Phase II Randomized Trial Evaluating Neoadjuvant Therapy With Neratinib and/or Trastuzumab Followed by Postoperative Trastuzumab in Women With Locally Advanced HER2-positive Breast Cancer

Sequential AC followed by a taxane initiated concurrently with trastuzumab has become a
standard of care in the United States for operable HER2-positive breast cancer following
initial surgery.

Trastuzumab, a recombinant humanized monoclonal antibody against the extracellular domain of
the HER2 protein, was developed to block HER2 signaling pathways and has been shown to
substantially improve the efficacy of chemotherapy in women with metastatic and early-stage
HER2-positive breast cancers.

However, some patients develop recurrence and succumb to the disease following
trastuzumab-based adjuvant therapy. Evaluation of additional approaches that target this
pathway have shown promising results in trastuzumab-resistant breast cancer.

Neratinib (HKI-272), an orally administered small molecule, is an irreversible inhibitor of
pan ErbB receptor tyrosine kinases, which distinguishes this small molecule from lapatinib.
Because of the high degree of homology between kinase domains of EGFR and HER2, neratinib
inhibits both EGFR and HER2 function. Neratinib is designed to block kinase activity by
binding to the ATP site of the enzymes. In BT474 cell lines, HKI-272 effectively repressed
phosphorylation of MAPK and Akt signal transduction pathways, whereas trastuzumab failed to
completely inhibit HER2 receptor phosphorylation or downstream signaling events. In tumor
xenografts which overexpress HER2, neratinib has been observed to repress tumor growth in a
dose-dependent manner.

A comparison of overall response rates with lapatinib and neratinib in comparable patients,
albeit in separate Phase II studies, suggest favorable efficacy of neratinib as monotherapy
in trastuzumab-refractory patients (response rate of 5.1% vs. 26%) and in trastuzumab-naïve
patients (response rate of 24% vs. 56%). Taken together, the data support the rationale that
a small molecule TKI may be more efficacious than trastuzumab in the neoadjuvant setting, and
that neratinib may be more active than lapatinib.

The study started as a two-arm design with randomization to the control arm (Arm 1) and to
the investigational arm (Arm 2) in a 1:2 ratio. With the addition of a second investigation
arm, (Arm 3), the study becomes a three-arm design with a 1:1:1 allocation ratio (about equal
numbers of patients randomized to Arms 1, 2, and 3). The sample size will be up to 126
patients with about 42 evaluable patients in each arm. Patients who enter the trial but are
not treated for any reason will be replaced. Accrual is expected to occur over 18 months.
Patients will be randomized to one of three neoadjuvant therapy regimens: Patients in Arm 1
will receive 4 cycles of paclitaxel 80 mg/m2 administered on Days 1, 8, and 15 of a 28-day
cycle. Trastuzumab will begin concurrently with paclitaxel and will be given weekly for a
total of 16 doses (4 mg/kg loading dose, then 2 mg/kg weekly). Following
paclitaxel/trastuzumab, standard AC will be administered every 21 days for 4 cycles; Patients
in Arm 2 will receive 4 cycles of paclitaxel 80 mg/m2 administered on Days 1, 8, and 15 of a
28-day cycle. Neratinib 240 mg will be taken orally once daily beginning on Day 1 of
paclitaxel and continuing through Day 28 of the final cycle of paclitaxel. Standard AC
administered every 21 days for 4 cycles will be administered following paclitaxel/neratinib
therapy; Patients in Arm 3 will receive 4 cycles of paclitaxel 80 mg/m2 administered Days 1,
8, and 15 of a 28 day cycle with trastuzumab, beginning concurrently with paclitaxel, given
weekly for a total of 16 doses (4 mg/kg loading dose, then 2 mg/kg weekly). Neratinib 200 mg
will be taken orally once daily beginning on Day 1 of paclitaxel and continuing through Day
28 of the final cycle of paclitaxel. Standard AC will be administered every 21 days for 4
cycles following paclitaxel/trastuzumab/neratinib therapy.

