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    Clinical Trial Results:
    A Phase 3 Randomized, Double-Blind Study of PF-05280014 Plus Paclitaxel Versus Trastuzumab Plus Paclitaxel for the First-Line Treatment of Patients 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

    Results information
    Results version number
    		 v1
    This version publication date
    14 Oct 2017
    First version publication date
    14 Oct 2017
    Other versions
    		 v2

    Trial information

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    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., 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 800-718-1021, 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
    Interim
    Date of interim/final analysis
    16 Feb 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Aug 2016
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    To compare the objective response rate (ORR) in patients with metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer who received PF-05280014 in combination with paclitaxel to those who received trastuzumab EU in combination with paclitaxel.
    Protection of trial subjects
    This study was conducted in compliance with the ethical principles originating in or derived from the International Ethical Guidelines for Biomedical Research Involving Human Patients (Council for International Organizations of Medical Sciences 2002), the Declaration of Helsinki (World Medical Association 1996 and 2008), and in compliance with all International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines. In addition, all local regulatory requirements were followed; in particular, those affording greater protection to the safety of study participants.
    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
    		 12 Months
    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
    Czech Republic: 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 randomized to the study. Of these, 5 patients were randomized but did not receive study drug.

    Pre-assignment
    Screening details
    		 Participants 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, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 PF-05280014
    Arm description
    		 Participants with human epidermal growth factor receptor 2 (HER2)-positive breast cancer received PF-05280014 in combination with paclitaxel.
    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
    		 Participants with HER2-positive breast cancer received trastuzumab-EU in combination with paclitaxel.
    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
    11
    6
    Not completed
    338
    347
         Discontinued
    59
    68
         Ongoing at data cutoff
    279
    279

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    PF-05280014
    Reporting group description
    		 Participants with human epidermal growth factor receptor 2 (HER2)-positive breast cancer received PF-05280014 in combination with paclitaxel.

    Reporting group title
    Trastuzumab-EU
    Reporting group description
    		 Participants with HER2-positive breast cancer received trastuzumab-EU in combination with paclitaxel.

    Reporting group values
    		 PF-05280014 Trastuzumab-EU Total
    Number of subjects
    		 349 353 702
    Age Categorical
    Units: Subjects
        <18
    		 0 0 0
        18 to 64
    		 283 292 575
        65 to 84
    		 66 60 126
        ≥85
    		 0 1 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 54 ( 10.9 ) 54.1 ( 10.9 ) -
    Gender, Male/Female
    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
    		 Participants with human epidermal growth factor receptor 2 (HER2)-positive breast cancer received PF-05280014 in combination with paclitaxel.

    Reporting group title
    Trastuzumab-EU
    Reporting group description
    		 Participants with HER2-positive breast cancer received trastuzumab-EU in combination with paclitaxel.

