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    Clinical Trial Results:
    A Phase 3, Randomized Study of Margetuximab Plus Chemotherapy vs Trastuzumab Plus Chemotherapy in the Treatment of Patients with HER2+ Metastatic Breast Cancer Who Have Received Prior Anti-HER2 Therapies and Require Systemic Treatment.

    Summary
    EudraCT number
    		 2015-000380-13
    Trial protocol
    		 BE   DE   PT   CZ   AT   FI   ES   DK   FR   PL   IT  
    Global end of trial date
    14 Jun 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Jun 2023
    First version publication date
    18 Jun 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CP-MGAH22-04
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02492711
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    MacroGenics, Inc
    Sponsor organisation address
    9704 Medical Center Dr., Rockville, United States, 20850
    Public contact
    Global Trial Manager, MacroGenics, Inc., 001 3012515172, info@macrogenics.com
    Scientific contact
    Global Trial Manager, MacroGenics, Inc., 001 3012515172, info@macrogenics.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    14 Jun 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Jun 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to evaluate the efficacy, as measured by progression-free survival (PFS) assessed by independent review and overall survival (OS), of margetuximab plus chemotherapy compared with trastuzumab plus chemotherapy in patients with advanced HER2+ breast cancer who 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 antiHER2 directed therapy in the metastatic setting, and who have received at least one, and no more than three, lines of therapy overall in the metastatic setting.
    Protection of trial subjects
    The trial was designed, conducted, and monitored in accordance with ethical principles that have their origin in the Declaration of Helsinki and in compliance with Good Clinical Practice (GCP) as required by the major regulatory authorities, and in accordance with all national and local laws and regulations of countries in which the trial was performed.
    Background therapy
    		 Physician'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
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Jul 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 7
    Country: Number of subjects enrolled
    Poland: 10
    Country: Number of subjects enrolled
    Portugal: 13
    Country: Number of subjects enrolled
    Spain: 61
    Country: Number of subjects enrolled
    United Kingdom: 14
    Country: Number of subjects enrolled
    Austria: 4
    Country: Number of subjects enrolled
    Belgium: 31
    Country: Number of subjects enrolled
    Czechia: 12
    Country: Number of subjects enrolled
    Denmark: 16
    Country: Number of subjects enrolled
    Finland: 4
    Country: Number of subjects enrolled
    France: 40
    Country: Number of subjects enrolled
    Germany: 17
    Country: Number of subjects enrolled
    Italy: 89
    Country: Number of subjects enrolled
    Canada: 12
    Country: Number of subjects enrolled
    Israel: 41
    Country: Number of subjects enrolled
    Korea, Republic of: 31
    Country: Number of subjects enrolled
    Puerto Rico: 4
    Country: Number of subjects enrolled
    United States: 218
    Worldwide total number of subjects
    624
    EEA total number of subjects
    304
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    490
    From 65 to 84 years
    132
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Before randomization, Investigators selected 1 of 4 chemotherapy agents (capecitabine, eribulin, gemcitabine, or vinorelbine) for each subject. Subjects were then randomized 1:1 to receive either margetuximab or trastuzumab with the selected chemotherapy. An non-randomized cohort was later added to evaluate lower infusion duration of margetuximab.

    Period 1
    Period 1 title
    Overall Study
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Margetuximab Plus Chemotherapy
    Arm description
    		 Margetuximab 15 mg/kg administered every 21 days with physician's choice of 1 of 4 backbone chemotherapy regimens
    Arm type
    		 Experimental

    Investigational medicinal product name
    margetuximab
    Investigational medicinal product code
    Other name
    MGAH22
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Margetuximab 15 mg/kg administered every 21 days

    Arm title
    		 Trastuzumab Plus Chemotherapy
    Arm description
    		 Trastuzumab administered every 21 days with physician's choice of 1 of 4 backbone chemotherapy regimens
    Arm type
    		 Active comparator

    Investigational medicinal product name
    trastuzumab
    Investigational medicinal product code
    Other name
    Herceptin
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab 8 mg/kg initial dose then 6 mg/kg given every 21 days

