HER-2 Positive Breast Cancer, Metastatic Neoplasm
Conditions
Brief summary
The purpose of this study is to determine whether patients with metastatic breast cancer treated with margetuximab plus chemotherapy have longer progression free survival (PFS) and overall survival (OS) than patients treated with trastuzumab plus chemotherapy. A non-randomized sub-study cohort of approximately 88 patients will be enrolled to evaluate the safety of a reduced margetuximab infusion rate in patients receiving margetuximab either as monotherapy or in combination with chemotherapy.
Interventions
BIOLOGICALMargetuximab
15 mg/kg via IV (intravenous) infusion on day 1 of each 21 day cycle,
BIOLOGICALTrastuzumab
8 mg/kg via IV (intravenous) infusion for the first dose and 6 mg/kg for all subsequent doses via IV infusion on day 1 of each 21 day cycle
DRUGPhysician's choice of chemotherapy.
Capecitabine (Xeloda®):1000 mg/m2 BID for 14 days in a 21-day cycle, or Eribulin (Halaven®): 1.4 mg/m2 on days 1 and 8 of a 21-day cycle, or Gemcitabine (Gemzar®): 1000 mg/m2 on days 1 and 8 of a 21-day cycle, or Vinorelbine (Navelbine®): 25-30 mg/m2 on days 1 and 8 of a 21-day cycle
Sponsors
MacroGenics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically-proven metastatic or locally-advanced relapsed/refractory HER2+ breast cancer based on the most recently available tumor biopsy collected from the patient. Tumors may be estrogen receptor (ER)/progesterone receptor (PgR) positive or negative. * Have received at least 2 prior lines of anti-HER2 directed therapy in the metastatic setting, or in case of having received (neo)adjuvant pertuzumab, at least 1 prior line of anti-HER2 directed therapy in the metastatic setting. In either case, patients must have received prior treatment with pertuzumab, in the (neo)adjuvant or metastatic setting. Prior radiotherapy, hormonal therapies, and other anti-HER2 therapies are allowed. * Prior treatment with at least one, and no more than three, lines of therapy overall in the metastatic setting. Patients must have progressed on or following, the most recent line of therapy. * Resolution of all chemotherapy or radiation-related toxicities to ≤ Grade 1 * Life expectancy ≥ 12 weeks * Acceptable laboratory parameters * Women of childbearing potential must have negative pregnancy test performed within 14 days of randomization and on the first day of treatment. All subjects must agree to use an effective form of contraception for the duration of study treatment and for 7 months after the last dose of study drug. Infusion sub-study prior therapy requirements: Same as above, except: * Must have received 4 or more prior lines or therapy in the metastatic setting * Must have received prior trastuzumab, pertuzumab, and T-DM1
Exclusion criteria
* 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-detected brain metastases * History of uncontrolled seizures within 6 months of randomization * History of prior allogeneic bone marrow, stem-cell, or solid organ transplantation * History of clinically significant cardiovascular disease * Clinically-significant pulmonary compromise, including a requirement for supplemental oxygen use to maintain adequate oxygenation * Any condition that would be a contraindication to receiving trastuzumab as described in the approved local label or a condition that would prevent treatment with the physician's choice of chemotherapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Grade 3 or Higher Infusion Related Reactions | 22 days | Incidence of Grade 3 or higher infusion-related reactions for patients receiving 60-minute or 30-minute infusions of margetuximab in Cycle 2 of treatment |
| Progression-free Survival (PFS) as Determined by Independent Radiological Review. | Tumor assessments are conducted every 6 weeks for the first 24 weeks and then every 24 weeks until progression of cancer, average 5 months. | PFS is measured from the time of randomization until first documented disease progression or death from any cause, whichever is first. |
| Overall Survival (OS) Defined as the Number of Days From Randomization to the Date of Death (From Any Cause). | Throughout the study, average 21 months | Overall survival is the time from randomization until death from any cause |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To Evaluate Progression-free Survival (PFS), as Assessed by Study Investigators. | Tumor assessments are conducted every 6 weeks for the first 24 weeks and then every 24 weeks until progression of cancer, up to 6.5 years. | — |
| To Evaluate the Objective Response Rate (ORR) as Determined by Independent Radiological Review. | Tumor assessments are conducted every 6 weeks for the first 24 weeks and then every 24 weeks until progression of cancer, up to 6.5 years. | Objective response rate includes all patients with either a complete response (CR) or a partial response (PR) to study treatment |
| Infusion Rate Sub-study All Safety | Throughout the study, average duration 6 months | Incidence of all grades of infusion-related reactions |
Countries
Austria, Belgium, Canada, Czechia, Denmark, Finland, France, Germany, Israel, Italy, Netherlands, Poland, Portugal, Puerto Rico, South Korea, Spain, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Margetuximab Plus Chemotherapy Margetuximab 15 mg/kg administered every 21 days with physician's choice of 1 of 4 backbone chemotherapy regimens. | 266 |