    Subject analysis set title
    PF-05280014
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants 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 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 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
    Participants 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 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 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 participants 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 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.
    End point type
    Primary
    End point timeframe
    From the date of randomization until the cutoff date of 24 August 2016 when all participants 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 participants
        number (confidence interval 95%)
    62.5 (57.2 to 67.6)
    66.5 (61.3 to 71.4)
    Statistical analysis title
    		 Analysis of ORR
    Statistical analysis description
    RR and associated 95% CI are unstratified and based on the Miettinen and Nurminen method.
    Comparison groups
    Trastuzumab-EU v PF-05280014
    Number of subjects included in analysis
    707
    Analysis specification
    Pre-specified
    Analysis type
    		 [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 (1)-year PFS rate was analyzed based on the time from date of randomization to first documentation of progressive disease (PD), or death due to any cause in the absence of documented PD, based on the assessments of the central radiology review in accordance with RECIST 1.1. The 95% CI for the median time to event was based on the Brookmeyer and Crowley method. The 95% CI for the hazard ratio was based on the Cox’s proportional hazards model. 9999 = not estimable, there were insufficient events to estimate the upper bound of the 95% CI.
    End point type
    Secondary
    End point timeframe
    From the date of randomization until 378 days post-randomization as of the cutoff date of 24 August 2016.
    End point values
    		 PF-05280014 Trastuzumab-EU
    Number of subjects analysed
    352
    355
    Units: Months
        median (confidence interval 95%)
    12.16 (11.89 to 13.4)
    12.22 (11.83 to 9999)
    Statistical analysis title
    		 Analysis of PFS
    Comparison groups
    PF-05280014 v Trastuzumab-EU
    Number of subjects included in analysis
    707
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.691 [2]
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 1.37
    Notes
    [2] - 1-sided p-value from the log-rank test 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 was defined as the time from date of the first documentation of objective tumor response (CR or PR) to the first documentation of PD, or to death due to any cause in the absence of documented PD, based on the assessments of the central radiology review in accordance with RECIST 1.1. The 95% CI for the median time to event was based on the Brookmeyer and Crowley method. The 95% CI for the hazard ratio was based on the Cox’s proportional hazards model. 9999 = not estimable, there were insufficient events to estimate the value of median and 95% CI for the PF-05280014 group and insufficient events to estimate the upper bound of the 95% CI for the Trastuzumab-EU group.
    End point type
    Secondary
    End point timeframe
    From the date of randomization until 378 days post-randomization as of the cutoff date of 24 August 2016.
    End point values
    		 PF-05280014 Trastuzumab-EU
    Number of subjects analysed
    352
    355
    Units: Months
        median (confidence interval 95%)
    9999 (9999 to 9999)
    10.61 (10.22 to 9999)
    Statistical analysis title
    		 Analysis of DOR
    Comparison groups
    PF-05280014 v Trastuzumab-EU
    Number of subjects included in analysis
    707
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.661 [3]
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 1.56
    Notes
    [3] - 1-sided p-value from the log-rank test stratified by Prior Trastuzumab Exposure (Yes/No) and Estrogen Receptor (ER) Status (ER positive vs. ER negative).

    Secondary: One-year Survival Rate: ITT Population

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    End point title
    		 One-year Survival Rate: ITT Population
    End point description
    One-year survival rate was analyzed based on the time from date of randomization to the date of death due to any cause while the participant was on the study. The 95% CI for the median time to event was based on the Brookmeyer and Crowley method. The 95% CI for the hazard ratio was based on the Cox’s proportional hazards model. 9999 = not estimable, there were insufficient events to estimate the values.
    End point type
    Secondary
    End point timeframe
    From the date of randomization until 378 days post-randomization as of the cutoff date of 24 August 2016.
    End point values
    		 PF-05280014 Trastuzumab-EU
    Number of subjects analysed
    352
    355
    Units: Months
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    Statistical analysis title
    		 Analysis of 1-year Survival Rate
    Comparison groups
    PF-05280014 v Trastuzumab-EU
    Number of subjects included in analysis
    707
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.581 [4]
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.048
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.669
         upper limit
    		 1.642
    Notes
    [4] - 1-sided p-value from the log-rank test stratified by prior trastuzumab exposure (Yes/No) and ER status (ER positive versus ER negative)

    Secondary: Serum Peak (1 Hour Post End of Infusion) Concentration of PF-05280014 at Selected Cycles: Pharmacokinetics (PK) Population

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    End point title
    		 Serum Peak (1 Hour Post End of Infusion) Concentration of PF-05280014 at Selected Cycles: Pharmacokinetics (PK) Population [5]
    End point description
    Human PK serum samples were analyzed for concentrations of PF-05280014 using a validated, sensitive, and specific enzyme-linked immuno-sorbent assay (ELISA).
    End point type
    Secondary
    End point timeframe
    Available peak PK concentration data collected at Cycle 1, Day 1 and Cycle 5, Day 1 as of the data cutoff date of 24 August 2016
    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: Quantification of trastuzumab concentrations was not part of the planned analyses.
    End point values
    		 PF-05280014
    Number of subjects analysed
    349
    Units: µg/mL
    median (full range (min-max))
        Cycle 1 Day 1 (N=267, NALQ=260)
    90.5 (0 to 246)
        Cycle 5 Day 1 (N=205, NALQ=204)
    95.6 (0 to 435)
    No statistical analyses for this end point

    Secondary: Serum Peak (1 Hour Post End of Infusion) Concentration of Trastuzumab-EU at Selected Cycles: PK Population

