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    Clinical Trial Results:
    A Randomized, Double Blind, Placebo-Controlled, Multicenter, Phase III Study Comparing the Activity of Paclitaxel Plus Trastuzumab Plus Lapatinib to Paclitaxel Plus Trastuzumab Plus Placebo in Women with ErbB2 Overexpressing Metastatic Breast Cancer. Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.nov for complete trial results. (249 characters)

    Summary
    EudraCT number
    		 2005-003432-22
    Trial protocol
    		 BE  
    Global end of trial date
    21 Oct 2019

    Results information
    Results version number
    		 v2(current)
    This version publication date
    28 Jan 2022
    First version publication date
    06 Nov 2020
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    CLAP016A2301/EGF104383 (GSK)
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00272987
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma, AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma, AG, +41 613241111, novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma, AG, +41 613241111, novartis.email@novartis.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
    21 Oct 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Oct 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Primary objective for open label phase: To determine the safety and tolerability of lapatinib when administered in combination with both paclitaxel and trastuzumab
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Dec 2005
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 61
    Country: Number of subjects enrolled
    Belgium: 2
    Worldwide total number of subjects
    63
    EEA total number of subjects
    2
    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)
    52
    From 65 to 84 years
    11
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Female participants (par.) with histologically confirmed invasive breast cancer (Stage IV disease) whose tumors overexpressed the ErbB2 protein, documented by either Immunohistochemistry (IHC) or fluorescence in situ hybridisation (FISH), were eligible for inclusion in this study.

    Pre-assignment
    Screening details
    		 Participants who met inclusion criteria were sequentially enrolled into three cohorts and received the open-label triple combination of paclitaxel, trastuzumab and lapatinib. The planned randomized phase of the study was terminated following the poor recruitment rate in the Open-label Phase.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg
    Arm description
    		 Participants received an intravenous (IV) infusion of paclitaxel 80 milligrams per meter squared (mg/m^2) over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg per kilogram (mg/kg) loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    4 mg/kg IV loading dose and 2 mg/kg IV weekly

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    80mg/m2 IV weekly for 3 weeks of a 4 week cycle

    Investigational medicinal product name
    Lapatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1000 mg PO daily

    Arm title
    		 Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg
    Arm description
    		 Participants received an IV infusion of paclitaxel 70 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The paclitaxel dose was systematically increased to 80 mg/m^2 after 2 cycles if 70 mg/m^2 was tolerated.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    70mg/m2 IV weekly for 3 weeks of a 4 week cycle; Paclitaxel dose was to be systematically increased to 80 mg/m2 after 2 cycles if 70 mg/m2 was tolerated.

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    4 mg/kg IV loading dose and 2 mg/kg IV weekly

    Investigational medicinal product name
    Lapatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1000 mg PO daily

    Arm title
    		 Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
    Arm description
    		 Participants received an IV infusion of paclitaxel 80 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 3 tablets of lapatinib (750 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The lapatinib dose was systematically increased to 1000 mg after 2 cycles if the 750 mg dose was tolerated.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    80mg/m2 IV weekly for 3 weeks of a 4 week cycle

    Investigational medicinal product name
    Lapatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    750 mg PO daily; Lapatinib dose was to be systematically increased to 1000 mg after 2 cycles if 750 mg was tolerated.

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    4 mg/kg IV loading dose and 2 mg/kg IV weekly

    Number of subjects in period 1
    		Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
    Started
    29
    14
    20
    Completed
    20
    10
    9
    Not completed
    9
    4
    11
         Adverse event, serious fatal
    1
    -
    -
         Consent withdrawn by subject
    1
    -
    3
         Disease progression
    1
    1
    2
         Adverse event, non-fatal
    1
    -
    -
         Sponsor Terminated study
    -
    1
    1
         Lost to follow-up
    3
    1
    1
         Lack of efficacy
    2
    1
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg
    Reporting group description
    		 Participants received an intravenous (IV) infusion of paclitaxel 80 milligrams per meter squared (mg/m^2) over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg per kilogram (mg/kg) loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal.

    Reporting group title
    Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg
    Reporting group description
    		 Participants received an IV infusion of paclitaxel 70 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The paclitaxel dose was systematically increased to 80 mg/m^2 after 2 cycles if 70 mg/m^2 was tolerated.

    Reporting group title
    Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
    Reporting group description
    		 Participants received an IV infusion of paclitaxel 80 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 3 tablets of lapatinib (750 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The lapatinib dose was systematically increased to 1000 mg after 2 cycles if the 750 mg dose was tolerated.

