MARGetuximab Or Trastuzumab (MARGOT) (MARGOT)

• ClinicalTrials.gov Identifier: NCT04425018
• Recruitment Status: Recruiting
• First Posted: June 11, 2020
• Last Update Posted: November 25, 2022
• Sponsor: Dana-Farber Cancer Institute
• Collaborators: MacroGenics; Translational Breast Cancer Research Consortium
• Information provided by (Responsible Party): Adrienne G. Waks, Dana-Farber Cancer Institute

Study Description

Brief Summary:

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)

Condition or disease	Intervention/treatment	Phase
Breast Cancer; Stage II Breast Cancer; Stage III Breast Cancer; HER2-positive Breast Cancer	Drug: Paclitaxel; Drug: Pertuzumab; Drug: Margetuximab; Drug: Trastuzumab	Phase 2

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 171 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: July 13, 2020
• Estimated Primary Completion Date: July 1, 2024
• Estimated Study Completion Date: July 1, 2027

Arms and Interventions

Arm	Intervention/treatment
Experimental: Paclitaxel + Pertuzumab + Margetuximab; 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; Pre-determined dose administered via IV, Day 1,8,15 of each cycle 4 study cycles, or 12 weeks.; Other Names: Taxol; Onxal; Drug: Pertuzumab; Pre-determined dose administered via IV - Day 1 of each 21- day cycle 4 study cycles, or 12 weeks.; Other Name: Perjeta; Drug: Margetuximab; Pre-determined dose administered by IV - Day 1 of each 21- day cycle 4 study cycles, or 12 weeks.; Other Name: Margenza
Experimental: Paclitaxel + Pertuzumab + Trastuzumab; 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; Pre-determined dose administered via IV, Day 1,8,15 of each cycle 4 study cycles, or 12 weeks.; Other Names: Taxol; Onxal; Drug: Pertuzumab; Pre-determined dose administered via IV - Day 1 of each 21- day cycle 4 study cycles, or 12 weeks.; Other Name: Perjeta; Drug: Trastuzumab; Pre-determined dose administered via IV Day 1 of each 21- day cycle for 4 study cycles, or 12 weeks.; Other Names: Herceptin; Kanjinti; Ogivri; Herzuma

Outcome Measures

Primary Outcome Measures :

1. Rate of pathologic complete response (pCR) [ Time Frame: 12 weeks ]
   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

Secondary Outcome Measures :

1. Rate of pathologic complete response [ Time Frame: 12 weeks ]
   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
2. Residual Cancer Burden (RCB) scores [ Time Frame: 12 weeks ]
   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:
3. Radiographic response rate [ Time Frame: 12 Weeks ]

   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:

4. Number of Participants with Treatment Related Adverse Events according to CTCAE v5.0 [ Time Frame: From first treatment to 12 weeks ]
   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
5. Event-free survival rate (EFS) [ Time Frame: 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
6. Event-free survival rate (EFS) Patients with RCB 0 or 1 [ Time Frame: 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
7. Event-free survival rate (EFS)Patients with RCB 2 or 3 [ Time Frame: 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
8. Event-free survival rate (EFS) Patients randomized to neoadjuvant TMP [ Time Frame: 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
9. Event-free survival rate (EFS) patients randomized to neoadjuvant THP [ Time Frame: 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
10. Event-free survival rate (EFS) -Patients with pCR [ Time Frame: 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
11. Event-free survival rate (EFS) -Patients without pCR [ Time Frame: 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
12. Recurrence-free interval rate (RFI) [ Time Frame: 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
13. Recurrence-free interval rate (RFI) RCB 0 or 1 [ Time Frame: 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
14. Recurrence-free interval rate (RFI) RCB 2 or 3 [ Time Frame: 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
15. Recurrence-free interval rate (RFI) Patients randomized to neoadjuvant TMP [ Time Frame: 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
16. Recurrence-free interval rate (RFI) Patients randomized to neoadjuvant THP [ Time Frame: 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
17. Recurrence-free interval rate (RFI) Patients with pCR [ Time Frame: 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
18. Recurrence-free interval rate (RFI) Patients without pCR [ Time Frame: 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
19. Overall survival Rate (OS) [ Time Frame: 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
20. Overall survival Rate (OS) Patients with RCB 0 or 1 [ Time Frame: 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
21. Overall survival Rate (OS) Patients with RCB 2 or 3 [ Time Frame: 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
22. Overall survival Rate (OS) Patients randomized to neoadjuvant TMP [ Time Frame: 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
23. Overall survival Rate (OS) randomized to neoadjuvant THP [ Time Frame: 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
24. Overall survival Rate (OS) Patients with pCR [ Time Frame: 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
25. Overall survival Rate (OS) Patients without CR [ Time Frame: 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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Contacts