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    End point title
    		 Serum Peak (1 Hour Post End of Infusion) Concentration of Trastuzumab-EU at Selected Cycles: PK Population [6]
    End point description
    Human PK serum samples were analyzed for concentrations of trastuzumab-EU using a validated, sensitive, and specific ELISA.
    End point type
    Secondary
    End point timeframe
    Available peak PK concentration data collected at Cycle 1, Day 1 and Cycle 5, Day 1 as of the data cutoff date of 24 August 2016
    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: Quantification of trastuzumab concentrations was not part of the planned analyses.
    End point values
    		 Trastuzumab-EU
    Number of subjects analysed
    353
    Units: µg/mL
    median (full range (min-max))
        Cycle 1 Day 1 (N=259, NALQ=255)
    90.8 (0 to 273)
        Cycle 5 Day 1 (N=220, NALQ=220)
    94.35 (8.96 to 353)
    No statistical analyses for this end point

    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 [7]
    End point description
    Human PK serum samples were analyzed for concentrations of PF-05280014 using a validated, sensitive, and specific ELISA.
    End point type
    Secondary
    End point timeframe
    Available trough concentrations collected from Cycle 1, Day 1 to Cycle 17, Day 1 as of the data cutoff date of 24 August 2016, except the EOT visit and unplanned records.
    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: Quantification of trastuzumab concentrations was not part of the planned analyses.
    End point values
    		 PF-05280014
    Number of subjects analysed
    349
    Units: µg/mL
    median (full range (min-max))
        Cycle 1 Day 1 (N=349, NALQ=17)
    0 (0 to 123)
        Cycle 1 Day 8 (N= 339, NALQ=334)
    27.9 (0 to 91.5)
        Cycle 3 Day 1 (N=309, NALQ=307)
    48.2 (0 to 110)
        Cycle 4 Day 1 (N=304, NALQ=303)
    53.5 (0 to 150)
        Cycle 5 Day 1 (N=289, NALQ=288)
    57 (0 to 182)
        Cycle 5 Day 8 (N=277, NALQ=277)
    57.4 (9.85 to 174)
        Cycle 7 Day 1 (N=266, NALQ=264)
    60.8 (0 to 152)
        Cycle 8 Day 1 (N=255, NALQ=254)
    62.2 (0 to 140)
        Cycle 11 Day 1 (N=212, NALQ=209)
    54.4 (0 to 148)
        Cycle 14 Day 1 (N=153, NALQ=152)
    50.9 (0 to 169)
        Cycle 17 Day 1 (N=106, NALQ=105)
    49.15 (0 to 131)
    No statistical analyses for this end point

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

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    End point title
    		 Serum Trough (Pre-dose) Concentration Trastuzumab-EU at Selected Cycles: PK Population [8]
    End point description
    Human PK serum samples were analyzed for concentrations of trastuzumab-EU using a validated, sensitive, and specific ELISA.
    End point type
    Secondary
    End point timeframe
    Available trough concentrations collected from Cycle 1, Day 1 to Cycle 17, Day 1 as of the data cutoff date of 24 August 2016, except the EOT visit and unplanned records.
    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: Quantification of trastuzumab concentrations was not part of the planned analyses.
    End point values
    		 Trastuzumab-EU
    Number of subjects analysed
    353
    Units: µg/mL
    median (full range (min-max))
        Cycle 1 Day 1 (N=348, NALQ=17)
    0 (0 to 98)
        Cycle 1 Day 8 (N=340, NALQ=339)
    29.8 (0 to 101)
        Cycle 3 Day 1 (N=319, NALQ=319)
    50.4 (1.74 to 171)
        Cycle 4 Day 1 (N=316, NALQ=312)
    54.35 (0 to 148)
        Cycle 5 Day 1 (N=303, NALQ=302)
    60 (0 to 244)
        Cycle 5 Day 8 (N=287, NALQ=287)
    61.2 (4.64 to 150)
        Cycle 7 Day 1 (N=275, NALQ=275)
    62.9 (1.93 to 340)
        Cycle 8 Day 1 (N=261, NALQ=261)
    65.6 (0.69 to 155)
        Cycle 11 Day 1 (N=215, NALQ=215)
    58.7 (1.52 to 251)
        Cycle 14 Day 1 (N=142, NALQ=142)
    55.1 (4.68 to 187)
        Cycle 17 Day 1 (N=101, NALQ=101)
    50.6 (15 to 126)
    No statistical analyses for this end point