    Reporting group values
    		 Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg Total
    Number of subjects
    		 29 14 20 63
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 25 11 16 52
        From 65-84 years
    		 4 3 4 11
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 51.5 ( 11.08 ) 56.1 ( 11.92 ) 52.2 ( 13.00 ) -
    Gender categorical
    Units: Subjects
        Female
    		 29 14 20 63
        Male
    		 0 0 0 0
    GenderNIH
    Units: Subjects
        Female
    		 29 14 20 63
        Male
    		 0 0 0 0
    Race/Ethnicity, Customized
    Units: Subjects
        African American/African Heritage
    		 7 2 4 13
        Native Hawaiian or Other Pacific Islander
    		 0 1 0 1
        White - White/Caucasian/European Heritage
    		 22 11 16 49
    AgeContinuous
    Units: Years
        arithmetic mean (standard deviation)
    		 51.5 ( 11.08 ) 56.1 ( 11.92 ) 52.2 ( 13.00 ) -

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg
    Reporting group description
    		 Participants received an intravenous (IV) infusion of paclitaxel 80 milligrams per meter squared (mg/m^2) over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg per kilogram (mg/kg) loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal.

    Reporting group title
    Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg
    Reporting group description
    		 Participants received an IV infusion of paclitaxel 70 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The paclitaxel dose was systematically increased to 80 mg/m^2 after 2 cycles if 70 mg/m^2 was tolerated.

    Reporting group title
    Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
    Reporting group description
    		 Participants received an IV infusion of paclitaxel 80 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 3 tablets of lapatinib (750 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The lapatinib dose was systematically increased to 1000 mg after 2 cycles if the 750 mg dose was tolerated.

    Primary: Extent of exposure to lapatinib, trastuzumab and paclitaxel by Mean/Standard Deviation

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    End point title
    		 Extent of exposure to lapatinib, trastuzumab and paclitaxel by Mean/Standard Deviation [1]
    End point description
    Extent of exposure is defined as the duration of the treatment administered during the study. The mean duration of exposure to lapatinib, trastuzumab and paclitaxel is calculated as the number of weeks between the start and end of treatment.
    End point type
    Primary
    End point timeframe
    From the date of the first dose of the investigational product to end of study, up to approx. 14 years
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: no statistical analysis was planned for this endpoint
    End point values
    		 Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
    Number of subjects analysed
    29
    14
    20
    Units: Weeks
    arithmetic mean (standard deviation)
        Lapatinib
    70.9 ( 115.44 )
    93.1 ( 147.92 )
    82.5 ( 135.79 )
        Trastuzumab
    60.7 ( 72.07 )
    72.2 ( 88.66 )
    62.3 ( 75.52 )
        Paclitaxel
    26.9 ( 16.88 )
    29.4 ( 23.00 )
    23.8 ( 14.87 )
    No statistical analyses for this end point

    Primary: Extent of exposure to lapatinib, trastuzumab and paclitaxel by Median/Min-Max

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    End point title
    		 Extent of exposure to lapatinib, trastuzumab and paclitaxel by Median/Min-Max [2]
    End point description
    Extent of exposure is defined as the duration of the treatment administered during the study. The mean duration of exposure to lapatinib, trastuzumab and paclitaxel is calculated as the number of weeks between the start and end of treatment.
    End point type
    Primary
    End point timeframe
    From the date of the first dose of the investigational product to end of study, up to approx. 14 years
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: no statistical analysis was planned for this endpoint
    End point values
    		 Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
    Number of subjects analysed
    29
    14
    20
    Units: Weeks
    median (full range (min-max))
        Lapatinib
    33.0 (3 to 615)
    38.5 (2 to 547)
    32.5 (1 to 574)
        Trastuzumab
    33.0 (2 to 343)
    37.0 (2 to 271)
    31.5 (1 to 245)
        Paclitaxel
    22.0 (2 to 86)
    23.5 (2 to 94)
    22.0 (1 to 63)
    No statistical analyses for this end point

    Primary: Number of participants with any adverse event (AE) or serious adverse event (SAE)

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    End point title
    		 Number of participants with any adverse event (AE) or serious adverse event (SAE) [3]
    End point description
    An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect. Medical or scientific judgment was exercised in deciding whether reporting was appropriate in other situations. Refer to the general AE/SAE module for a list of non-serious AEs and SAEs.
    End point type
    Primary
    End point timeframe
    From the date of the first dose of investigational product until 30 days after the last dose of investigational product, up to approx. 14 years
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: no statistical analysis was planned for this endpoint
    End point values
    		 Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
    Number of subjects analysed
    29
    14
    20
    Units: Participants
        Any AEs
    29
    14
    20
        Any SAEs
    14
    6
    5
    No statistical analyses for this end point

    Primary: Number of participants who died due to any cause

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    End point title
    		 Number of participants who died due to any cause [4]
    End point description
    Number of participants who died due to any cause throughout the study.
    End point type
    Primary
    End point timeframe
    From the date of the first dose of investigational product until 30 days after the last dose of investigational product, up to approx. 14 years
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: no statistical analysis was planned for this endpoint
    End point values
    		 Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
    Number of subjects analysed
    29
    14
    20
    Units: Participants
    12
    2
    1
    No statistical analyses for this end point

