DAPHNe: Paclitaxel/Trastuzumab/Pertuzumab in HER2-Positive BC

This research study is a Pilot Study, which means investigators are looking at the
feasibility of a new approach for deciding the optimal medical treatment for this type of
breast cancer. The FDA (the U.S. Food and Drug Administration) has approved paclitaxel,
trastuzumab, and pertuzumab as part of a pre-operative treatment option for this disease.

The purpose of this study is to evaluate whether participants and their doctors are willing
to accept a treatment recommendation for post-operative chemotherapy, on the basis of the
participant's response to pre-operative treatment with paclitaxel, trastuzumab, and
pertuzumab.

In addition, the investigators are evaluating how the body's immune system works with
paclitaxel, trastuzumab, and pertuzumab to kill cancer cells. For this reason, the
investigators will collect samples of the participant's breast tumor and samples of the
participant's blood over time to understand the reaction of the immune system to the
participant's tumor.

Inclusion Criteria:

- Patients must have Stage II or III (according to AJCC cancer staging manual anatomic
staging table, 8th edition) histologically confirmed invasive carcinoma of the breast.
A minimum tumor size of 1.5 cm determined by physical exam or imaging (whichever is
larger) is required. Patients with inflammatory breast carcinoma (T4d) are NOT
eligible.

- Tumors must be HER-2 positive, as assessed by standard local institutional protocol
(central testing is not required):

- IHC 3+

- 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 ratio <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. ER- and PR-assays should be performed by
immunohistochemical methods according to the local institution standard protocol.

- Bilateral breast cancers are allowed as long as both cancers are HER2-positive
(as defined in 3.1.2), or the contralateral cancer is a <1 cm, ER+, and HER2-
tumor.

- Patients with multifocal or multicentric disease are eligible as long as all
tumor foci that were tested for HER2 status at the local institution are
HER2-positive, and at least one tumor focus meets eligibility criteria.

- Breast imaging should include dedicated ultrasound of the ipsilateral axilla. For
subjects with a clinically positive axilla based on exam or imaging, a fine
needle aspiration or core biopsy procedure will be performed to determine the
presence of metastatic disease in the lymph nodes (though lymph node sampling
procedure need not be resulted prior to patient's registration on trial, as long
as all other eligibility are met).

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

- ECOG PS 0 or 1.

- Required laboratory values:

- ANC ≥ 1000/mm3

- Hemoglobin ≥ 9 g/dl

- Platelets ≥ 100,000/mm3

- Serum creatinine < 1.5 x ULN (institutional) OR calculated GFR ≥60mL/min.

-Total bilirubin ≤ 1.5 x ULN (institutional). For patients with Gilbert Syndrome, the
direct bilirubin should be within the institutional normal range OR total bilirubin ≤
2.0 mg/dL.

- AST and ALT ≤ 2.5x ULN (institutional)

- Left ventricular ejection fraction (LVEF) ≥ 50%.

- Premenopausal women must have a negative serum pregnancy test within 14 days of
registration, 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.

- 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 registration.

- 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) Class II or higher (see Appendix B), or serious cardiac arrhythmia
requiring medication.

- Significant symptoms (Grade ≥ 2) from 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