MARGetuximab Or Trastuzumab (MARGOT)
MARGetuximab Or Trastuzumab (MARGOT)
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

 -  Paclitaxel, Pertzumab and Trastuzumab (Herceptin)
This is a randomized open-label phase II trial comparing paclitaxel/margetuximab/pertuzumab
 (TMP) to paclitaxel/trastuzumab/pertuzumab (THP) in patients with anatomic stage II-III HER2
 positive breast cancer.

 -  The research study procedures include screening for eligibility and study treatment
 including laboratory evaluations, two mandatory research biopsies and follow up visits.

 -  Participants will be randomized, which means randomly assigned, to one of two treatment
 arms. The treatment arms in this study and the names of the study drugs in each arm are:

 -  Arm A: Paclitaxel, Pertzumab and Margetuximab

 -  Arm B: Paclitaxel, Pertzumab and Trastuzumab

 Participants will receive study treatment for 12 weeks prior to surgery and will be followed
 for 10 years after surgery. After surgery, some participants will continue to receive the
 study drug margetuximab for a year in total, if they respond very well to the first 12 weeks
 of treatment with margetuximab.

 It is expected that about 171 people will take part in this research study.

 This research study is a Phase II clinical trial. Phase II clinical trials test the safety
 and effectiveness of an investigational drug combination to learn whether the drug
 combination works in treating a specific disease. "Investigational" means that the drug
 combination is being studied.

 The FDA (the U.S. Food and Drug Administration) has approved paclitaxel, trastuzumab
 (Herceptin), and pertuzumab as part of a pre-operative treatment option for stage II-III
 HER2-positive breast cancer.

 The use of margetuximab has not been approved by the FDA, for treatment of HER2-positive
 breast cancer, or any other type of cancer. In other clinical studies, this drug has
 prevented or slowed the growth of breast cancer.

 Previous studies also suggest that margetuximab could be more or equally as effective as
 trastuzumab for patients with certain immune system features and stage II-III HER2-positive
 breast cancer.
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 has determined 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 registration. 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.