: must be < grade 1

- Able to swallow and retain oral medication

EXCLUSION CRITERIA

- Evidence of disease outside the breast or chest wall, except for ipsilateral axillary
, supraclavicular, or infraclavicular lymph nodes.

- Prior chemotherapy, immunotherapy, or hormonal therapy for breast cancer.

- More than 3 months between histologic diagnosis and registration on this study.

- History of other malignancy within the last 5years, except curatively treated basal
cell carcinoma of the skin or carcinoma in situ of the cervix.

- Psychological, familial, sociological or geographical conditions which do not permit
weekly medical follow-up and compliance with the study protocol. Those who are
medically-unstable, including but not limited to active infection, acute hepatitis,
deep vein thrombosis requiring anticoagulant therapy, gastrointestinal bleeding,
uncontrolled hypercalcemia, uncontrolled diabetes, dementia, seizures, superior vena
cava syndrome, and those whose circumstances do not permit completion of the study or
the required follow-up.

- Congestive heart failure, abnormal left ventricular ejection fraction (LVEF), angina
pectoris, uncontrolled cardiac arrhythmias, or other significant heart disease, or who
have had a myocardial infarction within the past year.

- Pregnant or lactating

- Of childbearing potential and not employing adequate contraception

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to GW572016.

- HIV-positive and receiving combination anti-retroviral therapy are excluded from the
study because of possible pharmacokinetic interactions with lapatinib. Appropriate
studies will be undertaken in patients receiving combination anti-retroviral therapy
when indicated.

- GI tract disease resulting in an inability to take oral medication, malabsorption
syndrome, a requirement for IV alimentation, prior surgical procedures affecting
absorption, uncontrolled inflammatory GI disease (e.g., Crohn's, ulcerative colitis).

- History of severe hypersensitivity reaction to taxotere or other drugs formulated with
polysorbate 80.

- Current active hepatic or biliary disease (with exception of patients with Gilberts
syndrome, asymptomatic gallstones, or stable chronic liver disease per investigator
assessment ).