| Trastuzumab Plus Chemotherapy Trastuzumab administered every 21 days with physician's choice of 1 of 4 backbone chemotherapy regimens. | 270 |
| Margetuximab Infusion Substudy Margetuximab with or without chemotherapy | 88 |
| Total | 624 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 9 | 9 | 2 |
| Overall Study | change in chemotherapy | 0 | 1 | 0 |
| Overall Study | Death | 3 | 3 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 |
| Overall Study | never treated | 2 | 4 | 0 |
| Overall Study | Other | 0 | 0 | 1 |
| Overall Study | Physician Decision | 10 | 6 | 4 |
| Overall Study | study treatment delay | 2 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 10 | 16 | 5 |
Baseline characteristics
| Characteristic | Margetuximab Plus Chemotherapy | Trastuzumab Plus Chemotherapy | Margetuximab Infusion Substudy | Total |
|---|---|---|---|---|
| Age, Continuous | 54.4 years STANDARD_DEVIATION 11.4 | 55.7 years STANDARD_DEVIATION 11.5 | 54.5 years STANDARD_DEVIATION 12.5 | 55.1 years STANDARD_DEVIATION 11.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 16 Participants | 30 Participants | 7 Participants | 53 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 217 Participants | 214 Participants | 75 Participants | 506 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 33 Participants | 26 Participants | 6 Participants | 65 Participants |
| Race (NIH/OMB) other American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) other Asian | 20 Participants | 14 Participants | 9 Participants | 43 Participants |
| Race (NIH/OMB) other Black or African American | 16 Participants | 12 Participants | 8 Participants | 36 Participants |
| Race (NIH/OMB) other More than one race | 0 Participants | 0 Participants | 9 Participants | 9 Participants |
| Race (NIH/OMB) other Native Hawaiian or Other Pacific Islander | 1 Participants | 2 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) other Unknown or Not Reported | 24 Participants | 20 Participants | 0 Participants | 44 Participants |
| Race (NIH/OMB) other White | 205 Participants | 222 Participants | 62 Participants | 489 Participants |
| Region of Enrollment Austria | 3 participants | 1 participants | 0 participants | 4 participants |
| Region of Enrollment Belgium | 12 participants | 13 participants | 6 participants | 31 participants |
| Region of Enrollment Canada | 4 participants | 6 participants | 2 participants | 12 participants |
| Region of Enrollment Czechia | 4 participants | 8 participants | 0 participants | 12 participants |
| Region of Enrollment Denmark | 9 participants | 7 participants | 0 participants | 16 participants |
| Region of Enrollment Finland | 3 participants | 1 participants | 0 participants | 4 participants |
| Region of Enrollment France | 22 participants | 13 participants | 5 participants | 40 participants |
| Region of Enrollment Germany | 10 participants | 7 participants | 0 participants | 17 participants |
| Region of Enrollment Israel | 12 participants | 20 participants | 9 participants | 41 participants |
| Region of Enrollment Italy | 41 participants | 33 participants | 15 participants | 89 participants |
| Region of Enrollment Netherlands | 3 participants | 4 participants | 0 participants | 7 participants |
| Region of Enrollment Poland | 4 participants | 6 participants | 0 participants | 10 participants |
| Region of Enrollment Portugal | 5 participants | 6 participants | 2 participants | 13 participants |
| Region of Enrollment Puerto Rico | 1 participants | 1 participants | 2 participants | 4 participants |
| Region of Enrollment South Korea | 16 participants | 9 participants | 6 participants | 31 participants |
| Region of Enrollment Spain | 27 participants | 34 participants | 0 participants | 61 participants |
| Region of Enrollment United Kingdom | 9 participants | 5 participants | 0 participants | 14 participants |
| Region of Enrollment United States | 81 participants | 96 participants | 41 participants | 218 participants |
| Sex: Female, Male Female | 266 Participants | 267 Participants | 87 Participants | 620 Participants |
| Sex: Female, Male Male | 0 Participants | 3 Participants | 1 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 194 / 266 | 191 / 270 | 56 / 88 |
| other Total, other adverse events | 213 / 264 | 210 / 266 | 68 / 88 |
| serious Total, serious adverse events | 47 / 264 | 51 / 266 | 17 / 88 |
Outcome results
Primary
Number of Patients With Grade 3 or Higher Infusion Related Reactions
Incidence of Grade 3 or higher infusion-related reactions for patients receiving 60-minute or 30-minute infusions of margetuximab in Cycle 2 of treatment
Time frame: 22 days
Population: Only patients in the infusion substudy are included in this outcome measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Margetuximab Infusion Substudy | Number of Patients With Grade 3 or Higher Infusion Related Reactions | 0 Participants |
| Margetuximab Stage A2 | Number of Patients With Grade 3 or Higher Infusion Related Reactions | 0 Participants |
| Margetuximab Stage B | Number of Patients With Grade 3 or Higher Infusion Related Reactions | 0 Participants |
Primary
Overall Survival (OS) Defined as the Number of Days From Randomization to the Date of Death (From Any Cause).
