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MARGetuximab Or Trastuzumab (MARGOT) (MARGOT)

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ClinicalTrials.gov Identifier: NCT04425018
Recruitment Status : Recruiting
First Posted : June 11, 2020
Last Update Posted : July 29, 2020
Sponsor:
Collaborators:
MacroGenics
Translational Breast Cancer Research Consortium
Information provided by (Responsible Party):
Ian E. Krop, MD, PhD, Dana-Farber Cancer Institute

Tracking Information
First Submitted Date  ICMJE April 15, 2020
First Posted Date  ICMJE June 11, 2020
Last Update Posted Date July 29, 2020
Actual Study Start Date  ICMJE July 13, 2020
Estimated Primary Completion Date July 1, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 8, 2020)
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
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 8, 2020)
  • 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
  • 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:
  • 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:
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE MARGetuximab Or Trastuzumab (MARGOT)
Official Title  ICMJE 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
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
  • Paclitaxel, Pertzumab and Trastuzumab (Herceptin)
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 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Breast Cancer
  • Stage II Breast Cancer
  • Stage III Breast Cancer
  • HER2-positive Breast Cancer
Intervention  ICMJE
  • 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.
  • 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
Study Arms  ICMJE
  • 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
    Interventions:
    • Drug: Paclitaxel
    • Drug: Pertuzumab
    • Drug: Margetuximab
  • 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
    Interventions:
    • Drug: Paclitaxel
    • Drug: Pertuzumab
    • Drug: Trastuzumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 8, 2020)
171
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 1, 2027
Estimated Primary Completion Date July 1, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Ian E Krop, MD, PHD 617-632-6973 Ian_Krop@dfci.harvard.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04425018
Other Study ID Numbers  ICMJE 20-068
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
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
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: 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
Responsible Party Ian E. Krop, MD, PhD, Dana-Farber Cancer Institute
Study Sponsor  ICMJE Dana-Farber Cancer Institute
Collaborators  ICMJE
  • MacroGenics
  • Translational Breast Cancer Research Consortium
Investigators  ICMJE
Principal Investigator: Ian E Krop, MD, PHD Dana-Farber Cancer Institute
PRS Account Dana-Farber Cancer Institute
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP