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    Clinical Trial Results:
    A Phase 3 Randomised, Double-Blind Study of PF-05280014 Plus Paclitaxel Versus Trastuzumab Plus Paclitaxel for the First-Line Treatment of Subjects with HER2-Positive Metastatic Breast Cancer

    Summary
    EudraCT number
    		 2013-001352-34
    Trial protocol
    		 CZ   HU   ES   PT   PL   GR   LV   SK  
    Global end of trial date
    27 Jun 2020

    Results information
    Results version number
    		 v2(current)
    This version publication date
    23 Jun 2021
    First version publication date
    14 Oct 2017
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    B3271002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01989676
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer, Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.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
    05 Nov 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Jun 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the objective response rate (ORR) in subjects with metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer who receive PF-05280014 to those who receive trastuzumab-EU, each in combination with paclitaxel.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 Paclitaxel administered during the study (considered as background therapy) was the branded or generic product available in the local region.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Feb 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 1 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 5
    Country: Number of subjects enrolled
    Brazil: 17
    Country: Number of subjects enrolled
    Chile: 15
    Country: Number of subjects enrolled
    Czechia: 1
    Country: Number of subjects enrolled
    Greece: 3
    Country: Number of subjects enrolled
    Hungary: 4
    Country: Number of subjects enrolled
    India: 39
    Country: Number of subjects enrolled
    Japan: 32
    Country: Number of subjects enrolled
    Korea, Republic of: 36
    Country: Number of subjects enrolled
    Latvia: 1
    Country: Number of subjects enrolled
    Mexico: 4
    Country: Number of subjects enrolled
    Peru: 8
    Country: Number of subjects enrolled
    Philippines: 68
    Country: Number of subjects enrolled
    Poland: 28
    Country: Number of subjects enrolled
    Portugal: 3
    Country: Number of subjects enrolled
    Romania: 15
    Country: Number of subjects enrolled
    Russian Federation: 199
    Country: Number of subjects enrolled
    Serbia: 4
    Country: Number of subjects enrolled
    Slovakia: 3
    Country: Number of subjects enrolled
    South Africa: 36
    Country: Number of subjects enrolled
    Thailand: 9
    Country: Number of subjects enrolled
    Turkey: 11
    Country: Number of subjects enrolled
    Ukraine: 160
    Country: Number of subjects enrolled
    United States: 1
    Worldwide total number of subjects
    702
    EEA total number of subjects
    58
    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)
    575
    From 65 to 84 years
    126
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 707 subjects were randomised to the study. Of these, 5 subjects were randomised but did not receive the study drug.

    Pre-assignment
    Screening details
    		 Subjects who fulfilled the inclusion/exclusion criteria were randomly assigned to 1 of the 2 treatments of this study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 PF-05280014
    Arm description
    		 Subjects with human epidermal growth factor receptor 2 (HER2)-positive breast cancer received PF-05280014 on Days 1, 8, 15 and 22 of each 28-day cycle followed by paclitaxel on Days 1, 8 and 15 of each 28-day cycle both as intravenous (IV) infusions until the end of the study. The first infusion of PF-05280014 was 4 mg/kg over 90 minutes on Cycle 1 Day 1. Subsequent weekly infusions of PF-05280014 were 2 mg/kg over 30 to 90 minutes. Paclitaxel was administered at a dose of 80 mg/m^2 over 60 minutes. Following completion of the paclitaxel administration period and beginning no earlier than Week 33 of the study, the PF-05280014 could be changed at the discretion of the investigator to every 3 weeks at a dose of 6 mg/kg infused over 30 to 90 minutes depending on tolerability.
    Arm type
    		 Experimental

    Investigational medicinal product name
    PF-05280014
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    PF-05280014 was administered on Days 1, 8, 15 and 22 of each 28-day cycle intravenously followed by paclitaxel on Days 1, 8, and 15 of each 28-day cycle until at least Week 33 of the study. The first infusion of PF-05280014 was 4 mg/kg over 90 minutes on Cycle 1 Day 1. Subsequent weekly infusions of PF-05280014 were 2 mg/kg over 30 to 90 minutes. Paclitaxel was administered at a dose of 80 mg/m^2 over 60 minutes. Following completion of the paclitaxel administration period and beginning no earlier than Week 33 of the study, the PF-05280014 regimen could be changed at the discretion of the investigator to every 3 weeks at a dose of 6 mg/kg infused over 30 to 90 minutes depending on tolerability.