    Primary: Number of events of diarrhea with the indicated characteristics

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    End point title
    		 Number of events of diarrhea with the indicated characteristics [5]
    End point description
    Events of diarrhea are characterized as serious, related to investigational product, leading to withdrawal from the study and fatal. Participants could have been counted in more than one category.
    End point type
    Primary
    End point timeframe
    From the date of the first dose of investigational product until 30 days after the last dose of investigational product, up to approx. 3.5 years
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: no statistical analysis was planned for this endpoint
    End point values
    		 Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
    Number of subjects analysed
    28
    13
    13
    Units: Events of diarrhea
        Any Event
    358
    90
    37
        Serious
    4
    0
    0
        Related to investigational product
    347
    75
    26
        Leading to withdrawal from study
    2
    1
    1
        Fatal
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of events of rash with the indicated characteristics

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    End point title
    		 Number of events of rash with the indicated characteristics [6]
    End point description
    Events of rash are characterized as serious, related to investigational product, leading to withdrawal from the study and fatal. Participants could have been counted in more than one category.
    End point type
    Primary
    End point timeframe
    From the date of the first dose of investigational product until 30 days after the last dose of investigational product, up to approx. 3.5 years
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: no statistical analysis was planned for this endpoint
    End point values
    		 Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
    Number of subjects analysed
    24
    8
    15
    Units: Events of rash
        Any Event
    69
    23
    20
        Serious
    2
    0
    0
        Related to investigational product
    55
    12
    7
        Leading to withdrawal from study
    3
    0
    0
        Fatal
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of participants with the maximum toxicity grade for the indicated clinical hematology parameters

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    End point title
    		 Number of participants with the maximum toxicity grade for the indicated clinical hematology parameters [7]
    End point description
    Blood samples for clinical laboratory evaluation were taken at Baseline prior to the administration of investigational product and thereafter at each scheduled visit. Haematology parameters included haemoglobin, total white blood cell count (WBC), neutrophils, lymphocytes and platelets. Hematology data was summarized by the National Cancer Institute's Common toxicity criteria for adverse events (NCI CTCAE) toxicity grade (Version 3.0). Grade 1, mild; Grade 2, moderate; Grade 3, severe; Grade 4, life-threatening or disabling; Grade 5, death.
    End point type
    Primary
    End point timeframe
    Baseline and every 4 weeks thereafter up to withdrawal/study completion and 30 day follow-up, up to approx. 3.5 years
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: no statistical analysis was planned for this endpoint
    End point values
    		 Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
    Number of subjects analysed
    29
    14
    20
    Units: Participants
        Haemaglobin, Grade 1
    19
    11
    11
        Haemaglobin, Grade 2
    7
    1
    6
        Haemaglobin, Grade 3
    2
    0
    1
        Haemaglobin, Grade 4
    1
    0
    0
        Platelets, Grade 1
    3
    0
    0
        Platelets, Grade 2
    1
    0
    0
        Platelets, Grade 3
    0
    0
    0
        Platelets, Grade 4
    1
    0
    0
        Total WBC, Grade 1
    10
    6
    7
        Total WBC, Grade 2
    8
    4
    2
        Total WBC, Grade 3
    3
    1
    4
        Total WBC, Grade 4
    1
    0
    0
        Neutrophils, Grade 1
    7
    2
    5
        Neutrophils, Grade 2
    7
    4
    4
        Neutrophils, Grade 3
    3
    1
    5
        Neutrophils, Grade 4
    3
    0
    0
        Lymphocytes, Grade 1
    5
    3
    7
        Lymphocytes, Grade 2
    10
    4
    4
        Lymphocytes, Grade 3
    5
    3
    1
        Lymphocytes, Grade 4
    1
    0
    1
    No statistical analyses for this end point

    Primary: Number of participants with the maximum toxicity grade for the indicated clinical chemistry parameters

