Paclitaxel and Trastuzumab With or Without Lapatinib in Treating Patients With Stage II or Stage III Breast Cancer That Can Be Removed by Surgery

PRIMARY OBJECTIVE:

I. To determine if the pathologic complete response (pCR) in the breast to neoadjuvant weekly
paclitaxel with trastuzumab plus lapatinib (THL) is 20% greater than the pCR to weekly
paclitaxel with trastuzumab alone (TH).

SECONDARY OBJECTIVES:

I. To determine the pathologic complete response in the breast and axilla, using American
Joint Committee on Cancer (AJCC) Tumor, Lymph Nodes and Metastasis (TMN) criteria (version
6), to neoadjuvant weekly paclitaxel plus human epidermal growth factor 2 (HER2)- targeted
therapy in patients with HER2-positive operable breast cancer.

II. To evaluate residual cancer burden (RCB) as a predictor of long term relapse free
survival (RFS) and overall survival (OS).

III. To document the toxicity of all chemotherapeutic regimens (THL, TH). IV. To determine
the correlation between clinical, radiographic and pathologic response.

V. To compare overall survival (OS), relapse free survival (RFS) and time to first failure
(TFF) among the treatment groups.

VI. To obtain blood, fresh frozen and fixed tumor tissue to test specific hypotheses for
which biomarker data exist and to evaluate biomarkers in blood, serum and tissue that are
likely to influence response to and toxicity of trastuzumab alone or trastuzumab plus
lapatinib, when given with paclitaxel.

VII. To determine the surgical practice patterns for breast conservation and sentinel
lymphadenectomy in patients undergoing neoadjuvant chemotherapy.

VIII. To determine the radiotherapy practice patterns for post-mastectomy and regional nodal
irradiation in patients undergoing neoadjuvant chemotherapy.

IX. To evaluate pharmacogenomic determinants of toxicity.

OUTLINE: Patients are randomized to 1 of 3 treatment arms.

ARM I: Patients receive trastuzumab IV over 30-90 minutes and paclitaxel IV over 1 hour once
weekly and lapatinib ditosylate orally (PO) once daily for 16 weeks in the absence of disease
progression or unacceptable toxicity.

ARM II: Patients receive trastuzumab and paclitaxel as in arm I.

ARM III: Patients receive paclitaxel and lapatinib ditosylate as in arm I. (Discontinued as
of 6-15-11) Within 42 days after completion of neoadjuvant therapy, patients in both arms
undergo definitive surgery (breast conservation or total mastectomy).

After completion of study treatment, patients are followed every 6 months for 2 years and
then annually for up to 10 years.

Inclusion Criteria:

- Pathologic confirmation of invasive breast cancer; patients with inflammatory breast
cancer are not eligible

- Clinical stage II-III operable invasive breast cancer with intent to perform surgical
resection after neoadjuvant therapy

- Patients with multicentric or bilateral disease are eligible as long as the
target lesion meets the eligibility criteria for this study

- Staging to rule out metastatic disease is recommended for clinical stage III
patients

- Tumors must be HER2 positive defined as HER2 3+ by immunohistochemical (IHC) assays or
gene amplification by fluorescence in situ hybridization (FISH) with a ratio of >= 2
on invasive tumor

- Estrogen receptor (ER) and progesterone receptor (PgR) status must be known

- The target lesion in the breast must be >= 1 cm on physical examination or by
radiographic measurement; palpable axillary adenopathy will be documented but not
serve as measurable disease for the primary endpoint; patients with axillary disease
only are not eligible to participate

- Patient agrees to provide pretreatment biopsies

- No prior chemotherapy, hormone therapy, biologic, or radiation therapy with
therapeutic intent for this cancer

- Cardiac ejection fraction must be >= 50% by echocardiogram or multiple gated
acquisition (MUGA) scan

- Eastern Cooperative Oncology Group (ECOG) (Zubrod) performance status 0-1

- Patients must not be pregnant or nursing

- Absolute neutrophil count (ANC) >= 1,000/ul

- Platelet count >= 100,000/ul

- Bilirubin =< 1.5 times upper limit of normal

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 times upper
limit of normal (ULN)

- Serum beta-human chorionic gonadotropin (HCG) negative (in female patients unless
status-post (s/p) hysterectomy or menopausal or no menses for 24 consecutive months);
assay must have a sensitivity of at least 50 mIU/mL