    Arm title
    		 Trastuzumab-EU
    Arm description
    		 Subjects with HER2-positive breast cancer received trastuzumab-EU on Days 1, 8, 15 and 22 of each 28-day cycle followed by paclitaxel on Days 1, 8 and 15 of each 28-day cycle both as IV infusions until the end of the study. The first infusion of trastuzumab-EU was 4 mg/kg over 90 minutes on Cycle 1 Day 1. Subsequent weekly infusions of trastuzumab-EU were 2 mg/kg over 30 to 90 minutes. Paclitaxel was administered at a dose of 80 mg/m^2 over 60 minutes. Following completion of the paclitaxel administration period and beginning no earlier than Week 33 of the study, the trastuzuamab-EU could be changed at the discretion of the investigator to every 3 weeks at a dose of 6 mg/kg infused over 30 to 90 minutes depending on tolerability.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Trastuzumab-EU
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Trastuzumab-EU was administered on Days 1, 8, 15 and 22 of each 28-day cycle intravenously followed by paclitaxel on Days 1, 8, and 15 of each 28-day cycle until at least Week 33 of the study. The first infusion of trastuzumab-EU was 4 mg/kg over 90 minutes on Cycle 1 Day 1. Subsequent weekly infusions of trastuzumab-EU were 2 mg/kg over 30 to 90 minutes. Paclitaxel was administered at a dose of 80 mg/m^2 over 60 minutes. Following completion of the paclitaxel administration period and beginning no earlier than Week 33 of the study, the trastuzuamab-EU regimen could be changed at the discretion of the investigator to every 3 weeks at a dose of 6 mg/kg infused over 30 to 90 minutes depending on tolerability.

    Number of subjects in period 1
    		PF-05280014 Trastuzumab-EU
    Started
    349
    353
    Completed
    234
    217
    Not completed
    115
    136
         Adverse event, serious fatal
    52
    60
         No longer willing to participate in study
    26
    25
         Unspecified
    1
    2
         Lost to follow-up
    8
    18
         Subjects terminated from study by Sponsor
    26
    30
         Protocol deviation
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    PF-05280014
    Reporting group description
    		 Subjects with human epidermal growth factor receptor 2 (HER2)-positive breast cancer received PF-05280014 on Days 1, 8, 15 and 22 of each 28-day cycle followed by paclitaxel on Days 1, 8 and 15 of each 28-day cycle both as intravenous (IV) infusions until the end of the study. The first infusion of PF-05280014 was 4 mg/kg over 90 minutes on Cycle 1 Day 1. Subsequent weekly infusions of PF-05280014 were 2 mg/kg over 30 to 90 minutes. Paclitaxel was administered at a dose of 80 mg/m^2 over 60 minutes. Following completion of the paclitaxel administration period and beginning no earlier than Week 33 of the study, the PF-05280014 could be changed at the discretion of the investigator to every 3 weeks at a dose of 6 mg/kg infused over 30 to 90 minutes depending on tolerability.

    Reporting group title
    Trastuzumab-EU
    Reporting group description
    		 Subjects with HER2-positive breast cancer received trastuzumab-EU on Days 1, 8, 15 and 22 of each 28-day cycle followed by paclitaxel on Days 1, 8 and 15 of each 28-day cycle both as IV infusions until the end of the study. The first infusion of trastuzumab-EU was 4 mg/kg over 90 minutes on Cycle 1 Day 1. Subsequent weekly infusions of trastuzumab-EU were 2 mg/kg over 30 to 90 minutes. Paclitaxel was administered at a dose of 80 mg/m^2 over 60 minutes. Following completion of the paclitaxel administration period and beginning no earlier than Week 33 of the study, the trastuzuamab-EU could be changed at the discretion of the investigator to every 3 weeks at a dose of 6 mg/kg infused over 30 to 90 minutes depending on tolerability.

    Reporting group values
    		 PF-05280014 Trastuzumab-EU Total
    Number of subjects
    		 349 353 702
    Age Categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 283 292 575
        From 65-84 years
    		 66 60 126
        85 years and over
    		 0 1 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 54.0 ± 10.9 54.1 ± 10.9 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 349 353 702
        Male
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    PF-05280014
    Reporting group description
    		 Subjects with human epidermal growth factor receptor 2 (HER2)-positive breast cancer received PF-05280014 on Days 1, 8, 15 and 22 of each 28-day cycle followed by paclitaxel on Days 1, 8 and 15 of each 28-day cycle both as intravenous (IV) infusions until the end of the study. The first infusion of PF-05280014 was 4 mg/kg over 90 minutes on Cycle 1 Day 1. Subsequent weekly infusions of PF-05280014 were 2 mg/kg over 30 to 90 minutes. Paclitaxel was administered at a dose of 80 mg/m^2 over 60 minutes. Following completion of the paclitaxel administration period and beginning no earlier than Week 33 of the study, the PF-05280014 could be changed at the discretion of the investigator to every 3 weeks at a dose of 6 mg/kg infused over 30 to 90 minutes depending on tolerability.

    Reporting group title
    Trastuzumab-EU
    Reporting group description
    		 Subjects with HER2-positive breast cancer received trastuzumab-EU on Days 1, 8, 15 and 22 of each 28-day cycle followed by paclitaxel on Days 1, 8 and 15 of each 28-day cycle both as IV infusions until the end of the study. The first infusion of trastuzumab-EU was 4 mg/kg over 90 minutes on Cycle 1 Day 1. Subsequent weekly infusions of trastuzumab-EU were 2 mg/kg over 30 to 90 minutes. Paclitaxel was administered at a dose of 80 mg/m^2 over 60 minutes. Following completion of the paclitaxel administration period and beginning no earlier than Week 33 of the study, the trastuzuamab-EU could be changed at the discretion of the investigator to every 3 weeks at a dose of 6 mg/kg infused over 30 to 90 minutes depending on tolerability.