    Arm title
    		 Margetuximab Infusion Substudy
    Arm description
    		 Margetuximab with or without chemotherapy administered as a 120 minute first infusion in Cycle 1 followed by 60-minute or 30-minute infusion in Cycle 2
    Arm type
    		 Experimental

    Investigational medicinal product name
    margetuximab
    Investigational medicinal product code
    Other name
    MGAH22
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Margetuximab 15 mg/kg administered every 21 days, as a 120 minute first infusion in Cycle 1 followed by 60-minute or 30-minute infusion in Cycle 2

    Number of subjects in period 1
    		Margetuximab Plus Chemotherapy Trastuzumab Plus Chemotherapy Margetuximab Infusion Substudy
    Started
    266
    270
    88
    Completed
    230
    230
    75
    Not completed
    36
    40
    13
         Consent withdrawn by subject
    10
    16
    5
         Physician decision
    10
    6
    4
         Adverse event, non-fatal
    9
    9
    2
         Death
    3
    3
    -
         Other
    -
    -
    1
         Study treatment delay
    2
    1
    -
         Never treated
    2
    4
    -
         Lost to follow-up
    -
    -
    1
         Change in chemotherapy
    -
    1
    -
    Period 2
    Period 2 title
    Infusion Sub-Study
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Margetuximab Stage A1
    Arm description
    		 Margetuximab administered as a 120 minute first infusion in Cycle 1 followed by 60 minute infusion in Cycle 2
    Arm type
    		 Experimental

    Investigational medicinal product name
    margetuximab
    Investigational medicinal product code
    Other name
    MGAH22
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Margetuximab 15 mg/kg administered every 21 days

    Arm title
    		 Margetuximab Stage A2
    Arm description
    		 Margetuximab administered as a 120 minute first infusion in Cycle 1 followed by 30 minute infusion in Cycle 2
    Arm type
    		 Experimental

    Investigational medicinal product name
    margetuximab
    Investigational medicinal product code
    Other name
    MGAH22
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Margetuximab 15 mg/kg administered every 21 days

    Arm title
    		 Margetuximab Stage B
    Arm description
    		 Margetuximab administered as a 120 minute first infusion in Cycle 1 followed by 30 minute infusion in Cycle 2
    Arm type
    		 Experimental

    Investigational medicinal product name
    margetuximab
    Investigational medicinal product code
    Other name
    MGAH22
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Margetuximab 15 mg/kg administered every 21 days

    Number of subjects in period 2 [1]
    		Margetuximab Stage A1 Margetuximab Stage A2 Margetuximab Stage B
    Started
    8
    9
    71
    Completed
    8
    9
    71
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Period 2 consists of an additional non-randomized cohort that evaluated lower infusion duration of margetuximab. This period is separate from the preceding period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Margetuximab Plus Chemotherapy
    Reporting group description
    		 Margetuximab 15 mg/kg administered every 21 days with physician's choice of 1 of 4 backbone chemotherapy regimens

    Reporting group title
    Trastuzumab Plus Chemotherapy
    Reporting group description
    		 Trastuzumab administered every 21 days with physician's choice of 1 of 4 backbone chemotherapy regimens

    Reporting group title
    Margetuximab Infusion Substudy
    Reporting group description
    		 Margetuximab with or without chemotherapy administered as a 120 minute first infusion in Cycle 1 followed by 60-minute or 30-minute infusion in Cycle 2

    Reporting group values
    		 Margetuximab Plus Chemotherapy Trastuzumab Plus Chemotherapy Margetuximab Infusion Substudy Total
    Number of subjects
    		 266 270 88 624
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 54.4 ( 11.4 ) 55.7 ( 11.5 ) 54.5 ( 12.5 ) -
    Gender categorical
    Units: Subjects
        Female
    		 266 267 87 620
        Male
    		 0 3 1 4