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    End point title
    		 Number of participants with the maximum toxicity grade for the indicated clinical chemistry parameters [8]
    End point description
    Blood samples for clinical laboratory evaluation were taken at Baseline prior to the administration of investigational product and thereafter at each scheduled visit. Clinical chemistry parameters included values > upper limit of normal (ULN)=Hyper; values < lower limit of normal (LLN)=Hypo of sodium (Hypernatraemia and Hyponatraemia), potassium (Hyperkalaemia and Hypokalaemia), calcium (Hypercalcaemia and Hypocalcaemia), glucose (Hyperglycaemia and Hyperglycaemia), creatinine (if >2 milligram per deciliter [mg/dL]), aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phophatase, total bilirubin (if available bilirubin fractionation is recommended if the total bilirubin is > twice of ULN), and albumin. Clinical chemistry data was summarized by National Cancer Institute's Common toxicity criteria for adverse events (NCI CTCAE) toxicity grade (Version 3.0). Grade 1, mild; Grade 2, moderate; Grade 3, severe; Grade 4, life-threatening or disabling; Grade 5, death.
    End point type
    Primary
    End point timeframe
    Baseline and every 4 weeks thereafter up to withdrawal/study completion and 30 day follow-up, up to approx. 3.5 years
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: no statistical analysis was planned for this endpoint
    End point values
    		 Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
    Number of subjects analysed
    29
    14
    20
    Units: Participants
        Hypernatraemia, Grade 1
    0
    1
    1
        Hypernatraemia, Grade 2
    1
    0
    0
        Hypernatraemia, Grade 3
    0
    0
    0
        Hypernatraemia, Grade 4
    0
    0
    0
        Hyponatraemia, Grade 1
    8
    1
    1
        Hyponatraemia, Grade 2
    0
    0
    0
        Hyponatraemia, Grade 3
    0
    1
    0
        Hyponatraemia, Grade 4
    0
    0
    0
        Hyperkalaemia, Grade 1
    2
    0
    0
        Hyperkalaemia, Grade 2
    2
    1
    1
        Hyperkalaemia, Grade 3
    0
    0
    0
        Hyperkalaemia, Grade 4
    1
    0
    1
        Hypokalaemia, Grade 1
    11
    6
    6
        Hypokalaemia, Grade 2
    0
    0
    0
        Hypokalaemia, Grade 3
    6
    2
    0
        Hypokalaemia, Grade 4
    0
    0
    0
        Hypercalcaemia, Grade 1, n=29, 14, 19
    1
    0
    0
        Hypercalcaemia, Grade 2, n=29, 14, 19
    0
    0
    0
        Hypercalcaemia, Grade 3, n=29, 14, 19
    0
    0
    0
        Hypercalcaemia, Grade 4, n=29, 14, 19
    0
    0
    0
        Hypocalcaemia, Grade 1, n=29, 14, 19
    10
    3
    4
        Hypocalcaemia, Grade 2, n=29, 14, 19
    7
    2
    3
        Hypocalcaemia, Grade 3, n=29, 14, 19
    3
    0
    1
        Hypocalcaemia, Grade 4, n=29, 14, 19
    0
    0
    0
        Hyperglycaemia, Grade 1, n=29, 14, 19
    15
    9
    6
        Hyperglycaemia, Grade 2, n=29, 14, 19
    3
    3
    2
        Hyperglycaemia, Grade 3, n=29, 14, 19
    5
    0
    2
        Hyperglycaemia, Grade 4, n=29, 14, 19
    0
    0
    0
        Hypoglycemia, Grade 1, n=29, 14, 19
    5
    2
    2
        Hypoglycemia, Grade 2, n=29, 14, 19
    0
    1
    1
        Hypoglycemia, Grade 3, n=29, 14, 19
    0
    0
    0
        Hypoglycemia, Grade 4, n=29, 14, 19
    0
    0
    0
        Albumin, Grade 1, n=29, 14, 18
    5
    3
    1
        Albumin, Grade 2, n=29, 14, 18
    3
    0
    0
        Albumin, Grade 3, n=29, 14, 18
    1
    0
    0
        Albumin, Grade 4, n=29, 14, 18
    0
    0
    0
        Total Bilirubin, Grade 1
    2
    1
    3
        Total Bilirubin, Grade 2
    2
    2
    1
        Total Bilirubin, Grade 3
    1
    1
    0
        Total Bilirubin, Grade 4
    0
    0
    0
        Creatinine, Grade 1
    2
    0
    0
        Creatinine, Grade 2
    2
    0
    0
        Creatinine, Grade 3
    1
    0
    0
        Creatinine, Grade 4
    0
    0
    0
        Alkaline Phophatase, Grade 1
    14
    3
    5
        Alkaline Phophatase, Grade 2
    2
    0
    0
        Alkaline Phophatase, Grade 3
    2
    0
    0
        Alkaline Phophatase, Grade 4
    0
    0
    0
        ALT, Grade 1
    7
    1
    3
        ALT, Grade 2
    3
    3
    2
        ALT, Grade 3
    0
    0
    0
        ALT, Grade 4
    0
    0
    0
        AST, Grade 1
    6
    3
    6
        AST, Grade 2
    1
    1
    0
        AST, Grade 3
    1
    1
    0
        AST, Grade 4
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of events of hepatotoxicity with the indicated characteristics

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    End point title
    		 Number of events of hepatotoxicity with the indicated characteristics [9]
    End point description
    Events of hepatotoxicity are characterized as serious, related to investigational product, leading to withdrawal from the study and fatal. Participants could have been counted in more than one category.
    End point type
    Primary
    End point timeframe
    From the date of the first dose of investigational product until 30 days after the last dose of investigational product, up to approx. 3.5 years
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: no statistical analysis was planned for this endpoint
    End point values
    		 Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
    Number of subjects analysed
    6
    0 [10]
    2
    Units: Events of hepatotoxicity
        Any Event
    6
    2
        Serious
    0
    0
        Related to investigational product
    5
    0
        Leading to withdrawal from study
    0
    0
        Fatal
    0
    0
    Notes
    [10] - no patients analyzed in this arm had a hepatotoxisity event
    No statistical analyses for this end point