    Subject analysis set title
    PF-05280014
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects with HER2-positive breast cancer received PF-05280014 on Days 1, 8, 15 and 22 of each 28-day cycle followed by paclitaxel on Days 1, 8 and 15 of each 28-day cycle both as IV infusions until the end of the study. The first infusion of PF-05280014 was 4 mg/kg over 90 minutes on Cycle 1 Day 1. Subsequent weekly infusions of PF-05280014 were 2 mg/kg over 30 to 90 minutes. Paclitaxel was administered at a dose of 80 mg/m^2 over 60 minutes. Following completion of the paclitaxel administration period and beginning no earlier than Week 33 of the study, the PF-05280014 could be changed at the discretion of the investigator to every 3 weeks at a dose of 6 mg/kg infused over 30 to 90 minutes depending on tolerability.

    Subject analysis set title
    Trastuzumab-EU
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects with HER2-positive breast cancer received trastuzumab-EU on Days 1, 8, 15 and 22 of each 28-day cycle followed by paclitaxel on Days 1, 8 and 15 of each 28-day cycle both as IV infusions until the end of the study. The first infusion of trastuzumab-EU was 4 mg/kg over 90 minutes on Cycle 1 Day 1. Subsequent weekly infusions of trastuzumab-EU were 2 mg/kg over 30 to 90 minutes. Paclitaxel was administered at a dose of 80 mg/m^2 over 60 minutes. Following completion of the paclitaxel administration period and beginning no earlier than Week 33 of the study, the trastuzuamab-EU could be changed at the discretion of the investigator to every 3 weeks at a dose of 6 mg/kg infused over 30 to 90 minutes depending on tolerability.

    Primary: Objective Response Rate (ORR) Derived from Central Radiology Assessments: ITT Population

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    End point title
    		 Objective Response Rate (ORR) Derived from Central Radiology Assessments: ITT Population
    End point description
    ORR was defined as the percentage of subjects who achieved complete response (CR, complete disappearance of all target lesions with the exception of nodal disease; all target nodes must have decreased to normal size [short axis <10 mm]) or partial response (PR, >=30% decrease from baseline of the sum of diameters (SOD) of all target measurable lesions; the short diameter was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions) by Week 25 of the study and confirmed on a follow-up assessment (Week 33+/-14 days), based on the assessments of the central radiology review in accordance with RECIST 1.1. The ITT population was defined as all subjects who were randomised to study drug.
    End point type
    Primary
    End point timeframe
    From the date of randomisation until all subjects had either completed the Week 33 tumor assessment or discontinued study drug earlier than the Week 33 visit
    End point values
    		 PF-05280014 Trastuzumab-EU
    Number of subjects analysed
    352
    355
    Units: percentage of subjects
        number (confidence interval 95%)
    62.5 (57.2 to 67.6)
    66.5 (61.3 to 71.4)
    Statistical analysis title
    		 PF-05280014 versus Trastuzumab-EU
    Statistical analysis description
    Risk Ratio and associated 95% confidence interval (CI) are unstratified and based on the Miettinen and Nurminen method.
    Comparison groups
    PF-05280014 v Trastuzumab-EU
    Number of subjects included in analysis
    707
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [1]
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.842
         upper limit
    		 1.049
    Notes
    [1] - The hypothesis to be tested in this study was that the risk ratio of ORR of PF-05280014 versus that of trastuzumab-EU by Week 25 (+/-14 days) was within a pre-specified margin of 0.80 to 1.25.

    Secondary: One-year Progression-Free Survival (PFS) Rate Derived from Central Radiology Assessments: ITT Population

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    End point title
    		 One-year Progression-Free Survival (PFS) Rate Derived from Central Radiology Assessments: ITT Population
    End point description
    One-year PFS rate was analysed based on the time from date of randomisation to first documentation of progressive disease (PD), or death due to any cause in the absence of documented PD, based on assessments of central radiology review in accordance with RECIST 1.1. PD was defined for target disease as at least a 20% increase in sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in sum was observed during therapy) with a minimum absolute increase of 5 mm. For non-target disease PD: unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy; appearance of any new unequivocal malignant lesion was also considered PD. The 95% CI for median time to event was based on Brookmeyer and Crowley method. The ITT population was defined as all subjects who were randomised to study drug. 99999=there are insufficient events to estimate the upper bound of the 95% CI.
    End point type
    Secondary
    End point timeframe
    From the date of randomisation until 378 days post-randomisation
    End point values
    		 PF-05280014 Trastuzumab-EU
    Number of subjects analysed
    352
    355
    Units: months
        median (confidence interval 95%)
    12.16 (11.93 to 12.48)
    12.06 (11.79 to 99999)
    Statistical analysis title
    		 PF-05280014 versus Trastuzumab-EU
    Statistical analysis description
    The 95% CI for the hazard ratio was based on the Cox’s proportional hazard model.
    Comparison groups
    PF-05280014 v Trastuzumab-EU
    Number of subjects included in analysis
    707
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.505 [2]
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.26
    Notes
    [2] - 1-sided log-rank test was used to compare the PFS distribution between the two treatment groups and was stratified by prior trastuzumab exposure (Yes/No) and estrogen receptor (ER) status (ER positive vs. ER negative).

