MARGetuximab Or Trastuzumab (MARGOT)

Study Overview
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Brief Summary
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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)

Detailed Description
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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 U.S. Food and Drug Administration (FDA) has approved margetuximab (Margenza) for advanced HER2-positive breast cancer.

Official Title
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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

Conditions
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Breast Cancer, Stage II Breast Cancer, Stage III Breast Cancer, HER2-positive Breast Cancer

Intervention / Treatment
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* Drug: Paclitaxel
* Drug: Pertuzumab
* Drug: Margetuximab
* Drug: Trastuzumab


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Paclitaxel + Pertuzumab + Margetuximab<br>The research study procedures include screening for eligibility and study treatment including laboratory evaluations, two mandatory research biopsies and follow up visits.Cycle=21 days Paclitaxel- via IV, Day 1,8,15 of each cycle Margetuximab via IV, Day 1 of each cycle Pertuzumab via IV, Day 1 of each cycle | Drug: Paclitaxel<br>* Pre-determined dose administered via IV, Day 1,8,15 of each cycle 4 study cycles, or 12 weeks.<br>* Other names: Onxal;Drug: Pertuzumab<br>* Pre-determined dose administered via IV - Day 1 of each 21- day cycle 4 study cycles, or 12 weeks.<br>* Other names: Perjeta;Drug: Margetuximab<br>* Pre-determined dose administered by IV - Day 1 of each 21- day cycle 4 study cycles, or 12 weeks.<br>* Other names: Margenza;|
| Experimental: Paclitaxel + Pertuzumab + Trastuzumab<br>The research study procedures include screening for eligibility and study treatment including laboratory evaluations, two mandatory research biopsies and follow up visits.Cycle=21 days Paclitaxel- via IV, Day 1,8,15 of each cycle Pertuzumab via IV, Day 1 of each cycle Trastuzumab via IV, Day 1 of each cycle | Drug: Paclitaxel<br>* Pre-determined dose administered via IV, Day 1,8,15 of each cycle 4 study cycles, or 12 weeks.<br>* Other names: Onxal;Drug: Pertuzumab<br>* Pre-determined dose administered via IV - Day 1 of each 21- day cycle 4 study cycles, or 12 weeks.<br>* Other names: Perjeta;Drug: Trastuzumab<br>* Pre-determined dose administered via IV Day 1 of each 21- day cycle for 4 study cycles, or 12 weeks.<br>* Other names: Herzuma;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of pathologic complete response (pCR) | Compare rate of pathologic complete response (pCR, defined as RCB 0) in patients with the FF or FV CD16A genotype and anatomic stage II-III HER2+ breast cancer treated with 4 cycles of neoadjuvant TMP or THP | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of pathologic complete response | Compare rate of pCR (RCB 0) in patients treated with TMP or THP, according to hormone receptor-positive (HR+) or hormone receptor-negative (HR-) status | 12 weeks | 
| Residual Cancer Burden (RCB) scores | Assess Residual Cancer Burden (RCB) scores1 in patients treated with TMP or THP, overall and according to HR+ or HR- status. reported using the Residual Cancer Burden calculator from M.D Anderson: | 12 weeks | 
| Radiographic response rate | Assess radiographic response to neoadjuvant therapy in patients treated with TMP or THP, overall and according to HR+ or HR- status.Response criteria are based on the RECIST 1.1 criteria: | 12 Weeks | 
| Number of Participants with Treatment Related Adverse Events according to CTCAE v5.0 | Assessment of DLTs on Arm A during the first 21 days of treatment Maximum grade of all treatment-related adverse events according to CTCAE v5.0 Patient-reported outcomes | From first treatment to 12 weeks | 
| Event-free survival rate (EFS) | The distribution of the survival function and cumulative incidence function for EFS, summarized using the Kaplan Meier product limit estimator and 90% confidence interval (CI) using Greenwood's formula for the standard error | From enrollment to occurrence invasive local/regional recurrence distant recurrence or death from breast cancer or up to 10 years | 
| Event-free survival rate (EFS) Patients with RCB 0 or 1 | The distribution of the survival function and cumulative incidence function for EFS, summarized using the Kaplan Meier product limit estimator and 90% confidence interval (CI) using Greenwood's formula for the standard error | From enrollment to occurrence of invasive local/regional recurrence distant recurrence or death from breast cancer or up to 10 years | 
| Event-free survival rate (EFS)Patients with RCB 2 or 3 | The distribution of the survival function and cumulative incidence function for EFS, summarized using the Kaplan Meier product limit estimator and 90% confidence interval (CI) using Greenwood's formula for the standard error | From enrollment to occurrence of invasive local/regional recurrence distant recurrence or death from breast cancer or up to 10 years | 
| Event-free survival rate (EFS) Patients randomized to neoadjuvant TMP | The distribution of the survival function and cumulative incidence function for EFS, summarized using the Kaplan Meier product limit estimator and 90% confidence interval (CI) using Greenwood's formula for the standard error | From enrollment to occurrence of invasive local/regional recurrence distant recurrence or death from breast cancer or up to 10 years | 
| Event-free survival rate (EFS) patients randomized to neoadjuvant THP | The distribution of the survival function and cumulative incidence function for EFS, summarized using the Kaplan Meier product limit estimator and 90% confidence interval (CI) using Greenwood's formula for the standard error | From enrollment to occurrence of invasive local/regional recurrence distant recurrence or death from breast cancer or up to 10 years | 
| Event-free survival rate (EFS) -Patients with pCR | The distribution of the survival function and cumulative incidence function for EFS, summarized using the Kaplan Meier product limit estimator and 90% confidence interval (CI) using Greenwood's formula for the standard error | From enrollment to occurrence of invasive local/regional recurrence distant recurrence or death from breast cancer or up to 10 years | 
