MARGetuximab Or Trastuzumab (MARGOT)

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.

• Paclitaxel (Drug), also known as Taxol, Onxal: Pre-determined dose administered via IV, Day 1,8,15 of each cycle 4 study cycles, or 12 weeks.
• Pertuzumab (Drug), also known as Perjeta: Pre-determined dose administered via IV - Day 1 of each 21- day cycle 4 study cycles, or 12 weeks.
• Margetuximab (Drug), also known as Margenza: Pre-determined dose administered by IV - Day 1 of each 21- day cycle 4 study cycles, or 12 weeks.
• Trastuzumab (Drug), also known as Herceptin, Kanjinti, Ogivri, Herzuma: Pre-determined dose administered via IV Day 1 of each 21- day cycle for 4 study cycles, or 12 weeks.

Primary outcomes

• Pathologic Complete Response (pCR) [12 weeks]: Compare the percentage of pathologic complete response (pCR) between patients treated with neoadjuvant TMP versus THP. Subject was considered a pCR responder if they achieved RCB 0 (no residual disease at surgery) and did not receive any additional non-protocol neoadjuvant treatment. Subject was considered a pCR non-responder if they did not achieve RCB 0 (RCB I, II, or III, or did not receive surgery) or if they received additional non-protocol neoadjuvant therapy. RCB is used to assess the response to neoadjuvant chemotherapy in breast cancer patients and is in a scale of 0 to 3, defined using established guidelines (Symmans et al. JCO 2007; M.D Anderson http://www.mdanderson.org/breastcancer_RCB). Higher RCB score indicates more tumor burden remaining, thus worse outcome. RCB in this trial was determined according to local pathology review.

