Docetaxel, Carboplatin, and Trastuzumab and/or Lapatinib in Treating Women With Stage I, Stage II, or Stage III Breast Cancer That Can Be Removed by Surgery

OBJECTIVES:

Primary

- To investigate the clinical efficacy of neoadjuvant docetaxel and carboplatin in
combination with trastuzumab (Herceptin®) and/or lapatinib ditosylate by estimating the
pathologic complete response (pCR) rate in the breast and axilla of women with
HER2/neu-positive resectable stage I-III adenocarcinoma of the breast.

Secondary

- To estimate the molecular effects of lapatinib ditosylate and trastuzumab alone or in
combination on tumor tissues of these patients by assessing changes in gene expression
using serial gene microarray analysis.

- To assess for gene expression and/or biomarker changes that may be correlated with or
predict pCR and clinical response to lapatinib ditosylate and/or trastuzumab in these
patients.

- To evaluate the safety and tolerability of these regimens in these patients.

- To evaluate the clinical efficacy of these regimens by estimating the clinical
objective response rate (complete response and partial response) in these patients.

- To estimate the rate of congestive heart failure or drop in LVEF (> 10% points from
baseline and below lower limits of normal) in each of the three treatment arms.

OUTLINE: This is a multicenter study. Patients are stratified according to baseline tumor
size (≤ 3 cm vs > 3 cm) and hormone receptor status (estrogen receptor [ER]- and/or
progesterone receptor [PR]-positive vs ER- and PR- negative). Patients are randomized to 1
of 3 treatment arms.

- Arm I: Patients receive a trastuzumab IV over 90 minutes on day 1 in course 1. Patients
receive docetaxel IV, carboplatin IV, and trastuzumab IV over 30 minutes on day 1 in
courses 2-7. Courses repeat every 21 days in the absence of disease progression or
unacceptable toxicity.

- Arm II: Patients receive oral lapatinib ditosylate once daily on days 1-21 in course 1.
Patients receive docetaxel IV, carboplatin IV as in arm I and oral lapatinib ditosylate
once daily on days 1-21 in courses 2-7. Courses repeat every 21 days in the absence of
disease progression or unacceptable toxicity.

- Arm III: Patients receive trastuzumab IV as in arm I on day 1 and oral lapatinib
ditosylate as in arm II on days 1-21 in course 1. Patients receive docetaxel IV,
carboplatin IV, and trastuzumab IV as in arm I on day 1 and oral lapatinib ditosylate
as in arm II on days 1-21 in courses 2-7. Courses repeat every 21 days in the absence
of disease progression or unacceptable toxicity.

Within 4-6 weeks after completion of chemotherapy, all patients under go definitive surgery
and/or radiotherapy at the discretion of the treating physician. Tumor biopsy and blood
samples are collected for biomarker analysis and molecular analysis at baseline, after
course 1, and at the time of definitive breast surgery or completion of chemotherapy. Gene
expression changes are analyzed by mRNA microarray analysis and molecular changes in protein
expression profiles by IHC. Samples may also be analyzed by RT-PCR.

Inclusion Criteria:

- Women aged 18 to 70 years, inclusive

- Histologically or cytologically confirmed adenocarcinoma of the breast

- Stage I, II or III disease (early stage) with tumor measuring ≥ 1 cm and meeting any
the following criteria:

- Grade > 1

- Estrogen receptor- and progesterone receptor-negative

- Age ≤ 35 years

- HER2/neu-positivity by fluorescence in situ hybridization (FISH)

- Estrogen and progesterone receptor status known prior to study entry.

- ECOG performance status 0-1 Adequate organ function (ejection fraction>- lower limit
of normal) as determined by MUGA or echocardiogram.

- If female of childbearing potential, pregnancy test is negative and is willing to use
effective contraception while on treatment and for at least 3 months after the last
dose of study therapy.

- patient is accessible and willing to comply with treatment, tissue acquisition and
follow up.

- patient is willing to provide written informed consent prior to performance of any
study-related procedure.

- Adequate organ function as defined by the following laboratory values

- Absolute neutrophil count ≥ 1,500/mm³

- Platelet count ≥ 100,000/mm³

- Hemoglobin ≥ 9.0 g/dL

- Creatinine < 1.5 mg/dL

- Total bilirubin ≤ 1.0 times upper limit of normal (ULN) (< 3 times ULN in patients
with Gilbert's syndrome confirmed by genotyping or Invader UGTIA1 molecular assay)

- Alkaline phosphatase (AP), ALT, and AST must meet 1 of the following criteria:

- AP normal AND AST/ALT ≤ 2.5 times upper limit of normal (ULN)

- AP ≤ 2.5 times ULN AND ALT/AST ≤ 1.5 times ULN

- AP ≤ 5 times ULN AND AST/ALT normal

Exclusion Criteria:

- Inflammatory breast cancer, defined as the presence of erythema or induration
involving > 1/3 of the breast

- Bilateral invasive breast cancer

- Metastatic disease

- Concurrent therapy with any other non-protocol anti-cancer therapy

- history of any other malignancy within the past 5 years, with the exception of
nonmelanoma skin cancer or carcinoma in situ of the cervix

- pre-existing motor or sensory neurotoxicity ≥ grade 2 by NCI NTCAE version 3.0

- cardiac disease including any of the following:

- Myocardial infarction within the past 6 months

- Unstable angina

- New York Heart Association class II-IV congestive heart failure

- inflammatory bowel disease or other bowel condition causing chronic diarrhea and
requiring active therapy

- active, uncontrolled infection requiring parenteral antimicrobials

- known hypersensitivity to Chinese hamster ovary products or other recombinant human
or humanized antibodies and/or known hypersensitivity to any of the study drugs or
their ingredients (e.g., polysorbate 80 in docetaxel)

- other medical or psychiatric disorder that, in the opinion of the treating physician,
would contraindicate the use of study drugs or place the subject at undue risk for
treatment complications

- hormonal agent (e.g., raloxifene, tamoxifen citrate, or other selective estrogen
receptor modulators) for osteoporosis or prevention of breast cancer. subjects must
have discontinued these agents 14 days prior to first baseline biopsy.

- prior ipsilateral radiotherapy for invasive or noninvasive breast cancer or to the
ipsilateral chest wall for any malignancy

- prior chemotherapy, radiotherapy, or endocrine therapy for currently diagnosed
invasive or noninvasive breast cancer

- concurrent ovarian hormonal replacement therapy. Prior treatment must be stopped
prior to first baseline biopsy.

- male subjects

- pregnant or lactating subjects