    Primary: Change from Baseline in systolic blood pressure and diastolic blood pressure at the indicated time points

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    End point title
    		 Change from Baseline in systolic blood pressure and diastolic blood pressure at the indicated time points [11]
    End point description
    Blood pressure measurement included systolic blood pressure (SBP) and diastolic blood pressure (DBP) at Baseline and every 4 weeks thereafter up to withdrawal/study completion and at the 30 day follow-up visit. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
    End point type
    Primary
    End point timeframe
    Baseline and every 4 weeks thereafter up to withdrawal/study completion and 30 day follow-up, up to approx. 3.5 years
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: no statistical analysis was planned for this endpoint
    End point values
    		 Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
    Number of subjects analysed
    29
    14
    20
    Units: Millimeter of mercury (mmHg)
    arithmetic mean (standard deviation)
        SBP, Week 4, n=28, 12, 18
    0.5 ( 16.29 )
    -7.2 ( 20.70 )
    -3.9 ( 22.76 )
        SBP, Week 8, n=27, 13, 17
    4.6 ( 12.35 )
    -8.6 ( 22.25 )
    -2.7 ( 24.73 )
        SBP, Week 12, n=24, 12, 16
    3.2 ( 18.46 )
    -6.9 ( 17.09 )
    -9.3 ( 23.54 )
        SBP, Week 16, n= 23, 11, 15
    0.8 ( 18.10 )
    -6.6 ( 15.26 )
    -7.9 ( 24.43 )
        SBP, Week 20, n=23, 8, 12
    1.7 ( 17.80 )
    -11.5 ( 14.69 )
    -13.8 ( 25.15 )
        SBP, Week 24, n=21, 10, 6
    2.9 ( 13.87 )
    -1.8 ( 11.81 )
    -7.8 ( 26.06 )
        SBP, Week 28, n=17, 7, 5
    2.3 ( 19.10 )
    -5.7 ( 20.38 )
    -5.2 ( 10.71 )
        SBP, Week 32, n=16, 8, 3
    3.2 ( 23.11 )
    -16.4 ( 10.03 )
    -6.3 ( 5.51 )
        SBP, Week 36, n=13, 7, 3
    1.6 ( 15.85 )
    -8.7 ( 12.19 )
    -26.7 ( 37.75 )
        SBP, Week 40, n=12, 7, 2
    -2.2 ( 24.44 )
    -3.4 ( 9.62 )
    -34.0 ( 38.18 )
        SBP, Week 44, n=11, 6, 2
    2.7 ( 14.47 )
    -3.8 ( 9.83 )
    -38.0 ( 32.53 )
        SBP, Week 48, n=11, 6, 1
    6.5 ( 18.76 )
    -6.7 ( 11.18 )
    -84.0 ( 999 )
        SBP, Week 52, n=9, 5, 0
    7.7 ( 14.47 )
    -3.8 ( 24.78 )
    999 ( 999 )
        SBP, Week 56, n=9, 5, 0
    8.4 ( 13.53 )
    -8.2 ( 18.74 )
    999 ( 999 )
        SBP, Week 60, n=10, 4, 0
    9.3 ( 22.07 )
    -17.0 ( 9.31 )
    999 ( 999 )
        SBP, Week 64, n=10, 4, 0
    3.5 ( 16.53 )
    -11.3 ( 11.24 )
    999 ( 999 )
        SBP, Week 68, n=7, 2, 0
    0.1 ( 10.71 )
    -6.5 ( 12.02 )
