Breast cancer
Conditions
Interventions
Through an infusion, the patient will receive margetuximab plus chemotherapy or
trastuzumab plus chemotherapy. The study doctor will choose which chemotherapy
the patient will receive. He can choose
Sponsors
MacroGenics, Limited
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: Inclusion Criteria;To be included in this study, patients must: General 1. Be able to provide informed consent and documentation of informed consent prior to initiation of any study-related tests or procedures that are not part of standard-of-care for the patient*s disease. Patients must also be willing and able to comply with study procedures, including the acquisition of specified research specimens and completion of HRQoL assessments. 2. Be * 18 years old. Patients may be male or female. 3. Have histologically-proven, metastatic or locally-advanced, relapsed/refractory HER2+ (3+ by IHC or ISH-amplified as per American Society of Clinical Oncology [ASCO] and the College of American Pathologists [CAP] Guidelines) breast cancer based on the most recently available tumor biopsy collected from the patient. HER2 status must be documented from a reference laboratory that conforms to standards set for accreditation by CAP or an equivalent accreditation authority. Confirmatory IHC testing is not required for study entry. Tumors may be estrogen receptor (ER)/progesterone receptor (PR) positive or negative. 4. Have received prior treatment with pertuzumab, trastuzumab, and ado-trastuzumab emtansine in the neoadjuvant, adjuvant, or metastatic setting. Prior radiotherapy, hormonal therapies, and other anti-HER2 therapies are allowed. 5. Have received treatment with at least one, and no more than three, lines of therapy in the metastatic setting. Prior neo-adjuvant or adjuvant therapy that resulted in relapse within 6 months of the completion of therapy will be considered a line of treatment for metastatic disease. Eligible patients must have progressed on or following, the most recent line of therapy. 6. Resolution of all chemotherapy or radiation-related toxicities to * Grade 1 (with exception of * Grade 2 alopecia, stable sensory neuropathy, or stable electrolyte disturbances that are managed by supplementation). 7. Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Appendix 4). 8. Have life expectancy * 12 weeks. 9. Have measurable or evaluable disease as per RECIST 1.1 criteria and documented by CT and/or MRI.;Laboratory Features 10. Have acceptable laboratory parameters as follows: a. Platelet count * 100 × 103/µL without having received a transfusion or growth factor support within 4 weeks prior to the initiation of study drug. b. Hemoglobin * 9.0 g/dL without having received a transfusion within 4 weeks prior to the initiation of study drug. c. Absolute neutrophil count * 1.5 × 103/µL in the absence of any growth factor support given within 4 weeks prior to the initiation of study drug. d. Alanine aminotransferase (ALT)/ aspartate aminotransferase (AST) * 3.0 × the upper limit of normal (ULN), except patients with liver metastases, who may enroll with ALT/AST * 5.0 × ULN. e. Total bilirubin * 1.5 × ULN, except patients with Gilbert*s syndrome, who may enroll if the conjugated bilirubin is within laboratory normal limits. f. Creatinine 50 mL/min.;Reproductive Features 11. Female patients of childbearing potential (not surgically sterilized and between menarche and 1 year post menopause) must have a negative result from a serum pregnancy test performed within 7 days of randomization and on the day of first study treatment. All study subjects must agree to use highly effective con
Exclusion criteria
Exclusion criteria: Exclusion Criteria: ;Patients who meet any of the following criteria will be excluded from the study: 1. Patients with known, untreated brain metastasis. Patients with signs or symptoms of brain metastasis must have a CT or MRI performed within 4 weeks prior to randomization to specifically exclude the presence of radiographically-detectable brain metastases. Patients with known, treated metastases should have a baseline MRI within 4 weeks of study entry and are eligible provided all therapy for the metastases concluded at least 4 weeks prior to the initiation of study drug, or, if continued steroid therapy is indicated following therapy, they have been on a stable dose of steroids (* 10 mg of prednisone or equivalent) for at least 4 weeks with no symptoms. 2. History of uncontrolled seizures within 6 months of randomization. 3. History of prior allogeneic bone marrow, stem-cell, or solid organ transplantation. 