| Event-free survival rate (EFS) -Patients without pCR | The distribution of the survival function and cumulative incidence function for EFS, summarized using the Kaplan Meier product limit estimator and 90% confidence interval (CI) using Greenwood's formula for the standard error | From enrollment to occurrence of invasive local/regional recurrence distant recurrence or death from breast cancer or up to 10 years | 
| Recurrence-free interval rate (RFI) | The distribution of the survival function and cumulative incidence function for RFI summarized using the Kaplan Meier product limit estimator and 90% confidence interval (CI) using Greenwood's formula for the standard error | patients who undergo surgery for breast cancer as the interval from the time of surgery until the occurrence of invasive local/regional recurrence distant recurrence or death from breast cancer or up to 10 years | 
| Recurrence-free interval rate (RFI) RCB 0 or 1 | The distribution of the survival function and cumulative incidence function for RFI summarized using the Kaplan Meier product limit estimator and 90% confidence interval (CI) using Greenwood's formula for the standard error | patients who undergo surgery for breast cancer as the interval from the time of surgery until the occurrence of invasive local/regional recurrence distant recurrence or death from breast cancer or up to 10 years | 
| Recurrence-free interval rate (RFI) RCB 2 or 3 | The distribution of the survival function and cumulative incidence function for RFI summarized using the Kaplan Meier product limit estimator and 90% confidence interval (CI) using Greenwood's formula for the standard error | patients who undergo surgery for breast cancer as the interval from the time of surgery until the occurrence of invasive local/regional recurrence distant recurrence or death from breast cancer or up to 10 years | 
| Recurrence-free interval rate (RFI) Patients randomized to neoadjuvant TMP | The distribution of the survival function and cumulative incidence function for RFI summarized using the Kaplan Meier product limit estimator and 90% confidence interval (CI) using Greenwood's formula for the standard error | patients who undergo surgery for breast cancer as the interval from the time of surgery until the occurrence of invasive local/regional recurrence distant recurrence or death from breast cancer or up to 10 years | 
| Recurrence-free interval rate (RFI) Patients randomized to neoadjuvant THP | The distribution of the survival function and cumulative incidence function for RFI summarized using the Kaplan Meier product limit estimator and 90% confidence interval (CI) using Greenwood's formula for the standard error | patients who undergo surgery for breast cancer as the interval from the time of surgery until the occurrence of invasive local/regional recurrence distant recurrence or death from breast cancer or up to 10 years | 
| Recurrence-free interval rate (RFI) Patients with pCR | The distribution of the survival function and cumulative incidence function for RFI summarized using the Kaplan Meier product limit estimator and 90% confidence interval (CI) using Greenwood's formula for the standard error | patients who undergo surgery for breast cancer as the interval from the time of surgery until the occurrence of invasive local/regional recurrence distant recurrence ror death from breast cancer or up to 10 years | 
| Recurrence-free interval rate (RFI) Patients without pCR | The distribution of the survival function and cumulative incidence function for RFI summarized using the Kaplan Meier product limit estimator and 90% confidence interval (CI) using Greenwood's formula for the standard error | patients who undergo surgery for breast cancer as the interval from the time of surgery until the occurrence of invasive local/regional recurrence distant recurrence or death from breast cancer or up to 10 years | 
| Overall survival Rate (OS) | The distribution of the survival function and cumulative incidence function for OS, summarized using the Kaplan Meier product limit estimator and 90% confidence interval (CI) using Greenwood's formula for the standard error | up to 10 years from definitive surgery. | 
| Overall survival Rate (OS) Patients with RCB 0 or 1 | The distribution of the survival function and cumulative incidence function for OS, summarized using the Kaplan Meier product limit estimator and 90% confidence interval (CI) using Greenwood's formula for the standard error | up to 10 years from definitive surgery. | 
| Overall survival Rate (OS) Patients with RCB 2 or 3 | The distribution of the survival function and cumulative incidence function for OS, summarized using the Kaplan Meier product limit estimator and 90% confidence interval (CI) using Greenwood's formula for the standard error | up to 10 years from definitive surgery. | 
| Overall survival Rate (OS) Patients randomized to neoadjuvant TMP | The distribution of the survival function and cumulative incidence function for OS, summarized using the Kaplan Meier product limit estimator and 90% confidence interval (CI) using Greenwood's formula for the standard error | up to 10 years from definitive surgery. | 
| Overall survival Rate (OS) randomized to neoadjuvant THP | The distribution of the survival function and cumulative incidence function for OS, summarized using the Kaplan Meier product limit estimator and 90% confidence interval (CI) using Greenwood's formula for the standard error | up to 10 years from definitive surgery. | 
| Overall survival Rate (OS) Patients with pCR | The distribution of the survival function and cumulative incidence function for OS, summarized using the Kaplan Meier product limit estimator and 90% confidence interval (CI) using Greenwood's formula for the standard error | up to 10 years from definitive surgery. | 
| Overall survival Rate (OS) Patients without CR | The distribution of the survival function and cumulative incidence function for OS, summarized using the Kaplan Meier product limit estimator and 90% confidence interval (CI) using Greenwood's formula for the standard error | up to 10 years from definitive surgery. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast Cancer, Stage II Breast Cancer, Stage III Breast Cancer, HER2-positive Breast Cancer