    Secondary: Anti-Drug Antibodies (ADA) Incidence: Safety Population

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    End point title
    		 Anti-Drug Antibodies (ADA) Incidence: 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 analyze ADA samples. Serum samples were first screened for ADA. Any samples that were positive in the screening assay were further analyzed to confirm the positive result and determine the antibody titers. All samples were taken prior to dosing. The number of participants with a positive sample (titer≥1.0) is provided.
    End point type
    Secondary
    End point timeframe
    Available data from Baseline through Cycle 17, Day 1 as of the data cutoff date of 24 August 2016, except the EOT visit and unplanned records.
    End point values
    		 PF-05280014 Trastuzumab-EU
    Number of subjects analysed
    349
    353
    Units: Not Applicable
        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=253, 263)
    0
    0
        Cycle 11 Day 1 (n=218, 222)
    0
    0
        Cycle 14 Day 1 (n=160, 147)
    0
    0
        Cycle 17 Day 1 (n=107, 105)
    0
    1
        Overall (Post-treatment) (n=323, 331)
    0
    1
    No statistical analyses for this end point

    Secondary: Neutralizing Antibodies (NAb) Incidence at Cycle 1 Day 1 Prior to Treatment: Safety Population

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    End point title
    		 Neutralizing Antibodies (NAb) Incidence at Cycle 1 Day 1 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 analyzed for the presence or absence of NAb (neutralizing anti-PF-05280014 or neutralizing anti-trastuzumab-EU antibodies) following a tiered approach using screening and titer determination. All samples at baseline (prior to treatment) or post-treatment were taken prior to dosing. All participants with the exception of 1 participant in the trastuzumab-EU group tested negative for ADA (titer <1.00) from Cycle 1, Day 1 post-treatment through Cycle 17, Day 1. The corresponding NAb result for this Cycle 17, Day 1 ADA positive sample was not yet available; thus, not reported. The number of participants at Baseline (prior to treatment) with a positive NAb sample (titer≥1.48) is provided.
    End point type
    Secondary
    End point timeframe
    Available data from Baseline to Cycle 17, Day 1 as of the data cutoff date of 24 August 2016, except the EOT visit and unplanned records.
    End point values
    		 PF-05280014 Trastuzumab-EU
    Number of subjects analysed
    348
    350
    Units: Not Applicable
    16
    8
    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) were reported from the time the participant 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.
    Adverse event reporting additional description
    Incidence of treatment emergent AEs/SAEs was comparable across treatment groups, and defined as AEs occurring from first dose of study drug (or any pre-existing event that worsened in severity after dosing) through 70 days after the last dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Trastuzumab-EU
    Reporting group description
    		 Participants 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 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 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
    PF-05280014
    Reporting group description
    		 Participants 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 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 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
    		 Trastuzumab-EU PF-05280014
    Total subjects affected by serious adverse events
         subjects affected / exposed
    54 / 353 (15.30%)
    51 / 349 (14.61%)
         number of deaths (all causes)
    24
    16
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant pleural effusion
         subjects affected / exposed
    0 / 353 (0.00%)
    2 / 349 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian germ cell teratoma benign
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 349 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 349 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Uterine leiomyoma
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 349 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 353 (0.00%)
    2 / 349 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 349 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 349 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 349 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    General disorders and administration site conditions
    Cyst rupture
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 349 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 349 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Disease progression
         subjects affected / exposed
    12 / 353 (3.40%)
    12 / 349 (3.44%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 12
         deaths causally related to treatment / all
    0 / 12
    0 / 12
    Fatigue
         subjects affected / exposed
    1 / 353 (0.28%)
    1 / 349 (0.29%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 353 (0.85%)
    0 / 349 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 349 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 349 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Endometrial hyperplasia
         subjects affected / exposed
    2 / 353 (0.57%)
    0 / 349 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metrorrhagia
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 349 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine prolapse
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 349 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 349 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alveolitis allergic