    Secondary: Duration of Response (DOR) per Central Radiology Assessments: ITT Population

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    End point title
    		 Duration of Response (DOR) per Central Radiology Assessments: ITT Population
    End point description
    DOR:time from first documentation of OR(CR or PR) to first documentation of PD/death due to any cause, based on central radiology review.Per RECIST v1.1, CR:complete disappearance of all target (T) lesions with exception of nodal disease; all T nodes reduced in short axis <10 mm. PR: >=30% decrease from baseline of SOD of T lesions; short diameter used in sum for T nodes, longest diameter used in sum for other T lesions. PD for T disease:at least 20% increase in SOD of T lesions above smallest sum observed with minimum absolute increase of 5 mm. For non-T disease:unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy; appearance of any new unequivocal malignant lesion was also considered PD. 95% CI for median time to event based on Brookmeyer and Crowley method. ITT population was analysed. “N”=subjects evaluable for this endpoint. 99999=there are insufficient events to estimate upper bound of 95% CI.
    End point type
    Secondary
    End point timeframe
    From the date of randomisation until 378 days post-randomisation
    End point values
    		 PF-05280014 Trastuzumab-EU
    Number of subjects analysed
    224
    238
    Units: months
        median (confidence interval 95%)
    11.27 (10.41 to 11.27)
    10.58 (10.22 to 99999)
    Statistical analysis title
    		 PF-05280014 versus Trastuzumab-EU
    Statistical analysis description
    The 95% CI for the hazard ratio was based on the Cox’s proportional hazard model.
    Comparison groups
    PF-05280014 v Trastuzumab-EU
    Number of subjects included in analysis
    462
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.304 [3]
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.67
         upper limit
    		 1.27
    Notes
    [3] - 1-sided log-rank test was used to compare the DOR distribution between the two treatment groups and was stratified by prior trastuzumab exposure (Yes/No) and ER status (ER positive vs. ER negative).

    Secondary: Overall Survival: ITT Population

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    End point title
    		 Overall Survival: ITT Population
    End point description
    Overall survival was analysed based on the time from date of randomisation to the date of death due to any cause. Subjects last known to be alive were censored on the date of last contact. The 95% CI for the median time to event was based on the Brookmeyer and Crowley Method. The ITT population was defined as all subjects who were randomised to study drug. Here, 99999 signifies that there are insufficient events to estimate the median survival and the 95% CI.
    End point type
    Secondary
    End point timeframe
    From the date of randomisation until end of study (approximately 6 years)
    End point values
    		 PF-05280014 Trastuzumab-EU
    Number of subjects analysed
    352
    355
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    		 PF-05280014 versus Trastuzumab-EU
    Statistical analysis description
    The 95% CI for the hazard ratio was based on the Cox’s proportional hazard model.
    Comparison groups
    PF-05280014 v Trastuzumab-EU
    Number of subjects included in analysis
    707
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.339 [4]
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.929
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.656
         upper limit
    		 1.316
    Notes
    [4] - 1-sided log-rank test was used to compare the OS distribution between the two treatment groups and was stratified by prior trastuzumab exposure (Yes/No) and ER status (ER positive vs. ER negative).

    Secondary: Serum Trough (Pre-dose) Concentration of PF-05280014 at Selected Cycles: PK Population

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    End point title
    		 Serum Trough (Pre-dose) Concentration of PF-05280014 at Selected Cycles: PK Population [5]
    End point description
    Human PK serum samples were analysed for concentrations of PF-05280014 using a validated, sensitive, and specific ELISA. PK population. "n"=subjects evaluable at specified time points only. Here, 99999 signifies that the Cycle 17 Day 1 (C17D1) samples summarised previously at PCD (Week 33) fell outside of cut-off used for final analysis (Week 53), to limit data for up to 1-year post randomisation, which was more conservative from previous Week 33 analysis. While comparing data between Week 33 and Week 53, there was a significant drop off in number of samples summarised at C17D1 and was down to zero for this endpoint.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Day 1 of Cycles 1, 3, 4, 5, 7, 8, 11, 14, 17 and Day 8 of Cycles 1 and 5
    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: No statistical analysis was performed for this endpoint
    End point values
    		 PF-05280014
    Number of subjects analysed
    349
    Units: mcg/mL
    median (full range (min-max))
        Cycle 1 Day 1 (n= 349)
    0.00 (0.00 to 123)
        Cycle 1 Day 8 (n= 339)
    27.90 (0.00 to 91.5)
        Cycle 3 Day 1 (n= 309)
    48.20 (0.00 to 110)
        Cycle 4 Day 1 (n= 304)
    53.50 (0.00 to 150)
        Cycle 5 Day 1 (n= 288)
    57.00 (0.00 to 182)
        Cycle 5 Day 8 (n= 277)
    57.40 (9.85 to 174)
        Cycle 7 Day 1 (n= 265)
    60.50 (0.00 to 152)
        Cycle 8 Day 1 (n= 256)
    62.25 (0.00 to 140)
        Cycle 11 Day 1 (n= 220)
    54.65 (0.00 to 148)
        Cycle 14 Day 1 (n= 188)
    50.70 (0.00 to 189)
        Cycle 17 Day 1 (n= 0)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Serum Peak Concentration of PF-05280014 at Selected Cycles: Pharmacokinetics (PK) Population

