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.