    End points

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    End points reporting groups
    Reporting group title
    Margetuximab Plus Chemotherapy
    Reporting group description
    		 Margetuximab 15 mg/kg administered every 21 days with physician's choice of 1 of 4 backbone chemotherapy regimens

    Reporting group title
    Trastuzumab Plus Chemotherapy
    Reporting group description
    		 Trastuzumab administered every 21 days with physician's choice of 1 of 4 backbone chemotherapy regimens

    Reporting group title
    Margetuximab Infusion Substudy
    Reporting group description
    		 Margetuximab with or without chemotherapy administered as a 120 minute first infusion in Cycle 1 followed by 60-minute or 30-minute infusion in Cycle 2
    Reporting group title
    Margetuximab Stage A1
    Reporting group description
    		 Margetuximab administered as a 120 minute first infusion in Cycle 1 followed by 60 minute infusion in Cycle 2

    Reporting group title
    Margetuximab Stage A2
    Reporting group description
    		 Margetuximab administered as a 120 minute first infusion in Cycle 1 followed by 30 minute infusion in Cycle 2

    Reporting group title
    Margetuximab Stage B
    Reporting group description
    		 Margetuximab administered as a 120 minute first infusion in Cycle 1 followed by 30 minute infusion in Cycle 2

    Primary: Progression-free Survival (PFS) as Determined by Independent Radiological Review.

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    End point title
    		 Progression-free Survival (PFS) as Determined by Independent Radiological Review. [1]
    End point description
    PFS is measured from the time of randomization until first documented disease progression or death from any cause, whichever is first.
    End point type
    Primary
    End point timeframe
    Tumor assessments are conducted every 6 weeks for the first 24 weeks and then every 24 weeks until progression of cancer, average 5 months.
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is not relevant to the infusion sub-study arm.
    End point values
    		 Margetuximab Plus Chemotherapy Trastuzumab Plus Chemotherapy
    Number of subjects analysed
    266
    270
    Units: months
        median (confidence interval 95%)
    5.8 (5.52 to 6.97)
    4.9 (4.17 to 5.59)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Stratified Cox Proportional Model
    Comparison groups
    Trastuzumab Plus Chemotherapy v Margetuximab Plus Chemotherapy
    Number of subjects included in analysis
    536
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0334
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.593
         upper limit
    		 0.979

    Primary: Overall Survival (OS) Defined as the Number of Days From Randomization to the Date of Death (From Any Cause)

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    End point title
    		 Overall Survival (OS) Defined as the Number of Days From Randomization to the Date of Death (From Any Cause) [2]
    End point description
    Overall survival is the time from randomization until death from any cause
    End point type
    Primary
    End point timeframe
    Throughout the study, average 21 months
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is not relevant to the infusion sub-study arm.
    End point values
    		 Margetuximab Plus Chemotherapy Trastuzumab Plus Chemotherapy
    Number of subjects analysed
    266
    270
    Units: months
        median (confidence interval 95%)
    21.6 (0.66 to 61.44)
    21.9 (0.07 to 64.53)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Stratified Cox Proportional Model
    Comparison groups
    Trastuzumab Plus Chemotherapy v Margetuximab Plus Chemotherapy
    Number of subjects included in analysis
    536
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6204 [3]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.774
         upper limit
    		 1.165
    Notes
    [3] - Stratified Log-Rank Test

    Primary: Number of Patients With Grade 3 or Higher Infusion Related Reactions

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    End point title
    		 Number of Patients With Grade 3 or Higher Infusion Related Reactions [4]
    End point description
    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
    End point type
    Primary
    End point timeframe
    22 days
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This endpoint was specific to the infusion substudy arm only.
    End point values
    		 Margetuximab Stage A1 Margetuximab Stage A2 Margetuximab Stage B
    Number of subjects analysed
    8
    9
    71
    Units: Participants
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Progression-free Survival (PFS), as Assessed by Study Investigators.

