MARGetuximab Or Trastuzumab (MARGOT): A phase II study comparing neoadjuvant paclitaxel/margetuximab/pertuzumab to paclitaxel/trastuzumab/pertuzumab in patients with Stage II-III HER2-positive breast cancer

The purpose of this study is to determine how well participants with stage II-III
HER2-positive breast cancer respond to pre-operative treatment using one of two different
combinations of drugs.

Drugs and Combinations used:

- Paclitaxel, Pertzumab and Margetuximab (Margenza)

- Paclitaxel, Pertzumab and Trastuzumab (Herceptin)

Inclusion Criteria:

- 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 (in breast mass or axillary lymph node) determined by physical exam or
imaging (whichever is larger) is required. Patients with inflammatory breast carcinoma
(T4d) are NOT eligible.

- Centrally confirmed to have a low affinity CD16 germline genotype (FF or FV)

- HER-2 positive by 2018 American Society of Clinical Oncology/College of American
Pathologists criteria, as assessed by standard institutional guidelines (central
testing is not required).

- ER/PR determination is required. ER- and PR-assays should be performed by
immunohistochemical methods according to standard institutional guidelines

- 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+ tumor.

- Patients with multifocal or multicentric disease are eligible if the treating
investigator hasdetermined the patient should be treated as HER2-positive.

- 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 performance status 0 or 1

- Required laboratory values demonstrating adequate organ function:

- 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%.

- Women of childbearing potential must have a negative serum pregnancy test within 14
days of treatment start. Childbearing potential is defined as: those who have not been
surgically sterilized and/or have had a menstrual period in the past 12 months

- 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 or contralateral DCIS or LCIS are eligible.

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

- Non-English-speaking patients are eligible but will be exempt from patient-completed
questionnaires.

- Willing and able to sign informed consent.

- Willing to undergo breast biopsy for research purposes.

Exclusion Criteria:

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

- Active, unresolved infection requiring intervention

- 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, 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.

- Patients with any prior history of invasive breast cancer within the past 5 years are
not eligible. Non-metastatic invasive breast cancers diagnosed more than 5 years ago
and any other type of prior non-metastatic cancer is allowed.