    999 ( 999 )
        SBP, Week 72, n=7, 1, 0
    7.1 ( 13.25 )
    -20.0 ( 999 )
    999 ( 999 )
        SBP, Week 76, n=6, 0, 0
    4.5 ( 12.96 )
    999 ( 999 )
    999 ( 999 )
        SBP, Week 80, n=6, 0, 0
    8.7 ( 6.92 )
    999 ( 999 )
    999 ( 999 )
        SBP, Week 84, n=6, 0, 0
    7.0 ( 20.20 )
    999 ( 999 )
    999 ( 999 )
        SBP, Week 88, n=6, 0, 0
    -2.7 ( 16.32 )
    999 ( 999 )
    999 ( 999 )
        SBP, Week 92, n=5, 0, 0
    10.4 ( 16.59 )
    999 ( 999 )
    999 ( 999 )
        SBP, Week 96, n=4, 0, 0
    -0.5 ( 4.12 )
    999 ( 999 )
    999 ( 999 )
        SBP, Week 100, n=5, 0, 0
    10.8 ( 7.53 )
    999 ( 999 )
    999 ( 999 )
        SBP, Week 104, n=5, 0, 0
    7.0 ( 16.00 )
    999 ( 999 )
    999 ( 999 )
        SBP, Week 108, n=5, 0, 0
    4.6 ( 7.89 )
    999 ( 999 )
    999 ( 999 )
        SBP, Week 112, n=4, 0, 0
    12.3 ( 10.72 )
    999 ( 999 )
    999 ( 999 )
        SBP, Week 116, n=4, 0, 0
    9.3 ( 15.22 )
    999 ( 999 )
    999 ( 999 )
        SBP, Week 120, n=3, 0, 0
    13.3 ( 19.86 )
    999 ( 999 )
    999 ( 999 )
        SBP, Week 124, n=3, 0, 0
    7.3 ( 8.50 )
    999 ( 999 )
    999 ( 999 )
        SBP, Week 128, n=2, 0, 0
    -11.0 ( 9.90 )
    999 ( 999 )
    999 ( 999 )
        SBP, Week 132, n=2, 0, 0
    -10.5 ( 10.61 )
    999 ( 999 )
    999 ( 999 )
        SBP, Week 136, n=2, 0, 0
    -4.0 ( 18.38 )
    999 ( 999 )
    999 ( 999 )
        SBP, Week 140, n=2, 0, 0
    4.5 ( 23.33 )
    999 ( 999 )
    999 ( 999 )
        SBP, Week 144, n=1, 0, 0
    10.0 ( 0 )
    999 ( 999 )
    999 ( 999 )
        SBP, Week 148, n=1, 0, 0
    25.0 ( 999 )
    999 ( 999 )
    999 ( 999 )
        SBP, Withdrawal/Study Conclusion, n=23, 10, 8
    0.5 ( 16.13 )
    -1.3 ( 15.64 )
    7.0 ( 20.28 )
        SBP, 30 Day Follow-up, n=25, 9, 5
    2.4 ( 19.18 )
    -3.9 ( 17.03 )
    13.8 ( 19.25 )
        DBP, Week 4, n=28, 12, 18
    -2.5 ( 10.36 )
    -3.9 ( 10.50 )
    -4.8 ( 11.10 )
        DBP, Week 8, n=27, 13, 17
    -0.6 ( 11.41 )
    -8.9 ( 11.54 )
    -1.2 ( 12.46 )
        DBP, Week 12, n=24, 12, 16
    -0.3 ( 10.19 )
    -6.2 ( 10.37 )
    -4.2 ( 12.87 )
        DBP, Week 16, n= 23, 11, 15
    -3.4 ( 12.98 )
    -3.2 ( 8.42 )
    -4.4 ( 15.18 )
        DBP, Week 20, n=23, 8, 12
    -3.0 ( 12.65 )
    -1.6 ( 9.53 )
    -9.1 ( 13.65 )
        DBP, Week 24, n=21, 10, 6
    -1.2 ( 11.30 )
    -1.8 ( 6.56 )
    -5.2 ( 13.08 )
        DBP, Week 28, n=17, 7, 5
    -1.8 ( 14.27 )
    -2.1 ( 8.15 )
    -2.0 ( 5.05 )
        DBP, Week 32, n=16, 8, 3
    -2.2 ( 13.70 )
    -6.3 ( 10.24 )
    -4.7 ( 6.51 )
