Phase II Randomized Trial of Neoadjuvant Trastuzumab and/or Lapatinib Plus Chemotherapy (Sequential FEC75 and Paclitaxel) in Women With ErbB2- (HER2/Neu-) Overexpressing Invasive Breast Cancer

Inclusion Criteria:

- Have signed an informed consent form (ICF) and a Patient Authorization Form (HIPAA).

- Have histologically or cytologically confirmed ErbB2- (HER2/neu-) overexpressing
invasive breast cancer (T2-4, N0-2).

- ErbB2 overexpressing breast cancer, defined as one of the following definitions:

- 3+ staining by immunohistochemistry (IHC),

- a fluorescent in situ hybridization (FISH) result of more than six HER2 gene copies
per nucleus

- a FISH ratio of more than 2.2.

- Have either measurable or evaluable disease.

- Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1
(Refer to Section 11.4).

- Have LVEF within the institutional range of normal as measured by either
echocardiogram (ECHO) or MUGA scans. The same modality must be used consistently
throughout the study.

- Be deemed able to tolerate 8 cycles of preoperative chemotherapy, including 4 cycles
with an anthracycline (epirubicin).

- Must be willing to undergo 2 mandatory core biopsies (4 passes each) after diagnosis
to obtain tissue for biologic expression profiling. Any subject with clinically
palpable residual disease may undergo an optional third biopsy to allow
identification of presumed pathways of resistance to therapy. This information might
be useful in providing the subject with options for other targeted therapies if
definitive surgery confirms residual disease. Definitive local therapy with surgery
and radiation therapy as indicated will be performed after completion of 12 weeks of
paclitaxel-based chemotherapy.

- Are able to swallow and retain oral medication (intact pill).

- Are able to complete all screening assessments as outlined in the protocol.

- Have adequate organ function as defined in Table 4:

Table 1 Baseline Laboratory Values

Hematologic:

ANC (absolute neutrophil count) >1.5 x 109/L hemoglobin >9 g/dL platelets >75 x 109/L

Hepatic:

albumin >2.5 g/dL serum bilirubin <1.25 x ULN AST / ALT <3 x ULN if no documented liver
metastases AST / ALT <3 x ULN with documented liver metastases

Renal:

serum creatinine <2.0 mg/dL

- OR - calculated creatinine clearance >40 mL/min

- Are subjects aged >18 years with any menopausal status:

Non-child-bearing potential (i.e., women with functioning ovaries who have a current
documented tubal ligation or hysterectomy, or women who are postmenopausal)

Child-bearing potential (i.e., women with functioning ovaries and no documented impairment
of oviductal or uterine function that would cause sterility.) This category includes women
with oligomenorrhea (severe), women who are perimenopausal, and young women who have begun
to menstruate. These subjects must have a negative serum pregnancy test at screening and
agree to one of the following:

Complete abstinence from intercourse from 2 weeks prior to administration of the first
dose of study medication until 28 days after the final dose of study medication; or
Consistent and correct use of one of the following acceptable methods of birth control:
male partner who is sterile prior to the female subject's entry into the study and is the
sole sexual partner for that female subject; any intrauterine device (IUD) with a
documented failure rate of less than 1% per year; oral contraceptives (either combined or
progestogen only) where not contraindicated for this subject population or per local
practice.; or barrier methods, including diaphragm or condom with a spermicide.

Please note that breast cancer subjects on this trial cannot receive injectable
levonorgestrel or injectable progestogen due to the potential for an adverse effect of
anti-hormonal therapies on chemotherapy administered for breast cancer [Albain, 2002].
Progestogen may also affect the proliferative rate of endocrine-responsive tumors.

Exclusion Criteria:

- Have received any prior chemotherapy.

- Had prior therapy with an ErbB1 and/or ErbB2 inhibitor.

- Are receiving concurrent anti-cancer therapy (chemotherapy, immunotherapy, and
biologic therapy) while taking study medication.

- 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 active cardiac disease, defined as one or more of the following:

History of uncontrolled or symptomatic angina History of arrhythmias requiring
medications, or clinically significant Myocardial infarction <6 months from study entry
Uncontrolled or symptomatic congestive heart failure Ejection fraction below the
institutional normal limit Any other cardiac condition, which in the opinion of the
treating physician, would make this protocol unreasonably hazardous for the patient

- Are pregnant or breastfeeding.

- Have received concurrent treatment with an investigational agent or participate in
another clinical trial.

- Have received concurrent treatment with prohibited medications (refer to Section
5.8.2 for details on prohibited medications).

- Have 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 any of the agents used in this study or their excipients.

- Are receiving therapeutic anti-coagulation therapy (i.e. warfarin, heparin).