A Study of AC Followed by a Combination of Paclitaxel Plus Trastuzumab or Lapatinib or Both Given Before Surgery to Patients With Operable HER2 Positive Invasive Breast Cancer

Women with breast cancers that overexpress HER2 are at greater risk for disease progression
and death than women whose tumors do not overexpress HER2. Trastuzumab, a recombinant
humanized monoclonal antibody against the extracellular domain of the HER2 protein blocks
downstream signaling of HER2 and substantially improves the efficacy of chemotherapy in
women with metastatic and early-stage HER2-positive breast cancers. Because resistance to
trastuzumab eventually results in progressive disease in the metastatic setting and
contributes to recurrence following adjuvant trastuzumab-based therapy, it is important to
develop agents other than trastuzumab that target HER2 signaling through different
mechanisms of action. Lapatinib is an oral, small molecule, dual tyrosine kinase inhibitor
of HER2 and EGFR. Lapatinib has shown a lack of cross-resistance with trastuzumab in
preclinical studies and activity in women with HER2-positive, metastatic breast cancer that
has progressed during trastuzumab treatment. Trastuzumab blocks the downstream signaling of
HER2 by binding to the extracellular domain of the receptor. Lapatinib binds to the
intracellular domains of HER2 and EGFR and prevents activation of downstream signaling
pathways. Because of this different mechanism of action, lapatinib may be effective in
trastuzumab-resistant disease. The study will also provide important safety information on
trastuzumab and lapatinib combinations immediately following anthracycline exposure, and
also provide an initial direct comparison of cardiac effects of trastuzumab and lapatinib
when incorporated into a standard sequential AC followed by weekly paclitaxel (neo)adjuvant
regimen.

Availability of a second agent that can interrupt HER2-signaling pathways through completely
different mechanisms than those of trastuzumab offers the potential for further improvement
in the management of patients with HER2-overexpressing breast cancer in both the adjuvant
and metastatic setting. Co-administration of both trastuzumab and lapatinib with
chemotherapy may be important in improving outcomes in subsets of HER2-positive breast
cancers. However, use of two inhibitors of the HER2 pathway will increase costs and may
increase toxicity, so it will be important to identify the subsets of patients who would
benefit from the dual therapy. Inhibition of HER2 with a single agent clearly is sufficient
for many patients as evidenced by the results of the trastuzumab trials. Therefore,
co-administration to unselected populations of women with HER2-positive breast cancers would
not represent an optimal approach. Given the activity of lapatinib, it is likely that it
will also be sufficiently active in inhibiting HER2-pathway activation in some patients to
allow for its use as the sole inhibitor of the HER2 pathway. Different populations may also
derive greater benefit from one of the HER2-blocking agents relative to the other.
Identification of potential predictive factors for pathologic complete response to the
combination or to either agent administered alone in neoadjuvant trials would provide
important information for adjuvant trials designed to definitively address these important
issues.

This study will compare 3 combined chemotherapy regimens: AC followed by paclitaxel plus
trastuzumab and lapatinib, AC followed by paclitaxel plus lapatinib, and AC followed by
paclitaxel plus trastuzumab given before surgery to patients with HER2-positive breast
cancer.

Inclusion criteria:

- Female

- 18 years or older

- ECOG performance status of 0 or 1

- Primary breast tumor palpable and measures greater than or equal to 2.0 cm by
physical exam

- Diagnosis of invasive adenocarcinoma made by core needle biopsy

- Breast cancer determined to be HER2-positive

- LVEF assessment by MUGA scan or ECG within 3 months prior to randomization

- Blood counts must meet the following criteria:

- ANC greater than or equal to 1200/mm3

- Platelet count greater than or equal to 100,000/mm3

- Hemoglobin greater than or equal to 10 g/dL

- Serum creatinine less than or equal to ULN for the lab

- Adequate hepatic function by these criteria:

- Total bilirubin less than or equal to the ULN for the lab unless the patient has
a bilirubin elevation greater than ULN to 1.5 x ULN resulting from Gilbert's
disease or similar syndrome due to slow conjugation of bilirubin; and

- Alkaline phosphatase less than or equal to 2.5 x ULN; and

- AST less than or equal to 1.5 x ULN for the lab.

- If skeletal pain present or alkaline phosphatase greater than ULN (but less than or
equal to 2.5 x ULN), bone scan or PET scan must not demonstrate metastatic disease

- If AST or alkaline phosphatase greater than ULN , liver imaging (CT, MRI or PET scan)
must not demonstrate definitive metastatic disease and the requirements in criterion
for hepatic function must be met

- Able to swallow oral medications

Exclusion criteria:

- FNA alone to diagnose the primary tumor

- Excisional biopsy or lumpectomy was performed prior to randomization

- Surgical axillary staging procedure prior to randomization. Exceptions: 1) FNA or
core biopsy of an axillary node for any patient, and 2) although not recommended, a
pre-neoadjuvant therapy SN biopsy for patients with clinically negative axillary
nodes.

- Tumors clinically staged as T4

- Ipsilateral cN2b or cN3 disease (Patients with cN1 or cN2a disease are eligible)

- Definitive clinical or radiologic evidence of metastatic disease

- Synchronous bilateral invasive breast cancer

- Requirement for chronic use of any of the medications or substances specified in the
protocol

- Treatment including RT, chemotherapy, and/or targeted therapy for the currently
diagnosed breast cancer prior to randomization

- Any sex hormonal therapy, e.g., birth control pills, ovarian hormone replacement
therapy, etc. (These patients are eligible if therapy is discontinued prior to
randomization)

- Continued therapy with any hormonal agent such as raloxifene, tamoxifen, or other
SERM. (Patients are eligible only if these medications are discontinued prior to
randomization)

- Prior history of breast cancer, including DCIS (Patients with a history of LCIS are
eligible)

- Prior therapy with anthracyclines, taxanes, trastuzumab, or lapatinib for any
malignancy

- Other malignancies unless the patient is considered to be disease-free for 5 or more
years prior to randomization and is deemed by her physician to be at low risk for
recurrence. Patients with the following cancers are eligible if diagnosed and treated
within the past 5 years: carcinoma in situ of the cervix, carcinoma in situ of the
colon, melanoma in situ, and basal cell and squamous cell carcinoma of the skin.

- Cardiac disease that would preclude the use of the drugs included in the B-41
treatment regimens. This includes but is not confined to:

- Active cardiac disease:

- angina pectoris requiring the use of anti-anginal medication;

- ventricular arrhythmias except for benign premature ventricular
contractions controlled by medication;

- conduction abnormality requiring a pacemaker;

- supraventricular and nodal arrhythmias requiring a pacemaker or not
controlled with medication; and

- clinically significant valvular disease.

- History of cardiac disease:

- myocardial infarction;

- congestive heart failure; or

- cardiomyopathy.

- Uncontrolled hypertension, defined as blood pressure greater than 150/90 mm/Hg on
antihypertensive therapy

- History of or current symptomatic interstitial pneumonitis or pulmonary fibrosis or
definitive evidence of interstitial pneumonitis or pulmonary fibrosis described on CT
or chest x-ray in asymptomatic patients

- Sensory/motor neuropathy greater than or equal to grade 2, as defined by the NCI's
CTCAE v3.0

- Malabsorption syndrome, ulcerative colitis, resection of the stomach or small bowel,
or other disease significantly affecting gastrointestinal function

- Other non-malignant systemic disease that would preclude treatment with any of the
treatment regimens or would prevent required follow-up

- Conditions that would prohibit administration of corticosteroids

- Administration of any investigational agents within 30 days before randomization

- Pregnancy or lactation