Contact: Adrienne Waks, MD; 617-632-6973; Adrienne_Waks@DFCI.HARVARD.EDU

Locations

United States, Connecticut

Yale Cancer Center; Not yet recruiting

New Haven, Connecticut, United States, 06510

Contact: Maryam B. Lustberg, MD, PhD maryam.lustberg@yale.edu

Principal Investigator: Maryam B Lustberg, MD, PhD

United States, District of Columbia

Georgetown University Medical Center; Recruiting

Washington, District of Columbia, United States, 20007

Contact: Nellie Novielli noviella@georgetown.edu

Principal Investigator: Claudine Isaacs, MD

MedStar Washington Hospital Center; Recruiting

Washington, District of Columbia, United States, 20010

Contact: Stacy Malloy stacy.k.malloy@medstar.net

Principal Investigator: Claudine Isaacs, MD

United States, Illinois

The University of Chicago Medical Center; Withdrawn

Chicago, Illinois, United States, 60637

University of Chicago Comprehensive Cancer Center at Silver Cross Hospital; Withdrawn

New Lenox, Illinois, United States, 60451

University of Chicago Medical Center for Advanced Care Orland Park; Withdrawn

Orland Park, Illinois, United States, 60462

United States, Massachusetts

Dana Farber Cancer Institute; Recruiting

Boston, Massachusetts, United States, 02215

Contact: Adrienne Waks, MD adrienne_waks@dfci.harvard.edu

Principal Investigator: Adrienne Waks, MD

Dana-Farber Brigham Cancer Center - Foxborough; Not yet recruiting

Foxboro, Massachusetts, United States, 02035

Contact: Natalie Sinclair 781-624-4800 nsinclair1@partners.org

Principal Investigator: Natalie Sinclair, MD

Dana-Farber at Milford; Recruiting

Milford, Massachusetts, United States, 01757

Contact: Natalie Sinclair, MD NSINCLAIR1@PARTNERS.ORG

Principal Investigator: Natalie Sinclair, MD

Dana-Farber at South Shore Hospital; Recruiting

Weymouth, Massachusetts, United States, 02190

Contact: Thomas O'Connor, M.D. 781-337-9091 thomasp_o'connor@dfci.harvard.edu

Principal Investigator: Thomas O'Connor, MD

United States, New York

Montefiore Medical Center; Recruiting

Bronx, New York, United States, 10461

Contact: Jesus Anampa, MD janampa@montefiore.org

Principal Investigator: Jesus Anampa, MD

United States, North Carolina

University of North Carolina at Chapel Hill; Recruiting

Chapel Hill, North Carolina, United States, 27599

Contact: Crissey Tait crissey_tait@med.unc.edu

Principal Investigator: Lisa Carey, MD

United States, Pennsylvania

UPMC Hillman Cancer Center - Arnold Palmer at Mountain View; Recruiting

Greensburg, Pennsylvania, United States, 15601

Contact: Joshua Plassmeyer plassmeyerjm@upmc.edu

Principal Investigator: Adam Brufsky, MD

UPMC Hillman Cancer Center - Arnold Palmer at Norwin; Recruiting

Irwin, Pennsylvania, United States, 15642

Contact: Joshua Plassmeyer plassmeyerjm@upmc.edu

Principal Investigator: Adam Brufsky, MD

University of Pittsburgh Medical Center; Recruiting

Pittsburgh, Pennsylvania, United States, 15213

Contact: Joshua Plassmeyer plassmeyerjm@upmc.edu

Principal Investigator: Adam Brufsky, MD

United States, Texas

Baylor College of Medicine Medical Center; Recruiting

Houston, Texas, United States, 77030

Contact: Anne Pavlick 713-798-7814 acpavlic@bcm.ed

Principal Investigator: Mothaffar Rimawi, MD

MD Anderson Cancer Center; Recruiting

Houston, Texas, United States, 77030

Contact: Pamela Lewis plewis@mdanderson.org

Principal Investigator: Paula Pohlmann, MD

United States, Washington

University of Washington Fred Hutchinson Cancer Care; Recruiting

Seattle, Washington, United States, 98109

Contact: Rachel Yung, MD rlyung@seattlecca.org

Principal Investigator: Rachel Yung, MD

Sponsors and Collaborators

Dana-Farber Cancer Institute

MacroGenics

Translational Breast Cancer Research Consortium

Investigators

• Principal Investigator: Adrienne Waks, MD; Dana-Farber Cancer Institute

More Information

• Responsible Party: Adrienne G. Waks, Principal Investigator, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT04425018
• Other Study ID Numbers: 20-068
• First Posted: June 11, 2020
• Last Update Posted: November 25, 2022
• Last Verified: November 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: [contact information for Sponsor Investigator or designee]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)
• Time Frame: Data can be shared no earlier than 1 year following the date of publication
• Access Criteria: Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Adrienne G. Waks, Dana-Farber Cancer Institute:

Breast Cancer; Stage II Breast Cancer; Stage III Breast Cancer; HER2-positive Breast Cancer

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Paclitaxel; Trastuzumab; Pertuzumab; Margetuximab; Antineoplastic Agents, Phytogenic; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents, Immunological