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    End point title
    		 Progression-free Survival (PFS), as Assessed by Study Investigators. [5]
    End point description
    End point type
    Secondary
    End point timeframe
    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
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is not relevant to the infusion sub-study arm.
    End point values
    		 Margetuximab Plus Chemotherapy Trastuzumab Plus Chemotherapy
    Number of subjects analysed
    160
    177
    Units: months
        median (confidence interval 95%)
    5.6 (5.06 to 6.67)
    4.2 (3.98 to 5.39)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Stratified Cox Proportional Model
    Comparison groups
    Margetuximab Plus Chemotherapy v Trastuzumab Plus Chemotherapy
    Number of subjects included in analysis
    337
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0014 [6]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.556
         upper limit
    		 0.87
    Notes
    [6] - Stratified Log-Rank Test

    Secondary: Objective Response Rate (ORR) as Determined by Independent Radiological Review

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    End point title
    		 Objective Response Rate (ORR) as Determined by Independent Radiological Review [7]
    End point description
    Objective response rate includes all patients with either a complete response (CR) or a partial response (PR) to study treatment
    End point type
    Secondary
    End point timeframe
    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
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is not relevant to the infusion sub-study arm.
    End point values
    		 Margetuximab Plus Chemotherapy Trastuzumab Plus Chemotherapy
    Number of subjects analysed
    262
    262
    Units: Participants
        CR
    7
    4
        PR
    51
    38
        No response, PD, not evaluable or not available
    204
    220
    No statistical analyses for this end point

    Secondary: Infusion Rate Sub-study All Safety

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    End point title
    		 Infusion Rate Sub-study All Safety
    End point description
    Incidence of all grades of infusion-related reactions
    End point type
    Secondary
    End point timeframe
    Throughout the study, average duration 6 months
    End point values
    		 Margetuximab Stage A1 Margetuximab Stage A2 Margetuximab Stage B
    Number of subjects analysed
    8
    9
    71
    Units: Participants
        Infusion related reaction Cycle 1
    1
    1
    16
        Infusion related reaction Cycle 2 or higher
    0
    0
    2
        No infusion related reaction
    7
    8
    55
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were collected from the time of first dose through 30 days after the last dose, average 6 months. All-cause mortality was collected from the first dose until the primary completion date, average 2 years.
    Adverse event reporting additional description
    AEs are based on physical exam, patient reports, and significant abnormal laboratory values. AEs were not collected in survival follow up. Only SAEs were collected in survival follow up if related to study treatment. Only patients who received study treatments were assessed for safety.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.10
    Reporting groups
    Reporting group title
    Margetuximab Plus Chemotherapy
    Reporting group description
    		 Margetuximab administered every 21 days with physician's choice of 1 of 4 backbone chemotherapy regimens.

    Reporting group title
    Trastuzumab Plus Chemotherapy
    Reporting group description
    		 Trastuzumab administered every 21 days with physician's choice of 1 of 4 backbone chemotherapy regimens

    Reporting group title
    Margetuximab Infusion Substudy
    Reporting group description
    		 Margetuximab with or without chemotherapy