4. Treatment with any local or systemic anti-neoplastic therapy or any investigational therapy within the 2 weeks prior to the initiation of study drug. Bisphosphonates and receptor activator of nuclear factor kappa B ligand (RANKL) inhibitors are allowed provided treatment starts prior to the start of study therapy. 5. Treatment with corticosteroids (i.e., > 10 mg prednisone per day or equivalent) or other immune suppressive drugs within the 2 weeks prior to the initiation of study drug. Steroids for topical use, inhalational use, nasal spray, or ophthalmic solution are allowed. 6. History of clinically significant cardiovascular disease including but not limited to: a. Myocardial infarction or unstable angina within 6 months prior to the initiation of study drug. b. Stroke or transient ischemic attack within 6 months prior to the initiation of study drug c. Clinically significant cardiac arrhythmias. d. Uncontrolled (persistent) hypertension defined as systolic blood pressure (SBP) >180 mmHg or diastolic blood pressure (DBP) >100 mmHg. e. Congestive heart failure (New York Heart Association [NYHA] class II-IV). f. Pericarditis or clinically significant pericardial effusion. g. Myocarditis. h. Left ventricle ejection fraction (LVEF) < 50% by echocardiogram or multi-gated acquisition (MUGA) scan. 7. Clinically-significant pulmonary compromise, including a requirement for supplemental oxygen use to maintain adequate oxygenation. 8. Evidence of active viral, bacterial, or systemic fungal infection requiring parenteral treatment within 7 days prior to the initiation of study drug. 9. Known positive testing for human immunodeficiency virus or acquired immune deficiency syndrome. 10. Active hepatitis B or hepatitis C infection or positive test for hepatitis B surface antigen, hepatitis B core antigen, or hepatitis C polymerase chain reaction (PCR). 11. Second primary malignancy that has not been in remission for at least 2 years from the anticipated start of study treatment. Exceptions of treated malignancies that do not require a 2 year remission include: non-melanoma skin cancer; cervical carcinoma in situ; squamous intraepithelial lesion; localized prostate cancer (Gleason score < 6); resected melanoma in situ or ductal carcinoma in situ. Patients with second primary breast cancers within 2 years are eligible provided that both primary tumors were HER2+ (3+ by IHC or ISH amplified). 12. History of trauma or major surgery within 4 weeks prior to the i
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Statistical Methods: Sample Size Determination There are 2 primary endpoints in this study. The first primary endpoint is centrally determined PFS and the second primary endpoint is OS. These two endpoints will be assessed in a hierarchical manner with PFS being assessed first. OS will only be assessed if a statistically significant difference is obtained in PFS. It is estimated that the median PFS for patients treated with trastuzumab and chemotherapy is 4 months. To detect a 2 month improvement in median PFS from 4 months to 6 months (HR=0.67) in patients treated with margetuximab plus chemotherapy, a total of 257 PFS events are required to provide 90% power at a 2-sided alpha=0.05. The analysis of the primary PFS endpoint will occur when about 257 events have occurred and when all patients have enrolled and had at least one post-baseline assessment or in the absence of a post-baseline tumor assessment, have experienced clearly documented clinical disease progression, whichever occurs later. The sample size is calculated to ensure 80% power for the analysis of OS. The median OS for patients treated with trastuzumab plus chemotherapy is estimated to be 12 months. This study is designed to detect an increase to a median OS of 16 months in patients treated with margetuximab plus chemotherapy (hazard ratio [HR]=0.75). To detect a 4-month improvement in OS from 12 months to 16 months, a total of 385 events are required to provide 80% power at a 2-sided alpha=0.05. It is anticipated that about 530 patients will be accrued to achieve this number of events. Patients will be enrolled over 18 months, and estimated to remain on study for an average of 18 months, for a total anticipated study duration of approximately 36 months. Efficacy Analyses Primary Efficacy Endpoints The primary analysis for PFS will be conducted when about 257 PFS events have occurred. Analysis of OS will be conducted at the time of PFS analysis and subsequently when 50% o | — |
Secondary
| Measure | Time frame |
|---|---|
| Analysis of Secondary Endpoints: The secondary endpoints of investigator-assessed PFS and ORR will be assessed using the Hochberg step-up procedure for multiplicity adjustment. P-values will be assessed in descending order. If the least significant p-value | — |
Countries
Netherlands
Outcome results
None listed