Overall survival is the time from randomization until death from any cause
Time frame: Throughout the study, average 21 months
Population: The OS outcome measure is calculated only for the randomized study efficacy population. The 88 participants in the sub-study were not part of the efficacy population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Margetuximab Plus Chemotherapy | Overall Survival (OS) Defined as the Number of Days From Randomization to the Date of Death (From Any Cause). | 21.6 months |
| Trastuzumab Plus Chemotherapy | Overall Survival (OS) Defined as the Number of Days From Randomization to the Date of Death (From Any Cause). | 21.9 months |
p-value: 0.620495% CI: [0.774, 1.165]Log Rank
Primary
Progression-free Survival (PFS) as Determined by Independent Radiological Review.
PFS is measured from the time of randomization until first documented disease progression or death from any cause, whichever is first.
Time frame: Tumor assessments are conducted every 6 weeks for the first 24 weeks and then every 24 weeks until progression of cancer, average 5 months.
Population: The PFS outcome measure is calculated only for the randomized study efficacy population. The 88 participants in the sub-study were not part of the efficacy population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Margetuximab Plus Chemotherapy | Progression-free Survival (PFS) as Determined by Independent Radiological Review. | 5.8 months |
| Trastuzumab Plus Chemotherapy | Progression-free Survival (PFS) as Determined by Independent Radiological Review. | 4.9 months |
p-value: 0.033495% CI: [0.593, 0.979]Log Rank
Secondary
Infusion Rate Sub-study All Safety
Incidence of all grades of infusion-related reactions
Time frame: Throughout the study, average duration 6 months
Population: Only patients in the infusion substudy were evaluated for this outcome measure
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Margetuximab Infusion Substudy | Infusion Rate Sub-study All Safety | Infusion related reaction Cycle 2 or higher | 0 participants |
| Margetuximab Infusion Substudy | Infusion Rate Sub-study All Safety | Infusion related reaction Cycle 1 | 1 participants |
| Margetuximab Infusion Substudy | Infusion Rate Sub-study All Safety | No infusion related reaction | 7 participants |
| Margetuximab Stage A2 | Infusion Rate Sub-study All Safety | Infusion related reaction Cycle 2 or higher | 0 participants |
| Margetuximab Stage A2 | Infusion Rate Sub-study All Safety | Infusion related reaction Cycle 1 | 1 participants |
| Margetuximab Stage A2 | Infusion Rate Sub-study All Safety | No infusion related reaction | 8 participants |
| Margetuximab Stage B | Infusion Rate Sub-study All Safety | Infusion related reaction Cycle 1 | 16 participants |
| Margetuximab Stage B | Infusion Rate Sub-study All Safety | No infusion related reaction | 55 participants |
| Margetuximab Stage B | Infusion Rate Sub-study All Safety | Infusion related reaction Cycle 2 or higher | 2 participants |
Secondary
To Evaluate Progression-free Survival (PFS), as Assessed by Study Investigators.
Time frame: Tumor assessments are conducted every 6 weeks for the first 24 weeks and then every 24 weeks until progression of cancer, up to 6.5 years.
Population: Analysis population consisted of all patient who had investigator-assessed responses to treatment as of the interim analysis. The outcome measure is calculated only for the randomized study population. The 88 participants in the sub-study were not part of the efficacy population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Margetuximab Plus Chemotherapy | To Evaluate Progression-free Survival (PFS), as Assessed by Study Investigators. | 5.6 months |
| Trastuzumab Plus Chemotherapy | To Evaluate Progression-free Survival (PFS), as Assessed by Study Investigators. | 4.2 months |
p-value: 0.001495% CI: [0.556, 0.87]Log Rank
Secondary
To Evaluate the Objective Response Rate (ORR) as Determined by Independent Radiological Review.
Objective response rate includes all patients with either a complete response (CR) or a partial response (PR) to study treatment
Time frame: Tumor assessments are conducted every 6 weeks for the first 24 weeks and then every 24 weeks until progression of cancer, up to 6.5 years.
Population: Tumor response was assessed for patients with measurable disease at baseline. The cutoff data for analysis corresponds with the completion of enrollment. Detection of ORR requires at least 12 weeks, so the ORR may be underestimated. Outcome measure is calculated only for the randomized study population. The 88 participants in the sub-study were not part of the efficacy population.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Margetuximab Plus Chemotherapy | To Evaluate the Objective Response Rate (ORR) as Determined by Independent Radiological Review. | CR | 7 Participants |
| Margetuximab Plus Chemotherapy | To Evaluate the Objective Response Rate (ORR) as Determined by Independent Radiological Review. | PR | 51 Participants |
| Margetuximab Plus Chemotherapy | To Evaluate the Objective Response Rate (ORR) as Determined by Independent Radiological Review. | No response, progressive disease, not evaluable or not available | 204 Participants |
| Trastuzumab Plus Chemotherapy | To Evaluate the Objective Response Rate (ORR) as Determined by Independent Radiological Review. | CR | 4 Participants |
| Trastuzumab Plus Chemotherapy | To Evaluate the Objective Response Rate (ORR) as Determined by Independent Radiological Review. | PR | 38 Participants |
| Trastuzumab Plus Chemotherapy | To Evaluate the Objective Response Rate (ORR) as Determined by Independent Radiological Review. | No response, progressive disease, not evaluable or not available | 220 Participants |