    Serious adverse events
    		 Margetuximab Plus Chemotherapy Trastuzumab Plus Chemotherapy Margetuximab Infusion Substudy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    47 / 264 (17.80%)
    51 / 266 (19.17%)
    17 / 88 (19.32%)
         number of deaths (all causes)
    204
    202
    62
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Leukaemia
         subjects affected / exposed
    0 / 264 (0.00%)
    1 / 266 (0.38%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    0 / 264 (0.00%)
    1 / 266 (0.38%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Embolism
         subjects affected / exposed
    0 / 264 (0.00%)
    1 / 266 (0.38%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 264 (0.38%)
    0 / 266 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subclavian vein thrombosis
         subjects affected / exposed
    1 / 264 (0.38%)
    0 / 266 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vasculitis
         subjects affected / exposed
    1 / 264 (0.38%)
    0 / 266 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 264 (0.76%)
    3 / 266 (1.13%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 264 (0.00%)
    1 / 266 (0.38%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 264 (0.38%)
    1 / 266 (0.38%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 264 (0.00%)
    1 / 266 (0.38%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    0 / 264 (0.00%)
    1 / 266 (0.38%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 264 (0.38%)
    0 / 266 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Infusion site extravasation
         subjects affected / exposed
    1 / 264 (0.38%)
    0 / 266 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 264 (0.00%)
    1 / 266 (0.38%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 264 (0.00%)
    0 / 266 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Allergic oedema
         subjects affected / exposed
    1 / 264 (0.38%)
    0 / 266 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    1 / 264 (0.38%)
    4 / 266 (1.50%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 264 (0.38%)
    1 / 266 (0.38%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 264 (0.38%)
    0 / 266 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 264 (0.76%)
    0 / 266 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 264 (0.00%)
    1 / 266 (0.38%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 264 (0.38%)
    0 / 266 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    0 / 264 (0.00%)
    1 / 266 (0.38%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 264 (0.00%)
    0 / 266 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    1 / 264 (0.38%)
    1 / 266 (0.38%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 264 (0.00%)
    1 / 266 (0.38%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    0 / 264 (0.00%)
    1 / 266 (0.38%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    1 / 264 (0.38%)
    0 / 266 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    3 / 264 (1.14%)
    0 / 266 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    1 / 264 (0.38%)
    0 / 266 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 264 (0.00%)
    1 / 266 (0.38%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural haemorrhage
         subjects affected / exposed
    0 / 264 (0.00%)
    1 / 266 (0.38%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 264 (0.38%)
    0 / 266 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 264 (0.38%)
    0 / 266 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 264 (0.00%)
    1 / 266 (0.38%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 264 (0.38%)
    0 / 266 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 264 (0.38%)
    0 / 266 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Encephalopathy
         subjects affected / exposed
    0 / 264 (0.00%)
    1 / 266 (0.38%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 264 (0.00%)
    1 / 266 (0.38%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 264 (0.00%)
    1 / 266 (0.38%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 264 (0.38%)
    0 / 266 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 264 (0.00%)
    1 / 266 (0.38%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    4 / 264 (1.52%)
    10 / 266 (3.76%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    2 / 10
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    2 / 264 (0.76%)
    2 / 266 (0.75%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    4 / 264 (1.52%)
    1 / 266 (0.38%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 264 (0.38%)
    1 / 266 (0.38%)
    2 / 88 (2.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 264 (0.38%)
    1 / 266 (0.38%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 264 (0.38%)