Secondary outcomes

• Rate of Pathologic Complete Response in Hormone Receptor Positive (HR+) Subjects [12 weeks]: In hormone receptor positive (HR+) patients, compare the rate of pathologic complete response (pCR) between patients treated with neoadjuvant TMP versus THP. Subject was considered a pCR responder if they achieved RCB 0 (no residual disease at surgery) and did not receive any additional non-protocol neoadjuvant treatment. Subject was considered a pCR non-responder if they did not achieve RCB 0 (RCB I, II, or III, or did not receive surgery) or if they received additional non-protocol neoadjuvant therapy. RCB is used to assess the response to neoadjuvant chemotherapy in breast cancer patients and is in a scale of 0 to 3, defined using established guidelines (Symmans et al. JCO 2007; M.D Anderson http://www.mdanderson.org/breastcancer_RCB). Higher RCB score indicates more tumor burden remaining, thus worse outcome. RCB in this trial was determined according to local pathology review.
• Rate of Pathologic Complete Response in Hormone Receptor Negative (HR-) Subjects [12 weeks]: In hormone receptor negative (HR-) patients, compare the rate of pathologic complete response (pCR) between patients treated with neoadjuvant TMP versus THP. Subject was considered a pCR responder if they achieved RCB 0 (no residual disease at surgery) and did not receive any additional non-protocol neoadjuvant treatment. Subject was considered a pCR non-responder if they did not achieve RCB 0 (RCB I, II, or III, or did not receive surgery) or if they received additional non-protocol neoadjuvant therapy. RCB is used to assess the response to neoadjuvant chemotherapy in breast cancer patients and is in a scale of 0 to 3, defined using established guidelines (Symmans et al. JCO 2007; M.D Anderson http://www.mdanderson.org/breastcancer_RCB). Higher RCB score indicates more tumor burden remaining, thus worse outcome. RCB in this trial was determined according to local pathology review.
• Residual Cancer Burden (RCB) Scores [12 weeks]: Assess Residual Cancer Burden (RCB) scores in patients treated with TMP or THP, reported using the Residual Cancer Burden calculator from M.D Anderson. RCB is used to assess the response to neoadjuvant chemotherapy in breast cancer patients and is in a scale of 0 to 3, defined using established guidelines (Symmans et al. JCO 2007; M.D Anderson http://www.mdanderson.org/breastcancer_RCB). Higher RCB score indicates more tumor burden remaining, thus worse outcome. RCB in this trial was determined according to local pathology review.
• Residual Cancer Burden (RCB) Scores in Hormone Receptor Positive (HR+) Subjects [12 weeks]: Among hormone receptor positive (HR+) patients, assess Residual Cancer Burden (RCB) scores in patients treated with TMP or THP, reported using the Residual Cancer Burden calculator from M.D Anderson.
• Residual Cancer Burden (RCB) Scores in Hormone Receptor Negative (HR-) Subjects [12 weeks]: Among hormone receptor negative (HR-) subjects, assess Residual Cancer Burden (RCB) scores in patients treated with TMP or THP, reported using the Residual Cancer Burden calculator from M.D Anderson. RCB is used to assess the response to neoadjuvant chemotherapy in breast cancer patients and is in a scale of 0 to 3, defined using established guidelines (Symmans et al. JCO 2007; M.D Anderson http://www.mdanderson.org/breastcancer_RCB). Higher RCB score indicates more tumor burden remaining, thus worse outcome. RCB in this trial was determined according to local pathology review.
• Dose-limiting Toxicities (DLTs) in theTMP Arm (Paclitaxel/Margetuximab/Pertuzumab) During the First 21 Days of Treatment [From first treatment to 21 days]: Among the subjects treated with TMP (Paclitaxel/Margetuximab/Pertuzumab), report the number of subjects with dose-limiting toxicities (DLTs) during the first 21 days of treatment, where 21 days equals one cycle of treatment. DLTs are defined in Section 5.4 of the protocol, with the specified toxicities and lab values categorized and graded according to CTCAE v5.0.
• Maximum Grade of All Treatment-related Adverse Events During Neoadjuvant Treatment [Time from first dose of neoadjuvant treatment to start of de-escalated MP or HP protocol adjuvant therapy if subject received the de-escalated MP or HP protocol adjuvant therapy, up to 1 year after the last dose of their neoadjuvant treatment.]: Maximum grade of all treatment-related adverse events (TRAEs) according to CTCAE v5.0 during neoadjuvant treatment, recorded per patient per arm. Subjects with no TRAEs reported (Grade 0) and Grade 1 adverse events are combined into a single category because only adverse events of Grade 2 or more were consistently reported.
• Patient-reported Outcomes [From first treatment to 12 weeks]: Patient-reported outcomes for symptoms and quality of life (both physical and mental health) during neoadjuvant TMP and THP
• Event-free Survival Rate (EFS) [From enrollment to occurrence invasive local/regional recurrence distant recurrence or death from breast cancer or up to 10 years]: 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
• Event-free Survival Rate (EFS) Patients With RCB 0 or 1 [From enrollment to occurrence of invasive local/regional recurrence distant recurrence or death from breast cancer or up to 10 years]: 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
• Event-free Survival Rate (EFS)Patients With RCB 2 or 3 [From enrollment to occurrence of invasive local/regional recurrence distant recurrence or death from breast cancer or up to 10 years]: 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
• Event-free Survival Rate (EFS) Patients Randomized to Neoadjuvant TMP [From enrollment to occurrence of invasive local/regional recurrence distant recurrence or death from breast cancer or up to 10 years]: 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
• Event-free Survival Rate (EFS) Patients Randomized to Neoadjuvant THP [From enrollment to occurrence of invasive local/regional recurrence distant recurrence or death from breast cancer or up to 10 years]: 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
• Event-free Survival Rate (EFS) -Patients With pCR [From enrollment to occurrence of invasive local/regional recurrence distant recurrence or death from breast cancer or up to 10 years]: 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
• Event-free Survival Rate (EFS) -Patients Without pCR [From enrollment to occurrence of invasive local/regional recurrence distant recurrence or death from breast cancer or up to 10 years]: 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
• Recurrence-free Interval Rate (RFI) [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]: 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
• Recurrence-free Interval Rate (RFI) RCB 0 or 1 [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]: 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
• Recurrence-free Interval Rate (RFI) RCB 2 or 3 [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]: 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
• Recurrence-free Interval Rate (RFI) Patients Randomized to Neoadjuvant TMP [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]: 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
• Recurrence-free Interval Rate (RFI) Patients Randomized to Neoadjuvant THP [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]: 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
• Recurrence-free Interval Rate (RFI) Patients With pCR [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]: 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
• Recurrence-free Interval Rate (RFI) Patients Without pCR [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]: 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
• Overall Survival Rate (OS) [up to 10 years from definitive surgery.]: 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
• Overall Survival Rate (OS) Patients With RCB 0 or 1 [up to 10 years from definitive surgery.]: 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
• Overall Survival Rate (OS) Patients With RCB 2 or 3 [up to 10 years from definitive surgery.]: 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
• Overall Survival Rate (OS) Patients Randomized to Neoadjuvant TMP [up to 10 years from definitive surgery.]: 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
• Overall Survival Rate (OS) Randomized to Neoadjuvant THP [up to 10 years from definitive surgery.]: 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
• Overall Survival Rate (OS) Patients With pCR [up to 10 years from definitive surgery.]: 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
• Overall Survival Rate (OS) Patients Without CR [up to 10 years from definitive surgery.]: 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