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    End point title
    		 Serum Peak Concentration of PF-05280014 at Selected Cycles: Pharmacokinetics (PK) Population [6]
    End point description
    Human PK serum samples were analysed for concentrations of PF-05280014 using a validated, sensitive, and specific enzyme-linked immunosorbent assay (ELISA). PK population was used for analysis, included all subjects who received PF-05280014 or trastuzumab-EU and had no major protocol deviations that influenced PK assessments, and had at least 1 post dose concentration measurement. Here "number analysed (n)" signifies subjects evaluable at specified time points only.
    End point type
    Secondary
    End point timeframe
    1 hour post end of infusion on Day 1 of Cycles 1 and 5
    Notes
    [6] - 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: No statistical analysis was performed for this endpoint
    End point values
    		 PF-05280014
    Number of subjects analysed
    349
    Units: mcg/mL
    median (full range (min-max))
        Cycle 1 Day 1 (n= 278)
    89.85 (0.00 to 246)
        Cycle 5 Day 1 (n= 204)
    95.70 (0.00 to 435)
    No statistical analyses for this end point

    Secondary: Serum Peak Concentration of Trastuzumab-EU at Selected Cycles: PK Population

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    End point title
    		 Serum Peak Concentration of Trastuzumab-EU at Selected Cycles: PK Population [7]
    End point description
    Human PK serum samples were analysed for concentrations of trastuzumab-EU using a validated, sensitive, and specific ELISA. PK population was used for analysis, included all subjects who received PF-05280014 or trastuzumab-EU and had no major protocol deviations that influenced PK assessments, and had at least 1 post dose concentration measurement. Here "n" signifies subjects evaluable at specified time points only.
    End point type
    Secondary
    End point timeframe
    1 hour post end of infusion on Day 1 of Cycles 1 and 5
    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: No statistical analysis was performed for this endpoint
    End point values
    		 Trastuzumab-EU
    Number of subjects analysed
    353
    Units: mcg/mL
    median (full range (min-max))
        Cycle 1 Day 1 (n= 267)
    89.70 (0.00 to 273)
        Cycle 5 Day 1 (n= 221)
    94.40 (8.96 to 353)
    No statistical analyses for this end point

    Secondary: Serum Trough (Pre-dose) Concentration of Trastuzumab-EU at Selected Cycles: PK Population

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    End point title
    		 Serum Trough (Pre-dose) Concentration of Trastuzumab-EU at Selected Cycles: PK Population [8]
    End point description
    Human PK serum samples were analysed for concentrations of trastuzumab-EU using a validated, sensitive, and specific ELISA. PK population was used for analysis, included all subjects who received PF-05280014 or trastuzumab-EU and had no major protocol deviations that influenced PK assessments, and had at least 1 post dose concentration measurement. Here "n" signifies subjects evaluable at specified time points only.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Day 1 of Cycles 1, 3, 4, 5, 7, 8, 11, 14, 17 and Day 8 of Cycles 1 and 5
    Notes
    [8] - 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: No statistical analysis was performed for this endpoint
    End point values
    		 Trastuzumab-EU
    Number of subjects analysed
    353
    Units: mcg/mL
    median (full range (min-max))
        Cycle 1 Day 1 (n= 349)
    0.00 (0.00 to 98.0)
        Cycle 1 Day 8 (n= 340)
    29.80 (0.00 to 101)
        Cycle 3 Day 1 (n= 319)
    50.40 (1.74 to 171)
        Cycle 4 Day 1 (n= 316)
    54.35 (0.00 to 148)
        Cycle 5 Day 1 (n= 303)
    60.00 (0.00 to 244)
        Cycle 5 Day 8 (n= 287)
    61.20 (4.64 to 150)
        Cycle 7 Day 1 (n= 276)
    63.00 (1.93 to 340)
        Cycle 8 Day 1 (n= 262)
    65.55 (0.690 to 155)
        Cycle 11 Day 1 (n= 223)
    57.50 (1.52 to 251)
        Cycle 14 Day 1 (n= 173)
    54.60 (0.00 to 187)
        Cycle 17 Day 1 (n= 1)
    45.10 (45.1 to 45.1)
    No statistical analyses for this end point

