T-DM1+Pertuzumab in Pre-OP Early-Stage HER2+ BRCA

This research study is a Phase II clinical trial. Phase II clinical trials test the safety
and effectiveness of an investigational intervention to learn whether the intervention works
in treating a specific disease. "Investigational" means that the intervention is being
studied. The FDA (the U.S. Food and Drug Administration) has not approved T-DM1 for
pre-operative use in breast cancer but it has been approved for other uses in breast cancer.
The FDA has approved pertuzumab as a pre-operative treatment.

Inclusion Criteria:

- Patients must have HER2-positive Stage II or III histologically confirmed invasive
carcinoma of the breast. A minimum tumor size of 2 cm determined by physical exam or
imaging is required.

- HER-2 positive, confirmed by central testing (Clarient labs): IHC 3+ and/or FISH
positive based on one of the three following criteria:

- Single-probe average HER2 copy number≥6.0 signals/cell OR

- Dual-probe HER2/CEP17 <2.0 with an average HER2 copy number ≥6.0 signals/cell OR

- Dual-probe HER2/CEP17 ratio ≥2.0

- ER/PR determination is required.

- Bilateral breast cancers are allowed if both cancers are HER2-positive.

- Patients with multifocal or multicentric disease are eligible as long as one area
meets eligibility criteria.

- Breast imaging should include the ipsilateral axilla. For subjects with a clinically
negative axilla, a sentinel lymph node biopsy will be performed either before or after
preoperative therapy at the discretion of the subject's physicians. For subjects with
a clinically positive axilla, a needle aspiration, core biopsy or SLN procedure will
be performed to determine the presence of metastatic disease in the lymph nodes.

- Men and women (with any menopausal status) ≥ 18 years of age

- ECOG performance status 0 or 1

- Required laboratory values:

- ANC ≥1500/mm3

- Hemoglobin ≥ 9 g/dl

- Platelets ≥100,000/mm3

- Serum creatinine < 1.5 X ULN (institutional)

- Total bilirubin ≤ 1.0 X ULN (institutional) For patients with Gilbert syndrome,
the direct bilirubin should be within the institutional normal range.

- AST and ALT ≤ 1.5x ULN (institutional)

- Alkaline phosphatase ≤1.5x ULN (institutional)

- Documentation of hepatitis B virus (HBV) and hepatitis C virus (HCV) serologies is
required: this includes hepatitis B surface antigen (HBsAg) and/or total hepatitis B
core antibody (HBcAb) in addition to HCV antibody testing.

- Only for patients who test positive for hep B/C virus: PTT/INR < ULN (institutional)

- Left ventricular ejection fraction (LVEF) ≥ 55%

- Premenopausal women must have a negative serum pregnancy test, including women who
have had a tubal ligation and for women less than 12 months after the onset of
menopause.

- Women of childbearing potential and men with partners of childbearing potential must
be willing to use one highly effective form of non-hormonal contraception or two
effective forms of non-hormonal contraception by the patient and/or partner and
continue its use for the duration of the study treatment and for 7 months after the
last dose of study treatment.

- Potent CYP3A4 inhibitors, such as ketoconazole and erythromycin, should be avoided
during the study treatment period with T-DM1.

- Excessive alcohol intake should be avoided (occasional use is permitted).

- Patients with a history of ipsilateral DCIS are eligible.

- Patients undergoing breast conservation therapy (i.e. lumpectomy) must not have any
contraindications to radiation therapy.

- Willing and able to sign informed consent.

- Willing to provide tissue for research purposes.

Exclusion Criteria:

- Pregnant or nursing women due to the teratogenic potential of the study drugs.

- Active, unresolved infection.

- Receipt of intravenous antibiotics for infection within 7 days prior to enrollment.

- Patients with active liver disease, for example, due to hepatitis B virus, hepatitis C
virus, autoimmune hepatic disorder, or sclerosing cholangitis.

- Uncontrolled hypertension (systolic >180 mm Hg and/or diastolic >100 mm Hg) or
clinically significant (i.e. active) cardiovascular disease: cerebrovascular
accident/stroke or myocardial infarction within 6 months prior to first study
medication, unstable angina, congestive heart failure (CHF) of New York Heart
Association (NYHA) Grade II or higher, or serious cardiac arrhythmia requiring
medication.

- Significant symptoms (Grade ≥2) peripheral neuropathy.

- Other concurrent serious diseases that may interfere with planned treatment, including
severe pulmonary conditions/illness, uncontrolled infections, uncontrolled diabetes.

- Any prior treatment for the current breast cancer, including chemotherapy, hormonal
therapy, radiation or experimental therapy.