    0 / 266 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 264 (0.38%)
    0 / 266 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 264 (0.38%)
    0 / 266 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 264 (0.00%)
    0 / 266 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal toxicity
         subjects affected / exposed
    0 / 264 (0.00%)
    1 / 266 (0.38%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Impaired gastric emptying
         subjects affected / exposed
    1 / 264 (0.38%)
    0 / 266 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 264 (0.00%)
    1 / 266 (0.38%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Irritable bowel syndrome
         subjects affected / exposed
    1 / 264 (0.38%)
    0 / 266 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 264 (0.00%)
    0 / 266 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 264 (0.00%)
    0 / 266 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 264 (0.38%)
    0 / 266 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 264 (0.00%)
    0 / 266 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 264 (0.00%)
    1 / 266 (0.38%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 264 (0.00%)
    0 / 266 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 264 (0.38%)
    0 / 266 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 264 (0.00%)
    0 / 266 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 264 (0.00%)
    1 / 266 (0.38%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    0 / 264 (0.00%)
    1 / 266 (0.38%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    1 / 264 (0.38%)
    0 / 266 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    4 / 264 (1.52%)
    8 / 266 (3.01%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 8
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 264 (0.38%)
    3 / 266 (1.13%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 264 (0.76%)
    2 / 266 (0.75%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 264 (0.38%)
    2 / 266 (0.75%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast cellulitis
         subjects affected / exposed
    0 / 264 (0.00%)
    2 / 266 (0.75%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 264 (0.00%)
    1 / 266 (0.38%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 264 (0.38%)
    0 / 266 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acinetobacter infection
         subjects affected / exposed
    0 / 264 (0.00%)
    1 / 266 (0.38%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast abscess
         subjects affected / exposed
    0 / 264 (0.00%)
    1 / 266 (0.38%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    0 / 264 (0.00%)
    0 / 266 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 264 (0.00%)
    1 / 266 (0.38%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronavirus infection
         subjects affected / exposed
    1 / 264 (0.38%)
    0 / 266 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 264 (0.38%)
    0 / 266 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    0 / 264 (0.00%)
    1 / 266 (0.38%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 264 (0.00%)
    1 / 266 (0.38%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infected bite
         subjects affected / exposed
    0 / 264 (0.00%)
    1 / 266 (0.38%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 264 (0.38%)
    0 / 266 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    lung infection
         subjects affected / exposed
    0 / 264 (0.00%)
    1 / 266 (0.38%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mastitis
         subjects affected / exposed
    1 / 264 (0.38%)
    0 / 266 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mastoiditis
         subjects affected / exposed
    1 / 264 (0.38%)
    0 / 266 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Periorbital cellulitis
         subjects affected / exposed
    1 / 264 (0.38%)
    0 / 266 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    0 / 264 (0.00%)
    0 / 266 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 264 (0.00%)
    0 / 266 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 264 (0.38%)
    0 / 266 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    0 / 264 (0.00%)
    1 / 266 (0.38%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Streptococcal bacteraemia
         subjects affected / exposed
    1 / 264 (0.38%)
    0 / 266 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 264 (0.00%)
    1 / 266 (0.38%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 264 (0.00%)
    1 / 266 (0.38%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 264 (0.38%)
    0 / 266 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 264 (0.38%)
    0 / 266 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 264 (0.38%)