    Secondary: Number of Subjects With Positive Anti-Drug Antibodies (ADA) Sample: Safety Population

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    End point title
    		 Number of Subjects With Positive Anti-Drug Antibodies (ADA) Sample: Safety Population
    End point description
    Two sensitive, specific, and semi-quantitative electrochemiluminescent (ECL) immunoassays, 1 for detecting antibodies against PF-05280014 and the other for detecting antibodies against trastuzumab, were used to analyse ADA samples. Serum samples were first screened for ADA. Any samples that were positive in the screening assay were further analysed to confirm the positive result and determine the antibody titers. All samples were taken prior to dosing. The number of subjects with a positive sample (titer >=1.0) is provided. Safety population was used for analysis, included all subjects who received at least 1 dose of study drug. Here "n" signifies subjects evaluable at specified time points only. Here, 99999 signifies subjects were not tested for anti-drug antibodies.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Day 1 of Cycles 1, 3, 5, 8, 11, 14, 17
    End point values
    		 PF-05280014 Trastuzumab-EU
    Number of subjects analysed
    349
    353
    Units: subjects
        Cycle 1 Day 1 (prior to treatment) (n= 349, 350)
    30
    14
        Cycle 3 Day 1 (n= 308, 321)
    0
    0
        Cycle 5 Day 1 (n= 287, 303)
    0
    0
        Cycle 8 Day 1 (n= 255, 263)
    0
    0
        Cycle 11 Day 1 (n= 223, 224)
    0
    0
        Cycle 14 Day 1 (n= 192, 175)
    0
    0
        Cycle 17 Day 1 (n= 0, 1)
    99999
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Positive Neutralising Antibodies (Nab) Prior to Treatment: Safety Population

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    End point title
    		 Number of Subjects With Positive Neutralising Antibodies (Nab) Prior to Treatment: Safety Population
    End point description
    Human serum samples testing positive for the presence of ADA (anti-PF-05280014 or anti-trastuzumab-EU) were analysed for the presence or absence of NAb (neutralising anti-PF-05280014 or neutralising anti-trastuzumab-EU antibodies) following a tiered approach using screening and titer determination. The number of subjects at baseline (prior to treatment) with a positive NAb sample (titer >=1.48) is provided. Safety population was used for analysis, included all subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 (prior to treatment)
    End point values
    		 PF-05280014 Trastuzumab-EU
    Number of subjects analysed
    349
    350
    Units: subjects
    20
    9
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs) and serious AEs (SAEs) which occurred from the time the subject had taken at least 1 dose of study drug and the time of informed consent, respectively, through 70 days after the last dose of study drug (maximum up to 328 weeks)
    Adverse event reporting additional description
    The total number of deaths occurred during study are reported for all randomised subjects, not only for treated subjects, and included deaths which occurred beyond 70 days post last study drug dose (i.e. beyond 328 weeks). SAEs, Non-SAEs: safety population (all subjects who received at least 1 dose of study drug).
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    PF-05280014
    Reporting group description
    		 Subjects with HER2-positive breast cancer received PF-05280014 on Days 1, 8, 15 and 22 of each 28-day cycle followed by paclitaxel on Days 1, 8 and 15 of each 28-day cycle both as IV infusions until the end of the study. The first infusion of PF-05280014 was 4 mg/kg over 90 minutes on Cycle 1 Day 1. Subsequent weekly infusions of PF-05280014 were 2 mg/kg over 30 to 90 minutes. Paclitaxel was administered at a dose of 80 mg/m^2 over 60 minutes. Following completion of the paclitaxel administration period and beginning no earlier than Week 33 of the study, the PF-05280014 could be changed at the discretion of the investigator to every 3 weeks at a dose of 6 mg/kg infused over 30 to 90 minutes depending on tolerability.

    Reporting group title
    Trastuzumab-EU
    Reporting group description
    		 Subjects with HER2-positive breast cancer received trastuzumab-EU on Days 1, 8, 15 and 22 of each 28-day cycle followed by paclitaxel on Days 1, 8 and 15 of each 28-day cycle both as IV infusions until the end of the study. The first infusion of trastuzumab-EU was 4 mg/kg over 90 minutes on Cycle 1 Day 1. Subsequent weekly infusions of trastuzumab-EU were 2 mg/kg over 30 to 90 minutes. Paclitaxel was administered at a dose of 80 mg/m^2 over 60 minutes. Following completion of the paclitaxel administration period and beginning no earlier than Week 33 of the study, the trastuzuamab-EU could be changed at the discretion of the investigator to every 3 weeks at a dose of 6 mg/kg infused over 30 to 90 minutes depending on tolerability.