        DBP, Week 36, n=13, 7, 3
    -7.2 ( 6.48 )
    -3.3 ( 6.40 )
    -10.7 ( 11.02 )
        DBP, Week 40, n=12, 7, 2
    -9.3 ( 11.36 )
    -0.7 ( 13.76 )
    -8.0 ( 19.80 )
        DBP, Week 44, n=11, 6, 2
    -9.0 ( 6.59 )
    -2.3 ( 10.33 )
    -19.5 ( 6.36 )
        DBP, Week 48, n=11, 6, 1
    -3.9 ( 7.57 )
    -0.2 ( 8.13 )
    -34.0 ( 999 )
        DBP, Week 52, n=9, 5, 0
    -7.4 ( 13.46 )
    -3.0 ( 12.33 )
    999 ( 999 )
        DBP, Week 56, n=9, 5, 0
    9 ( 8.62 )
    9 ( 7.99 )
    999 ( 999 )
        DBP, Week 60, n=10, 4, 0
    -3.6 ( 11.56 )
    -6.3 ( 6.24 )
    999 ( 999 )
        DBP, Week 64, n=10, 4, 0
    -7.7 ( 12.27 )
    -5.3 ( 8.54 )
    999 ( 999 )
        DBP, Week 68, n=7, 2, 0
    -11.0 ( 6.40 )
    -3.5 ( 7.78 )
    999 ( 999 )
        DBP, Week 72, n=7, 1, 0
    3.0 ( 9.26 )
    -16.0 ( 999 )
    999 ( 999 )
        DBP, Week 76, n=6, 0, 0
    -4.8 ( 5.00 )
    999 ( 999 )
    999 ( 999 )
        DBP, Week 80, n=6, 0, 0
    -3.5 ( 5.58 )
    999 ( 999 )
    999 ( 999 )
        DBP, Week 84, n=6, 0, 0
    -5.8 ( 9.50 )
    999 ( 999 )
    999 ( 999 )
        DBP, Week 88, n=6, 0, 0
    -9.3 ( 11.48 )
    999 ( 999 )
    999 ( 999 )
        DBP, Week 92, n=5, 0, 0
    -3.8 ( 5.26 )
    999 ( 999 )
    999 ( 999 )
        DBP, Week 96, n=4, 0, 0
    -7.3 ( 6.29 )
    999 ( 999 )
    999 ( 999 )
        DBP, Week 100, n=5, 0, 0
    -4.4 ( 6.50 )
    999 ( 999 )
    999 ( 999 )
        DBP, Week 104, n=5, 0, 0
    -4.6 ( 9.10 )
    999 ( 999 )
    999 ( 999 )
        DBP, Week 108, n=5, 0, 0
    -2.0 ( 5.89 )
    999 ( 999 )
    999 ( 999 )
        DBP, Week 116, n=4, 0, 0
    -8.5 ( 9.33 )
    999 ( 999 )
    999 ( 999 )
        DBP, Week 120, n=3, 0, 0
    -6.0 ( 7.94 )
    999 ( 999 )
    999 ( 999 )
        DBP, Week 124, n=3, 0, 0
    -6.0 ( 6.00 )
    999 ( 999 )
    999 ( 999 )
        DBP, Week 128, n=2, 0, 0
    -12.5 ( 0.71 )
    999 ( 999 )
    999 ( 999 )
        DBP, Week 132, n=2, 0, 0
    -14.5 ( 4.95 )
    999 ( 999 )
    999 ( 999 )
        DBP, Week 136, n=2, 0, 0
    -17.0 ( 4.24 )
    999 ( 999 )
    999 ( 999 )
        DBP, Week 140, n=2, 0, 0
    -7.5 ( 10.61 )
    999 ( 999 )
    999 ( 999 )
        DBP, Week 144, n=1, 0, 0
    0.0 ( 0 )
    999 ( 999 )
    999 ( 999 )
        DBP, Week 148, n=1, 0, 0
    1.0 ( 999 )
    999 ( 999 )
    999 ( 999 )
        DBP, Withdrawal/Study Conclusion, n=23, 10, 8
    -0.5 ( 11.39 )
    -0.4 ( 12.08 )
    2.1 ( 8.64 )
        DBP, 30 Day Follow-up, n=25, 9, 5
    -0.8 ( 11.96 )
    0.8 ( 11.62 )
    3.2 ( 9.98 )
    No statistical analyses for this end point