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 349 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 349 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 349 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 349 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 349 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 353 (0.57%)
    5 / 349 (1.43%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 353 (0.00%)
    2 / 349 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Affective disorder
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 349 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 349 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Ejection fraction decreased
         subjects affected / exposed
    2 / 353 (0.57%)
    0 / 349 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 349 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 349 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    1 / 353 (0.28%)
    1 / 349 (0.29%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 349 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 353 (0.28%)
    1 / 349 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 353 (0.00%)
    2 / 349 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 349 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    3 / 353 (0.85%)
    0 / 349 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 349 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 353 (0.00%)
    2 / 349 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Cardiovascular insufficiency
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 349 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 349 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 349 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Intracranial venous sinus thrombosis
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 349 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    2 / 353 (0.57%)
    0 / 349 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 353 (0.00%)
    2 / 349 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vocal cord paralysis
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 349 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 353 (0.28%)
    3 / 349 (0.86%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 353 (0.28%)
    1 / 349 (0.29%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 353 (0.28%)
    3 / 349 (0.86%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 353 (0.28%)
    1 / 349 (0.29%)
         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
    0 / 353 (0.00%)
    1 / 349 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Macular degeneration
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 349 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 353 (0.28%)
    1 / 349 (0.29%)
         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
    1 / 353 (0.28%)
    0 / 349 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dyspepsia
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 349 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 349 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 349 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 349 (0.29%)
         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
    1 / 353 (0.28%)
    0 / 349 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis contact
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 349 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 353 (0.28%)
    1 / 349 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 349 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 349 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 349 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 349 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    4 / 353 (1.13%)
    1 / 349 (0.29%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 349 (0.29%)
         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
    0 / 353 (0.00%)
    1 / 349 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 349 (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
    1 / 353 (0.28%)
    0 / 349 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mastitis
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 349 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 349 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 349 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 353 (0.85%)
    4 / 349 (1.15%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 349 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 353 (0.57%)
    0 / 349 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 349 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 349 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 353 (0.57%)
    1 / 349 (0.29%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 349 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 349 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 353 (0.00%)
    2 / 349 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypernatraemia
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 349 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 353 (0.00%)
    4 / 349 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 349 (0.00%)
         occurrences causally related to treatment / all
    1 / 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
    		 Trastuzumab-EU PF-05280014
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    331 / 353 (93.77%)
    327 / 349 (93.70%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    41 / 353 (11.61%)
    29 / 349 (8.31%)
         occurrences all number
    100
    38
    Aspartate aminotransferase increased
         subjects affected / exposed
    26 / 353 (7.37%)
    25 / 349 (7.16%)
         occurrences all number
    69
    25
    Blood alkaline phosphatase increased