    0 / 266 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    1 / 264 (0.38%)
    0 / 266 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Margetuximab Plus Chemotherapy Trastuzumab Plus Chemotherapy Margetuximab Infusion Substudy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    213 / 264 (80.68%)
    210 / 266 (78.95%)
    68 / 88 (77.27%)
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    32 / 264 (12.12%)
    38 / 266 (14.29%)
    12 / 88 (13.64%)
         occurrences all number
    99
    90
    26
    Aspartate aminotransferase increased
         subjects affected / exposed
    22 / 264 (8.33%)
    34 / 266 (12.78%)
    12 / 88 (13.64%)
         occurrences all number
    41
    57
    30
    Alanine aminotransferase increased
         subjects affected / exposed
    26 / 264 (9.85%)
    26 / 266 (9.77%)
    11 / 88 (12.50%)
         occurrences all number
    49
    61
    24
    White blood cell count decreased
         subjects affected / exposed
    20 / 264 (7.58%)
    26 / 266 (9.77%)
    8 / 88 (9.09%)
         occurrences all number
    73
    60
    15
    Weight decreased
         subjects affected / exposed
    16 / 264 (6.06%)
    15 / 266 (5.64%)
    9 / 88 (10.23%)
         occurrences all number
    17
    19
    11
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    33 / 264 (12.50%)
    9 / 266 (3.38%)
    18 / 88 (20.45%)
         occurrences all number
    36
    15
    52
    Nervous system disorders
    Headache
         subjects affected / exposed
    50 / 264 (18.94%)
    43 / 266 (16.17%)
    11 / 88 (12.50%)
         occurrences all number
    82
    89
    14
    Neuropathy peripheral
         subjects affected / exposed
    26 / 264 (9.85%)
    28 / 266 (10.53%)
    7 / 88 (7.95%)
         occurrences all number
    36
    38
    8
    Dizziness
         subjects affected / exposed
    26 / 264 (9.85%)
    17 / 266 (6.39%)
    5 / 88 (5.68%)
         occurrences all number
    31
    20
    6
    Dysgeusia
         subjects affected / exposed
    16 / 264 (6.06%)
    15 / 266 (5.64%)
    7 / 88 (7.95%)
         occurrences all number
    17
    17
    7
    Peripheral sensory neuropathy
         subjects affected / exposed
    17 / 264 (6.44%)
    13 / 266 (4.89%)
    3 / 88 (3.41%)
         occurrences all number
    28
    23
    4
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    72 / 264 (27.27%)
    54 / 266 (20.30%)
    17 / 88 (19.32%)
         occurrences all number
    257
    154
    45
    Anaemia
         subjects affected / exposed
    48 / 264 (18.18%)
    61 / 266 (22.93%)
    18 / 88 (20.45%)
         occurrences all number
    100
    126
    42
    Thrombocytopenia
         subjects affected / exposed
    22 / 264 (8.33%)
    13 / 266 (4.89%)
    3 / 88 (3.41%)
         occurrences all number
    35
    24
    15
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    112 / 264 (42.42%)
    95 / 266 (35.71%)
    24 / 88 (27.27%)
         occurrences all number
    187
    144
    33
    Pyrexia
         subjects affected / exposed
    50 / 264 (18.94%)
    34 / 266 (12.78%)
    18 / 88 (20.45%)
         occurrences all number
    73
    62
    29
    Asthenia
         subjects affected / exposed
    49 / 264 (18.56%)
    32 / 266 (12.03%)
    7 / 88 (7.95%)
         occurrences all number
    102
    47
    8
    Oedema peripheral
         subjects affected / exposed
    21 / 264 (7.95%)
    26 / 266 (9.77%)
    5 / 88 (5.68%)
         occurrences all number
    34
    32
    6
    Mucosal inflammation
         subjects affected / exposed
    26 / 264 (9.85%)
    8 / 266 (3.01%)
    3 / 88 (3.41%)
         occurrences all number
    29
    9
    6
    Influenza like illness
         subjects affected / exposed
    18 / 264 (6.82%)
    11 / 266 (4.14%)
    5 / 88 (5.68%)
         occurrences all number
    22
    23
    7
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    88 / 264 (33.33%)
    87 / 266 (32.71%)
    33 / 88 (37.50%)
         occurrences all number
    133
    140
    44
    Diarrhoea
         subjects affected / exposed
    68 / 264 (25.76%)
    67 / 266 (25.19%)
    14 / 88 (15.91%)
         occurrences all number
    119
    107
    19
    Constipation
         subjects affected / exposed
    50 / 264 (18.94%)
    44 / 266 (16.54%)
    20 / 88 (22.73%)
         occurrences all number
    73
    51
    27
    Vomiting
         subjects affected / exposed
    55 / 264 (20.83%)
    38 / 266 (14.29%)
    19 / 88 (21.59%)
         occurrences all number
    79
    53
    24
    Abdominal pain
         subjects affected / exposed
    25 / 264 (9.47%)
    36 / 266 (13.53%)
    9 / 88 (10.23%)
         occurrences all number
    33
    53
    14
    Stomatitis
         subjects affected / exposed
    28 / 264 (10.61%)
    21 / 266 (7.89%)
    8 / 88 (9.09%)
         occurrences all number
    34
    33
    10
