Combination of Weekly Paclitaxel With Neratinib and Trastuzumab in Women With Metastatic HER2-positive Breast Cancer

Patients will receive concurrent therapy with paclitaxel (80 mg/m2 IV on days 1, 8, and 15
of a 28-day cycle), trastuzumab (4 mg/kg IV loading dose, then 2 mg/kg IV weekly), and
neratinib. The neratinib dose-escalation will include 4 dose levels (120 mg, 160 mg, 200
mg, and 240 mg) as a daily oral dose.

The neratinib dose-escalation for the study will proceed on the basis of dose-limiting
toxicity (DLT) during cycle 1. DLT will be defined as the occurrence of 1 or more of the
following events during cycle 1: any grade diarrhea that is associated with fever or
dehydration; grade 3 diarrhea lasting more than 2 days on optimal medical therapy; grade 4
diarrhea of any duration; grade 3 or 4 neutropenia associated with fever; grade 4
neutropenia lasting more than 7 days; grade 4 thrombocytopenia; grade 3 or 4
non-hematological toxicity; or any toxicity-related delay of more than 2 weeks to initiate
cycle 2. Patients will be enrolled at the next dose level when all evaluable patients at
the same dose level have completed the first treatment cycle. Enrolled patients will remain
on the assigned dose level treatment until toxicity or disease progression.

Inclusion Criteria:

- Co-morbid conditions should be taken into consideration, but not the diagnosis of
metastatic breast cancer.

- 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 ECOG performance status must be 0, 1, or 2.

- Patients must have the ability to swallow oral medication.

- Patients must have histologic or cytologic confirmation of the diagnosis of invasive
adenocarcinoma of the breast.

- There must be documentation that the patient has evidence (measurable or
non-measurable) of metastatic breast cancer. Histologic confirmation of metastatic
disease is not required.

- Patients must have ER analysis performed on the primary tumor prior to study entry.
If ER analysis is negative, then 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 study entry. Assays
using FISH or CISH require gene amplification. Assays using IHC require a strongly
positive (3+) staining score.

- At the time of study entry, blood counts performed within 4 weeks prior to study
entry must meet the following criteria: ANC must be greater than or equal to
1000/mm3; Platelet count must be greater than or equal to 100,000/mm3; Hemoglobin
must be greater than or equal to 9 g/dL

- The following criteria for evidence of adequate hepatic function performed within 4
weeks prior to study entry must be met: total bilirubin must be less than or equal to
1.5 x ULN; AST and ALT must be less than or equal to 2.5 x ULN for the lab or less
than or equal to 5 x ULN if liver metastasis

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

- The LVEF assessment by 2-D echocardiogram or MUGA scan performed within 90 days prior
to study entry must be greater than or equal to 50% regardless of the facility's LLN.

Exclusion Criteria:

- Previous therapy with neratinib for any malignancy.

- Symptomatic brain metastases or brain metastases requiring chronic steroids to
control symptoms.

- 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
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 90 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 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 study entry. (Note: Pregnancy testing should
be performed within 14 days prior to study entry according to institutional standards
for women of childbearing potential.)

- 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 study entry.