In all arms, clinical response will be assessed by palpation between the chemotherapy
regimens and prior to surgery. Following recovery from surgery, trastuzumab (8 mg/kg loading
dose, then 6 mg/kg) will be administered every 3 weeks to complete 1 year of targeted therapy
(either preoperative trastuzumab therapy or neratinib therapy). Patients will receive
adjuvant radiation therapy and endocrine therapy as clinically indicated.

At the time of local IRB approval of amendment #6, submission of fresh tumor samples for FB-7
correlative science studies will be optional for all patients. For patients who agree, a core
biopsy procedure to procure three fresh tumor samples will be performed before randomization
(after the patient has signed the consent form and has been screened for eligibility).
Submission of a tumor block from the diagnostic core biopsy sample and a tumor block from
gross residual disease greater than or equal to 1.0 cm, if found in the surgical specimen,
will be required. In addition, a blood sample collected after randomization (before the start
of study therapy) will also be required for the correlative science studies.

Beginning with Amendment #8, Arm 1 and Arm 2 were closed to accrual in the US subsequent to
FDA approval of pertuzumab when given in combination with trastuzumab for neoadjuvant therapy
in breast cancer. Pertuzumab and trastuzumab are both targeted therapy drugs. US patients
enrolled in the study will not be randomized but will be placed into the combined targeted
therapy group, Arm 3 NR, only. Randomization and study therapy for patients entered via
institutions outside of the US remains unchanged.

Inclusion Criteria:

- Patients should have a life expectancy of at least 10 years, excluding their diagnosis
of breast cancer.

- Submission of a block from the diagnostic biopsy sample and from the surgical sample,
if gross residual disease greater than or equal to 1.0 cm was removed at the time of
surgery, is required for all patients

- Patients of reproductive potential must agree to use an effective non-hormonal method
of contraception during therapy and for at least 6 months after the last dose of study
therapy.

- The Eastern Cooperative Oncology Group (ECOG) performance status must be 0 or 1.

- Patients must have the ability to swallow oral medication.

- The diagnosis of invasive adenocarcinoma of the breast must have been made by core
needle biopsy or by limited incisional biopsy.

- Patients must have ER analysis performed on the primary tumor prior to randomization.
If ER analysis is negative, then progesterone receptor (PgR) analysis must also be
performed. (Patients are eligible with either hormone receptor-positive or hormone
receptor-negative tumors.)

- Breast cancer must be determined to be HER2-positive prior to randomization. Assays
using FISH or CISH require gene amplification. Assays using IHC require a strongly
positive (3+) staining score.

- Clinical staging, based on the assessment by physical exam, must be American Joint
Committee on Cancer (AJCC) stage IIB, IIIA, IIIB, or IIIC: cT2 and cN1; cT3 and cN0 or
cN1; Any cT and cN2 or cN3; or cT4

- The patient must have a mass in the breast or axilla measuring greater than or equal
to 2.0 cm by physical exam, unless the patient has inflammatory breast cancer, in
which case measurable disease by physical exam is not required.

- At the time of randomization, blood counts performed within 4 weeks prior to
randomization must meet the following criteria: absolute neutrophil count (ANC) must
be greater than or equal to 1200/mm3; Platelet count must be greater than or equal to
100,000/mm3; Hemoglobin must be greater than or equal to 10 g/dL

- The following criteria for evidence of adequate hepatic function performed within 4
weeks prior to randomization must be met: total bilirubin must be less than or equal
to upper limit of normal (ULN) for the lab unless the patient has a bilirubin
elevation greater than ULN to 1.5 x ULN due to Gilbert's disease or similar syndrome
involving slow conjugation of bilirubin; and alkaline phosphatase must be less than or
equal to 2.5 x ULN for the lab; and aspartate aminotransferase (AST) and ALT must be
less than or equal to 1.5 x ULN for the lab.

- Patients with alkaline phosphatase greater than ULN but less than or equal to 2.5 x
ULN are eligible for inclusion in the study if liver imaging (CT, MRI, PET, or PET-CT
scan) performed within 4 weeks prior to randomization does not demonstrate metastatic
disease and the requirements for adequate hepatic function are met.