    Abdominal pain upper
         subjects affected / exposed
    22 / 264 (8.33%)
    21 / 266 (7.89%)
    1 / 88 (1.14%)
         occurrences all number
    27
    29
    1
    Dyspepsia
         subjects affected / exposed
    16 / 264 (6.06%)
    20 / 266 (7.52%)
    7 / 88 (7.95%)
         occurrences all number
    18
    21
    9
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    42 / 264 (15.91%)
    33 / 266 (12.41%)
    6 / 88 (6.82%)
         occurrences all number
    54
    50
    6
    Dyspnoea
         subjects affected / exposed
    34 / 264 (12.88%)
    29 / 266 (10.90%)
    13 / 88 (14.77%)
         occurrences all number
    42
    43
    16
    Epistaxis
         subjects affected / exposed
    18 / 264 (6.82%)
    19 / 266 (7.14%)
    2 / 88 (2.27%)
         occurrences all number
    23
    22
    2
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    47 / 264 (17.80%)
    39 / 266 (14.66%)
    13 / 88 (14.77%)
         occurrences all number
    51
    46
    13
    Palmer-plantar erthrodysaesthesia syndrome
         subjects affected / exposed
    33 / 264 (12.50%)
    43 / 266 (16.17%)
    1 / 88 (1.14%)
         occurrences all number
    69
    102
    3
    Rash
         subjects affected / exposed
    18 / 264 (6.82%)
    15 / 266 (5.64%)
    6 / 88 (6.82%)
         occurrences all number
    21
    25
    6
    Pruritus
         subjects affected / exposed
    13 / 264 (4.92%)
    13 / 266 (4.89%)
    7 / 88 (7.95%)
         occurrences all number
    15
    13
    7
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    15 / 264 (5.68%)
    15 / 266 (5.64%)
    6 / 88 (6.82%)
         occurrences all number
    16
    16
    7
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    32 / 264 (12.12%)
    25 / 266 (9.40%)
    7 / 88 (7.95%)
         occurrences all number
    42
    27
    8
    Arthralgia
         subjects affected / exposed
    28 / 264 (10.61%)
    23 / 266 (8.65%)
    10 / 88 (11.36%)
         occurrences all number
    35
    30
    17
    Back pain
         subjects affected / exposed
    23 / 264 (8.71%)
    27 / 266 (10.15%)
    7 / 88 (7.95%)
         occurrences all number
    24
    36
    11
    Myalgia
         subjects affected / exposed
    18 / 264 (6.82%)
    16 / 266 (6.02%)
    4 / 88 (4.55%)
         occurrences all number
    23
    20
    5
    Muscle spasms
         subjects affected / exposed
    17 / 264 (6.44%)
    11 / 266 (4.14%)
    7 / 88 (7.95%)
         occurrences all number
    18
    11
    9
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    25 / 264 (9.47%)
    26 / 266 (9.77%)
    5 / 88 (5.68%)
         occurrences all number
    39
    32
    8
    Upper respiratory tract infection
         subjects affected / exposed
    21 / 264 (7.95%)
    23 / 266 (8.65%)
    7 / 88 (7.95%)
         occurrences all number
    34
    24
    7
    Nasopharyngitis
         subjects affected / exposed
    21 / 264 (7.95%)
    19 / 266 (7.14%)
    1 / 88 (1.14%)
         occurrences all number
    27
    27
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    38 / 264 (14.39%)
    38 / 266 (14.29%)
    9 / 88 (10.23%)
         occurrences all number
    50
    45
    10
    Hypokalaemia
         subjects affected / exposed
    16 / 264 (6.06%)
    21 / 266 (7.89%)
    8 / 88 (9.09%)
         occurrences all number
    28
    36
    19

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Jan 2016
    This global amendment increased the number of allowable prior lines of therapy from 2 to 3; modified efficacy evaluation timing; and clarified eligibility.
    09 Feb 2017
    In this global amendment the requirement for 3 prior anti-HER2 targeted therapies (trastuzumab, pertuzumab, and T-DM1) was liberalized. After this amendment, subjects were required to have at least 2 prior lines of anti-HER2 targeted therapies in the MBC setting before study entry, 1 of which must have been pertuzumab.
    26 Jan 2018
    An additional non-randomized cohort was added to demonstrate tolerability of lowering infusion duration from 120 minutes in Cycle 1 to 30 minutes in Cycle 2 and thereafter. To ensure that eligibility for randomized versus infusion sub-study populations were non-overlapping, eligibility for this cohort included at least 4 prior lines of therapy for metastatic disease. Randomized subjects received 1 to 3 lines of prior therapy, whereas infusion sub-study subjects received at least 4 prior lines.
    08 Jun 2020
    This global amendment limited study procedures that may increase risk of iatrogenic exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) while preserving the ability to collect necessary safety and efficacy data.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/36332179
    http://www.ncbi.nlm.nih.gov/pubmed/33480963
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