MARGetuximab Or Trastuzumab (MARGOT)

Phase 2Active Not RecruitingNCT04425018

Dana-Farber Cancer Institute174 enrolled

Overview

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)

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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

174

Conditions

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

Interventions

PaclitaxelDRUG

Pre-determined dose administered via IV, Day 1,8,15 of each cycle 4 study cycles, or 12 weeks.

PertuzumabDRUG

Pre-determined dose administered via IV - Day 1 of each 21- day cycle 4 study cycles, or 12 weeks.

MargetuximabDRUG

Pre-determined dose administered by IV - Day 1 of each 21- day cycle 4 study cycles, or 12 weeks.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (14)

Georgetown University Medical Center

Washington D.C., District of Columbia, United States

MedStar Washington Hospital Center

Washington D.C., District of Columbia, United States

Outcomes

Primary Outcomes

Pathologic Complete Response (pCR)

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.

Time frame: 12 weeks

Secondary Outcomes

Rate of Pathologic Complete Response in Hormone Receptor Positive (HR+) Subjects

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.

Time frame: 12 weeks

Rate of Pathologic Complete Response in Hormone Receptor Negative (HR-) Subjects

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.

Data from ClinicalTrials.gov

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Pre-determined dose administered via IV Day 1 of each 21- day cycle for 4 study cycles, or 12 weeks.

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States

Dana Farber Cancer Institute

Boston, Massachusetts, United States

Dana-Farber Brigham Cancer Center - Foxborough

Foxborough, Massachusetts, United States

Dana-Farber at Milford

Milford, Massachusetts, United States

Dana-Farber at South Shore Hospital

Weymouth, Massachusetts, United States

Montefiore Medical Center

The Bronx, New York, United States

UPMC Hillman Cancer Center - Arnold Palmer at Mountain View

Greensburg, Pennsylvania, United States

UPMC Hillman Cancer Center - Arnold Palmer at Norwin

Irwin, Pennsylvania, United States

...and 4 more locations

Time frame: 12 weeks

Residual Cancer Burden (RCB) Scores

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.

Time frame: 12 weeks

Residual Cancer Burden (RCB) Scores in Hormone Receptor Positive (HR+) Subjects

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.

Time frame: 12 weeks

Residual Cancer Burden (RCB) Scores in Hormone Receptor Negative (HR-) Subjects

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.

Time frame: 12 weeks

Dose-limiting Toxicities (DLTs) in theTMP Arm (Paclitaxel/Margetuximab/Pertuzumab) During the First 21 Days of Treatment

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.

Time frame: From first treatment to 21 days

Maximum Grade of All Treatment-related Adverse Events During 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.

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.

Patient-reported Outcomes

Patient-reported outcomes for symptoms and quality of life (both physical and mental health) during neoadjuvant TMP and THP

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

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

Recurrence-free Interval Rate (RFI) RCB 0 or 1

Recurrence-free Interval Rate (RFI) RCB 2 or 3

Recurrence-free Interval Rate (RFI) Patients Randomized to Neoadjuvant TMP

Recurrence-free Interval Rate (RFI) Patients Randomized to Neoadjuvant THP

Recurrence-free Interval Rate (RFI) Patients With pCR

Recurrence-free Interval Rate (RFI) Patients Without pCR

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