T-DM1+Pertuzumab in Pre-OP Early-Stage HER2+ BRCA
T-DM1+Pertuzumab in Pre-OP Early-Stage HER2+ BRCA
This research study is studying a combination of drugs as a possible treatment for breast
 cancer that has tested positive for a protein called HER2.

 The names of the study interventions involved in this study are:

 -  Trastuzumab emtansine (also called T-DM1)

 -  Pertuzumab
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.