Paclitaxel and Pertuzumab with Margetuximab or Trastuzumab for the Treatment of HER2-Positive Stage II-III Invasive Breast Cancer, The MARGOT Trial
This phase II trial investigates how well paclitaxel and pertuzumab with margetuximab or trastuzumab works in treating patients with HER2-positive stage II-III invasive breast cancer. Chemotherapy drugs, such as paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Pertuzumab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. Trastuzumab and margetuximab are both forms of targeted therapy because they attach themselves to specific molecules (receptors) on the surface of tumor cells, known as HER2 receptors. When trastuzumab and margetuximab attach to HER2 receptors, the signals that tell the cells to grow are blocked and the tumor cell may be marked for destruction by the body's immune system. This trial is being done to determine how well HER2-positive breast cancer responds to pre-operative treatment using one of two different combination of drugs as a treatment for this diagnosis.
Inclusion Criteria
- Stage II or III (according to American Joint Committee on Cancer [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)
- Estrogen receptor (ER)/progesterone receptor (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, 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
- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
- Absolute neutrophil count (ANC) >= 1000/mm^3
- Hemoglobin >= 9 g/dl
- Platelets >= 100,000/mm^3
- Serum creatinine =< 1.5 x upper limit of normal (ULN) (institutional) OR calculated glomerular filtration rate (GFR) >= 60 mL/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
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x 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 ductal breast carcinoma in situ (DCIS) or lobular breast carcinoma in situ (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
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT04425018.
PRIMARY OBJECTIVE:
I. To compare rate of pathologic complete response (pCR, defined as residual cancer burden [RCB] 0) in patients with the FF or FV CD16A genotype and anatomic stage II-III HER2 positive (+) breast cancer treated with 4 cycles of neoadjuvant paclitaxel/margetuximab/pertuzumab (TMP) or paclitaxel/trastuzumab/pertuzumab (THP).
SECONDARY OBJECTIVES:
I. To 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.
II. To assess residual cancer burden (RCB) scores in patients treated with TMP or THP, overall and according to HR+ or HR- status.
III. To assess safety and tolerability of THP and TMP in the neoadjuvant and adjuvant setting.
IV. To measure event-free survival (EFS), recurrence-free interval (RFI), and overall survival (OS) in the overall study population.
V. To compare EFS, RFI, and OS in the following subgroups:
Va. Patients with pCR versus patients without pCR;
Vb. Patients with RCB 0 or 1, versus patients with RCB 2 or 3;
Vc. Patients randomized to neoadjuvant TMP, versus patients randomized to neoadjuvant THP.
CORRELATIVE, PATIENT-REPORTED OUTCOMES, AND EXPLORATORY OBJECTIVES:
I. To describe patient and physician considerations and decisions in choice of adjuvant therapy following preoperative treatment with THP or TMP.
II. To assess use of protocol-specified antibody doublet therapy only (MP or HP) without further cytotoxic chemotherapy in the adjuvant setting, among patients with stage II-III HER2+ breast cancer who achieve pCR following neoadjuvant TMP or THP.
III. To assess humoral and cellular immune responses to TMP versus THP, in both tissue and blood.
IV. To assess radiographic response to neoadjuvant therapy in patients treated with TMP or THP, overall and according to HR+ or HR- status.
V. To compare rate of pCR (RCB 0) in patients treated with TMP or THP, according to FF genotype or FV genotype.
VI. To determine the feasibility of sentinel lymph node mapping and biopsy after preoperative therapy in this cohort.
VII. To determine the incidence of additional nodal disease among patients in this cohort with positive sentinel lymph node(s), overall and stratified by size of largest sentinel lymph node metastasis.
VIII. To describe symptoms and quality of life (both physical and mental health) during neoadjuvant TMP and THP.
IX. To compare mean changes in physical health, mental health and fatigue from baseline to the pre-operative visit at the end of neoadjuvant therapy with TMP or THP.
X. To describe symptoms and quality of life (QOL) over time during therapy with TMP and THP.
XI. To explore the structure and function of the gut microbiome.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM A: Patients receive paclitaxel intravenously (IV) over 30-180 minutes on days 1, 8, and 15, pertuzumab IV over 30-60 minutes on day 1, and margetuximab IV over 120 minutes on day 1 and over 30 minutes for subsequent infusions, if first is well tolerated. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Within 14-42 days following the last dose of paclitaxel, patients undergo breast surgery (lumpectomy and/or mastectomy). Patients who achieve pCR at the time of surgery receive 13 additional cycles of pertuzumab and margetuximab in the absence of disease progression or unacceptable toxicity.
ARM B: Patients receive paclitaxel IV over 30-180 minutes on days 1, 8, and 15, pertuzumab IV over 30-60 minutes on day 1, and trastuzumab (or biosimilar) IV on day 1. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Within 14-42 days following the last dose of paclitaxel, patients undergo breast surgery (lumpectomy and/or mastectomy). Patients who achieve pCR at the time of surgery receive 13 additional cycles of pertuzumab IV or subcutaneously (SC) and trastuzumab (or biosimilar) in the absence of disease progression or unacceptable toxicity.
All patients undergo blood sample collection, biopsy, computed tomography (CT), bone scan, positron emission tomograpy (PET)/CT, echocardiography, multigated acquisition scan (MUGA), mammography, and ultrasound throughout study.
After completion of study treatment, patients are followed up yearly for 10 years.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationDana-Farber Harvard Cancer Center
Principal InvestigatorAdrienne Gropper Waks
- Primary ID20-068
- Secondary IDsNCI-2020-06704
- ClinicalTrials.gov IDNCT04425018