         subjects affected / exposed
    24 / 353 (6.80%)
    16 / 349 (4.58%)
         occurrences all number
    36
    20
    Ejection fraction decreased
         subjects affected / exposed
    34 / 353 (9.63%)
    30 / 349 (8.60%)
         occurrences all number
    44
    39
    Weight increased
         subjects affected / exposed
    20 / 353 (5.67%)
    15 / 349 (4.30%)
         occurrences all number
    27
    20
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    29 / 353 (8.22%)
    33 / 349 (9.46%)
         occurrences all number
    44
    53
    Vascular disorders
    Hypertension
         subjects affected / exposed
    26 / 353 (7.37%)
    34 / 349 (9.74%)
         occurrences all number
    53
    58
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    15 / 353 (4.25%)
    30 / 349 (8.60%)
         occurrences all number
    21
    42
    Headache
         subjects affected / exposed
    51 / 353 (14.45%)
    40 / 349 (11.46%)
         occurrences all number
    60
    52
    Neuropathy peripheral
         subjects affected / exposed
    33 / 353 (9.35%)
    29 / 349 (8.31%)
         occurrences all number
    48
    42
    Peripheral sensory neuropathy
         subjects affected / exposed
    83 / 353 (23.51%)
    93 / 349 (26.65%)
         occurrences all number
    139
    168
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    129 / 353 (36.54%)
    117 / 349 (33.52%)
         occurrences all number
    406
    299
    Leukopenia
         subjects affected / exposed
    40 / 353 (11.33%)
    33 / 349 (9.46%)
         occurrences all number
    103
    109
    Neutropenia
         subjects affected / exposed
    90 / 353 (25.50%)
    95 / 349 (27.22%)
         occurrences all number
    251
    282
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    43 / 353 (12.18%)
    50 / 349 (14.33%)
         occurrences all number
    53
    57
    Fatigue
         subjects affected / exposed
    49 / 353 (13.88%)
    42 / 349 (12.03%)
         occurrences all number
    80
    71
    Oedema peripheral
         subjects affected / exposed
    41 / 353 (11.61%)
    23 / 349 (6.59%)
         occurrences all number
    59
    29
    Pyrexia
         subjects affected / exposed
    26 / 353 (7.37%)
    39 / 349 (11.17%)
         occurrences all number
    49
    55
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    28 / 353 (7.93%)
    11 / 349 (3.15%)
         occurrences all number
    38
    17
    Constipation
         subjects affected / exposed
    26 / 353 (7.37%)
    20 / 349 (5.73%)
         occurrences all number
    43
    21
    Diarrhoea
         subjects affected / exposed
    65 / 353 (18.41%)
    56 / 349 (16.05%)
         occurrences all number
    116
    96
    Nausea
         subjects affected / exposed
    63 / 353 (17.85%)
    54 / 349 (15.47%)
         occurrences all number
    134
    160
    Stomatitis
         subjects affected / exposed
    12 / 353 (3.40%)
    23 / 349 (6.59%)
         occurrences all number
    20
    28
    Vomiting
         subjects affected / exposed
    24 / 353 (6.80%)
    26 / 349 (7.45%)
         occurrences all number
    33
    38
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    29 / 353 (8.22%)
    29 / 349 (8.31%)
         occurrences all number
    39
    41
    Dyspnoea
         subjects affected / exposed
    18 / 353 (5.10%)
    19 / 349 (5.44%)
         occurrences all number
    20
    29
    Epistaxis
         subjects affected / exposed
    22 / 353 (6.23%)
    15 / 349 (4.30%)
         occurrences all number
    29
    21
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    184 / 353 (52.12%)
    189 / 349 (54.15%)
         occurrences all number
    249
    243
    Pruritus
         subjects affected / exposed
    18 / 353 (5.10%)
    11 / 349 (3.15%)
         occurrences all number
    20
    14
    Rash
         subjects affected / exposed
    24 / 353 (6.80%)
    24 / 349 (6.88%)
         occurrences all number
    30
    34
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    35 / 353 (9.92%)
    39 / 349 (11.17%)
         occurrences all number
    56
    70
    Back pain
         subjects affected / exposed
    29 / 353 (8.22%)
    13 / 349 (3.72%)
         occurrences all number
    36
    17
    Bone pain
         subjects affected / exposed
    12 / 353 (3.40%)
    19 / 349 (5.44%)
         occurrences all number
    18
    25
    Myalgia
         subjects affected / exposed
    33 / 353 (9.35%)
    21 / 349 (6.02%)
         occurrences all number
    75
    33
    Pain in extremity
         subjects affected / exposed
    19 / 353 (5.38%)
    19 / 349 (5.44%)
         occurrences all number
    34
    26
    Infections and infestations
    Respiratory tract infection viral
         subjects affected / exposed
    11 / 353 (3.12%)
    20 / 349 (5.73%)
         occurrences all number
    13
    27
    Upper respiratory tract infection
         subjects affected / exposed
    40 / 353 (11.33%)
    30 / 349 (8.60%)
         occurrences all number
    68
    41
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    15 / 353 (4.25%)
    21 / 349 (6.02%)
         occurrences all number
    17
    25

    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 patients had been screened or randomized at the time of the amendment.
    10 Jul 2014
    This amendment was implemented due to feedback from a retrospective review by Parexel Informatics of randomized patients 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 patient treatment after the completion of Week 53 visit assessments, following communication with regulatory agencies.

    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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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