    Serious adverse events
    		 PF-05280014 Trastuzumab-EU
    Total subjects affected by serious adverse events
         subjects affected / exposed
    67 / 349 (19.20%)
    69 / 353 (19.55%)
         number of deaths (all causes)
    52
    60
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant pleural effusion
         subjects affected / exposed
    2 / 349 (0.57%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian germ cell teratoma benign
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial adenocarcinoma
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasopharyngeal neoplasm benign
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasm progression
    Additional description: Preferred term coding updates were made at different times for the 2 databases collecting adverse events. After reconciliation acceptable discrepancies between preferred terms were permitted.
         subjects affected / exposed
    2 / 349 (0.57%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 5
    0 / 4
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    2 / 349 (0.57%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypertension
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypotension
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Cyst rupture
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Fatigue
         subjects affected / exposed
    1 / 349 (0.29%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    15 / 349 (4.30%)
    16 / 353 (4.53%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 16
         deaths causally related to treatment / all
    0 / 12
    0 / 11
    Pyrexia
         subjects affected / exposed
    0 / 349 (0.00%)
    4 / 353 (1.13%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Endometrial hyperplasia
         subjects affected / exposed
    0 / 349 (0.00%)
    2 / 353 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metrorrhagia
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine prolapse
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonitis
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    5 / 349 (1.43%)
    2 / 353 (0.57%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    2 / 349 (0.57%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity pneumonitis
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Affective disorder
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Ejection fraction decreased
         subjects affected / exposed
    0 / 349 (0.00%)
    2 / 353 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 349 (0.00%)
    2 / 353 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    1 / 349 (0.29%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 349 (0.29%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin laceration
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 349 (0.29%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    2 / 349 (0.57%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 349 (0.29%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    0 / 349 (0.00%)
    4 / 353 (1.13%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    2 / 2
    Cardiac failure acute
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardio-respiratory arrest
         subjects affected / exposed
    2 / 349 (0.57%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiovascular insufficiency
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Myocardial infarction
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Ischaemic stroke
         subjects affected / exposed
    1 / 349 (0.29%)
    3 / 353 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    3 / 349 (0.86%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vocal cord paralysis
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral venous sinus thrombosis
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 349 (0.86%)
    2 / 353 (0.57%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Neutropenia
         subjects affected / exposed
    3 / 349 (0.86%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 349 (0.29%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 349 (0.29%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Macular degeneration
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 349 (0.29%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dyspepsia
         subjects affected / exposed
    0 / 349 (0.00%)
    2 / 353 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis contact
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin disorder
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 349 (0.29%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Thyroiditis subacute
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 349 (0.57%)
    4 / 353 (1.13%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mastitis
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    6 / 349 (1.72%)
    3 / 353 (0.85%)
         occurrences causally related to treatment / all
    2 / 6
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    2 / 349 (0.57%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 349 (0.00%)
    2 / 353 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 349 (0.86%)
    2 / 353 (0.57%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngotonsillitis
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    2 / 349 (0.57%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypernatraemia
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    4 / 349 (1.15%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 353 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 353 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 PF-05280014 Trastuzumab-EU
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    337 / 349 (96.56%)
    334 / 353 (94.62%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    42 / 349 (12.03%)
    45 / 353 (12.75%)
         occurrences all number
    59
    114
    Aspartate aminotransferase increased
         subjects affected / exposed
    36 / 349 (10.32%)
    31 / 353 (8.78%)
         occurrences all number
    41
    85
    Blood alkaline phosphatase increased
         subjects affected / exposed
    28 / 349 (8.02%)
    26 / 353 (7.37%)
         occurrences all number
    42
    51
    Ejection fraction decreased
         subjects affected / exposed
    49 / 349 (14.04%)
    45 / 353 (12.75%)
         occurrences all number
    61
    61
    Weight increased
         subjects affected / exposed
    20 / 349 (5.73%)
    22 / 353 (6.23%)
         occurrences all number
    32
    32
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    33 / 349 (9.46%)