- Patients with either unexplained skeletal pain or alkaline phosphatase that is greater
than ULN but less than or equal to 2.5 x ULN are eligible for inclusion in the study
if a bone scan, PET-CT scan, or PET scan performed within 4 weeks prior to
randomization does not demonstrate metastatic disease. Patients with suspicious
findings on bone scan or PET scan are eligible if suspicious findings are determined
to be benign by x-ray, MRI, or biopsy.

- Serum creatinine performed within 4 weeks prior to randomization must be less than or
equal to 1.5 x ULN for the lab.

- The left ventricular ejection fraction (LVEF) assessment by 2-D echocardiogram or
multiple gated acquisition(MUGA) scan performed within 90 days prior to randomization
must be greater than or equal to 50% regardless of the facility's LLN.

Exclusion Criteria:

- fine-needle aspiration (FNA) alone to diagnose the primary breast cancer.

- Excisional biopsy or lumpectomy performed prior to randomization.

- Surgical axillary staging procedure prior to randomization. (Procedures that are
permitted prior to study entry include: 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.)

- Definitive clinical or radiologic evidence of metastatic disease. (Note: Chest imaging
[mandatory for all patients] and other imaging [if required] must have been performed
within 90 days prior to randomization.)

- History of ipsilateral invasive breast cancer regardless of treatment or ipsilateral
ductal carcinoma in situ (DCIS) treated with radiation therapy (RT). (Patients with a
history of LCIS are eligible.)

- Contralateral invasive breast cancer at any time. (Patients with contralateral DCIS or
lobular carcinoma in situ (LCIS) are eligible.)

- History of non-breast malignancies (except for in situ cancers treated only by local
excision and basal cell and squamous cell carcinomas of the skin) within 5 years prior
to randomization.

- Known metastatic disease from any malignancy (solid tumor or hematologic).

- Previous therapy with anthracyclines, taxanes, cyclophosphamide, trastuzumab, or
neratinib for any malignancy.

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

- Continued endocrine therapy such as raloxifene or tamoxifen (or other SERM) or an
aromatase inhibitor. (Patients are eligible if these medications are discontinued
prior to randomization.)

- Any continued sex hormonal therapy, e.g., birth control pills and ovarian hormone
replacement therapy. Patients are eligible if these medications are discontinued prior
to randomization.

- Active hepatitis B or hepatitis C with abnormal liver function tests.

- Intrinsic lung disease resulting in dyspnea.

- Active infection or chronic infection requiring chronic suppressive antibiotics.

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

- Persistent greater than or equal to grade 2 diarrhea regardless of etiology.

- Sensory or motor neuropathy greater than or equal to grade 2, as defined by the NCI
Common Toxicity Criteria for Adverse Effects (CTCAE) v3.0.

- Conditions that would prohibit intermittent administration of corticosteroids for
paclitaxel premedication.

- Chronic daily treatment with corticosteroids with a dose of greater than or equal to
10 mg/day methylprednisolone equivalent (excluding inhaled steroids).

- Uncontrolled hypertension defined as a systolic BP greater than 150 mmHg or diastolic
BP greater than 90 mmHg, with or without anti-hypertensive medications. (Patients with
hypertension that is well-controlled on medication are eligible.)

- Cardiac disease (history of and/or active disease) that would preclude the use of any
of the drugs included in the treatment regimen. This includes but is not confined to:
Active cardiac disease: symptomatic angina pectoris within the past 180 days that
required the initiation of or increase in anti-anginal medication or other
intervention; ventricular arrhythmias except for benign premature ventricular
contractions; supraventricular and nodal arrhythmias requiring a pacemaker or not
controlled with medication; conduction abnormality requiring a pacemaker; valvular
disease with documented compromise in cardiac function; and symptomatic pericarditis.
History of cardiac disease: myocardial infarction documented by elevated cardiac
enzymes or persistent regional wall abnormalities on assessment of LV function;
history of documented congestive heart failure (CHF); and documented cardiomyopathy.

- Other nonmalignant systemic disease that would preclude the patient from receiving
study treatment or would prevent required follow-up.

- Pregnancy or lactation at the time of randomization.

- The investigator should assess the patient to determine if she has any psychiatric or
addictive disorder or other condition that, in the opinion of the investigator, would
preclude her from meeting the study requirements.

- Use of any investigational agent within 4 weeks prior to randomization.