Sex: All, ages: 18 Years to any

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.

Participant flow

Outcome results

• Pathologic Complete Response (pCR) (Primary), Count of participants, Participants: Paclitaxel + Pertuzumab + Margetuximab 65; Paclitaxel + Pertuzumab + Trastuzumab 24 (p 0.188)
• Rate of Pathologic Complete Response in Hormone Receptor Positive (HR+) Subjects (Secondary), Count of participants, Participants: Paclitaxel + Pertuzumab + Margetuximab 40; Paclitaxel + Pertuzumab + Trastuzumab 13 (p 0.0715)
• Rate of Pathologic Complete Response in Hormone Receptor Negative (HR-) Subjects (Secondary), Count of participants, Participants: Paclitaxel + Pertuzumab + Margetuximab 25; Paclitaxel + Pertuzumab + Trastuzumab 11 (p 0.7754)
• Residual Cancer Burden (RCB) Scores (Secondary), Count of participants, Participants: Paclitaxel + Pertuzumab + Margetuximab 65; Paclitaxel + Pertuzumab + Trastuzumab 24
• Residual Cancer Burden (RCB) Scores in Hormone Receptor Positive (HR+) Subjects (Secondary), Count of participants, Participants: Paclitaxel + Pertuzumab + Margetuximab 40; Paclitaxel + Pertuzumab + Trastuzumab 13
• Residual Cancer Burden (RCB) Scores in Hormone Receptor Negative (HR-) Subjects (Secondary), Count of participants, Participants: Paclitaxel + Pertuzumab + Margetuximab 25; Paclitaxel + Pertuzumab + Trastuzumab 11
• Dose-limiting Toxicities (DLTs) in theTMP Arm (Paclitaxel/Margetuximab/Pertuzumab) During the First 21 Days of Treatment (Secondary), Count of participants, Participants: Paclitaxel + Pertuzumab + Margetuximab 2
• Maximum Grade of All Treatment-related Adverse Events During Neoadjuvant Treatment (Secondary), Count of participants, Participants: Paclitaxel + Pertuzumab + Margetuximab 23; Paclitaxel + Pertuzumab + Trastuzumab 16
• Patient-reported Outcomes (Secondary)
• Event-free Survival Rate (EFS) (Secondary)
• Event-free Survival Rate (EFS) Patients With RCB 0 or 1 (Secondary)
• Event-free Survival Rate (EFS)Patients With RCB 2 or 3 (Secondary)
• Event-free Survival Rate (EFS) Patients Randomized to Neoadjuvant TMP (Secondary)
• Event-free Survival Rate (EFS) Patients Randomized to Neoadjuvant THP (Secondary)
• Event-free Survival Rate (EFS) -Patients With pCR (Secondary)
• Event-free Survival Rate (EFS) -Patients Without pCR (Secondary)
• Recurrence-free Interval Rate (RFI) (Secondary)
• Recurrence-free Interval Rate (RFI) RCB 0 or 1 (Secondary)
• Recurrence-free Interval Rate (RFI) RCB 2 or 3 (Secondary)
• Recurrence-free Interval Rate (RFI) Patients Randomized to Neoadjuvant TMP (Secondary)
• 10 more outcome measures not shown.

Adverse events

Time frame: Time from first dose of neoadjuvant treatment to start of de-escalated MP or HP protocol adjuvant therapy if subject received the de-escalated MP or HP protocol adjuvant therapy, up to 1 year after the last dose of their neoadjuvant treatment.

Serious adverse events by term

Other adverse events by term

98 more terms not shown.

• Study Protocol and Statistical Analysis Plan (PDF, 2025-07-24)

• Adrienne Waks, MD, Principal investigator, Dana-Farber Cancer Institute