    31 / 353 (8.78%)
         occurrences all number
    53
    44
    Vascular disorders
    Hypertension
         subjects affected / exposed
    40 / 349 (11.46%)
    33 / 353 (9.35%)
         occurrences all number
    67
    61
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    38 / 349 (10.89%)
    30 / 353 (8.50%)
         occurrences all number
    53
    38
    Headache
         subjects affected / exposed
    53 / 349 (15.19%)
    73 / 353 (20.68%)
         occurrences all number
    76
    89
    Neuropathy peripheral
         subjects affected / exposed
    33 / 349 (9.46%)
    34 / 353 (9.63%)
         occurrences all number
    47
    54
    Peripheral sensory neuropathy
         subjects affected / exposed
    93 / 349 (26.65%)
    85 / 353 (24.08%)
         occurrences all number
    186
    153
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    122 / 349 (34.96%)
    134 / 353 (37.96%)
         occurrences all number
    341
    474
    Leukopenia
         subjects affected / exposed
    36 / 349 (10.32%)
    45 / 353 (12.75%)
         occurrences all number
    114
    121
    Neutropenia
         subjects affected / exposed
    97 / 349 (27.79%)
    94 / 353 (26.63%)
         occurrences all number
    308
    283
    Thrombocytopenia
         subjects affected / exposed
    18 / 349 (5.16%)
    12 / 353 (3.40%)
         occurrences all number
    36
    20
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    53 / 349 (15.19%)
    46 / 353 (13.03%)
         occurrences all number
    63
    61
    Fatigue
         subjects affected / exposed
    46 / 349 (13.18%)
    51 / 353 (14.45%)
         occurrences all number
    80
    82
    Oedema peripheral
         subjects affected / exposed
    27 / 349 (7.74%)
    45 / 353 (12.75%)
         occurrences all number
    35
    67
    Pyrexia
         subjects affected / exposed
    41 / 349 (11.75%)
    29 / 353 (8.22%)
         occurrences all number
    63
    54
    Chills
         subjects affected / exposed
    17 / 349 (4.87%)
    18 / 353 (5.10%)
         occurrences all number
    17
    21
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    14 / 349 (4.01%)
    32 / 353 (9.07%)
         occurrences all number
    20
    43
    Constipation
         subjects affected / exposed
    24 / 349 (6.88%)
    31 / 353 (8.78%)
         occurrences all number
    26
    49
    Diarrhoea
         subjects affected / exposed
    61 / 349 (17.48%)
    65 / 353 (18.41%)
         occurrences all number
    104
    119
    Nausea
         subjects affected / exposed
    58 / 349 (16.62%)
    70 / 353 (19.83%)
         occurrences all number
    168
    145
    Stomatitis
         subjects affected / exposed
    23 / 349 (6.59%)
    13 / 353 (3.68%)
         occurrences all number
    31
    21
    Vomiting
         subjects affected / exposed
    28 / 349 (8.02%)
    26 / 353 (7.37%)
         occurrences all number
    40
    39
    Dyspepsia
         subjects affected / exposed
    16 / 349 (4.58%)
    18 / 353 (5.10%)
         occurrences all number
    22
    27
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    33 / 349 (9.46%)
    32 / 353 (9.07%)
         occurrences all number
    48
    49
    Dyspnoea
         subjects affected / exposed
    20 / 349 (5.73%)
    22 / 353 (6.23%)
         occurrences all number
    30
    25
    Epistaxis
         subjects affected / exposed
    15 / 349 (4.30%)
    23 / 353 (6.52%)
         occurrences all number
    21
    31
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    189 / 349 (54.15%)
    186 / 353 (52.69%)
         occurrences all number
    251
    259
    Pruritus
         subjects affected / exposed
    12 / 349 (3.44%)
    23 / 353 (6.52%)
         occurrences all number
    21
    31
    Rash
         subjects affected / exposed
    26 / 349 (7.45%)
    26 / 353 (7.37%)
         occurrences all number
    46
    33
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    44 / 349 (12.61%)
    38 / 353 (10.76%)
         occurrences all number
    79
    62
    Back pain
         subjects affected / exposed
    18 / 349 (5.16%)
    33 / 353 (9.35%)
         occurrences all number
    23
    47
    Bone pain
         subjects affected / exposed
    20 / 349 (5.73%)
    14 / 353 (3.97%)
         occurrences all number
    27
    20
    Myalgia
         subjects affected / exposed
    26 / 349 (7.45%)
    35 / 353 (9.92%)
         occurrences all number
    43
    84
    Pain in extremity
         subjects affected / exposed
    22 / 349 (6.30%)
    24 / 353 (6.80%)
         occurrences all number
    30
    40
    Infections and infestations
    Respiratory tract infection viral
         subjects affected / exposed
    23 / 349 (6.59%)
    13 / 353 (3.68%)
         occurrences all number
    34
    16
    Upper respiratory tract infection
         subjects affected / exposed
    36 / 349 (10.32%)
    46 / 353 (13.03%)
         occurrences all number
    55
    94
    Nasopharyngitis
         subjects affected / exposed
    21 / 349 (6.02%)
    19 / 353 (5.38%)
         occurrences all number
    34
    38
    Urinary tract infection
         subjects affected / exposed
    5 / 349 (1.43%)
    19 / 353 (5.38%)
         occurrences all number
    7
    24
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    23 / 349 (6.59%)
    21 / 353 (5.95%)
         occurrences all number
    28
    23

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Jul 2013
    This amendment was implemented in response to recommendations made by regulatory agencies during reviews performed prior to Health Authority, Institutional Review Board or Independent Ethics Committee submissions; no subjects had been screened or randomised at the time of the amendment.
    10 Jul 2014
    This amendment was implemented due to feedback from a retrospective review by Parexel Informatics of randomised subjects to determine if they had measurable disease (following investigator assessment), and subsequent to feedback from regulatory agencies.
    27 Sep 2016
    This amendment was implemented to update the study design to end subject treatment after the completion of Week 53 visit assessments, following communication with regulatory agencies.
    16 Mar 2017
    This amendment was implemented to update the study design to delineate two treatment periods to allow for continued treatment beyond Week 53, but with limited protocol required assessments.

    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
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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