    Primary: Change from Baseline in heart rate at the indicated time points

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    End point title
    		 Change from Baseline in heart rate at the indicated time points [12]
    End point description
    Heart rate was measured at Baseline and every 4 weeks thereafter up to withdrawal/study completion and at the 30 day follow-up visit. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
    End point type
    Primary
    End point timeframe
    Baseline and every 4 weeks thereafter up to withdrawal/study completion and 30 day follow-up, up to approx. 3.5 years
    Notes
    [12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: no statistical analysis was planned for this endpoint
    End point values
    		 Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
    Number of subjects analysed
    29
    14
    20
    Units: Beats per minute (BPM)
    arithmetic mean (standard deviation)
        Week 4, n=28, 12, 18
    -1.714 ( 10.9099 )
    -3.417 ( 26.3593 )
    3.333 ( 12.1268 )
        Week 8, n=27, 13, 17
    -5.667 ( 14.7908 )
    -3.231 ( 16.8481 )
    5.353 ( 10.7642 )
        Week 12, n=23, 12, 16
    -0.217 ( 10.7109 )
    -0.417 ( 15.6812 )
    -2.875 ( 10.6074 )
        Week 16, n= 22, 11, 14
    -0.478 ( 13.4667 )
    2.625 ( 15.1369 )
    -1.917 ( 10.9084 )
        Week 24, n=21, 10, 6
    -0.476 ( 16.7768 )
    -5.300 ( 15.1808 )
    5.167 ( 10.2843 )
        Week 28, n=16, 7, 5
    -4.313 ( 16.0155 )
    -1.429 ( 17.7281 )
    3.600 ( 8.5615 )
        Week 32, n=15, 8, 3
    -4.933 ( 16.6496 )
    -0.500 ( 11.1098 )
    0.333 ( 10.5987 )
        Week 36, n=13, 7, 3
    -5.000 ( 13.0128 )
    4.857 ( 18.4791 )
    7.000 ( 11.5326 )
        Week 40, n=12, 7, 2
    -1.000 ( 14.1614 )
    -3.571 ( 17.6149 )
    -2.500 ( 9.1924 )
        Week 44, n=11, 6, 2
    -3.000 ( 11.1624 )
    -5.000 ( 17.9778 )
    -0.500 ( 10.6066 )
        Week 48, n=10, 6, 1
    -5.500 ( 8.1955 )
    -2.500 ( 12.9422 )
    -14.000 ( 999 )
        Week 52, n=9, 5, 0
    -1.889 ( 14.4866 )
    -2.000 ( 11.8533 )
    999 ( 999 )
        Week 56, n=8, 5, 0
    -2.000 ( 13.4907 )
    -2.000 ( 15.2151 )
    999 ( 999 )
        Week 60, n=10, 4, 0
    -2.600 ( 13.3766 )
    1.500 ( 15.0222 )
    999 ( 999 )
        Week 64, n=9, 4, 0
    -4.667 ( 16.1245 )
    0.000 ( 15.3840 )
    999 ( 999 )
        Week 68, n=7, 2, 0
    -8.286 ( 21.1638 )
    1.000 ( 25.4558 )
    999 ( 999 )
        Week 72, n=7, 1, 0
    -0.714 ( 21.0295 )
    19.000 ( 999 )
    999 ( 999 )
        Week 76, n=6, 0, 0
    -0.500 ( 16.6463 )
    999 ( 999 )
    999 ( 999 )
        Week 80, n=5, 0, 0
    0.800 ( 14.4810 )
    999 ( 999 )
    999 ( 999 )
        Week 84, n=5, 0, 0
    9.200 ( 21.1234 )
    999 ( 999 )
    999 ( 999 )
        Week 88, n=5, 0, 0
    2.200 ( 24.6110 )
    999 ( 999 )
    999 ( 999 )
        Week 92, n=5, 0, 0
    -2.400 ( 10.1390 )
    999 ( 999 )
    999 ( 999 )
        Week 96, n=4, 0, 0
    -8.250 ( 7.6322 )
    999 ( 999 )
    999 ( 999 )
        Week 100, n=4, 0, 0
    -6.750 ( 13.1751 )
    999 ( 999 )
    999 ( 999 )
        Week 104, n=5, 0, 0
    -6.800 ( 15.3525 )
    999 ( 999 )
    999 ( 999 )
        Week 108, n=4, 0, 0
    -8.750 ( 6.4485 )
    999 ( 999 )
    999 ( 999 )
        Week 112, n=3, 0, 0
    -0.667 ( 15.0444 )
    999 ( 999 )
    999 ( 999 )
        Week 116, n=3, 0, 0
    -4.667 ( 14.5717 )
    999 ( 999 )
    999 ( 999 )
        Week 120, n=3, 0, 0
    -7.667 ( 9.4516 )
    999 ( 999 )
    999 ( 999 )
        Week 124, n=3, 0, 0
    -5.333 ( 13.2035 )
    999 ( 999 )
    999 ( 999 )
        Week 128, n=2, 0, 0
    1.000 ( 21.2132 )
    999 ( 999 )
    999 ( 999 )
        Week 132, n=2, 0, 0
    -4.000 ( 14.1421 )
    999 ( 999 )
    999 ( 999 )
        Week 136, n=2, 0, 0
    -4.000 ( 15.5563 )
    999 ( 999 )
    999 ( 999 )
        Week 140, n=2, 0, 0
    -3.500 ( 16.2635 )
    999 ( 999 )
    999 ( 999 )
        Week 144, n=1, 0, 0
    3.000 ( 999 )
    999 ( 999 )
    999 ( 999 )
        Week 148, n=1, 0, 0
    6.000 ( 999 )
    999 ( 999 )
    999 ( 999 )
        Withdrawal/Study Conclusion, n=23, 10, 8
    -1.435 ( 19.3481 )
    -7.900 ( 19.3990 )
    7.750 ( 9.8814 )
        30 Day Follow-up, n=25, 9, 5
    0.560 ( 13.1564 )
    -7.889 ( 17.3526 )
    13.200 ( 11.6060 )
    No statistical analyses for this end point

    Primary: Change from Baseline in body temperature at the indicated time points

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    End point title
    		 Change from Baseline in body temperature at the indicated time points [13]
    End point description
    Body temperature was measured at Baseline and every 4 weeks thereafter up to withdrawal/study completion and at the 30 day follow-up visit. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
    End point type
    Primary
    End point timeframe
    Baseline and every 4 weeks thereafter up to withdrawal/study completion and 30 day follow-up, up to approx. 3.5 years
    Notes
    [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: no statistical analysis was planned for this endpoint
    End point values
    		 Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
    Number of subjects analysed
    29
    14
    20
    Units: Degree Celsius
    arithmetic mean (standard deviation)
        Week 4, n=28, 12, 18
    -0.229 ( 0.5062 )
    -0.242 ( 0.3605 )
    0.078 ( 0.5976 )
        Week 8, n=27, 13, 17
    0.011 ( 0.5250 )
    -0.154 ( 0.4294 )
    0.247 ( 0.4652 )
        Week 12, n=24, 12, 15
    0.021 ( 0.4374 )
    -0.567 ( 0.4960 )
    0.173 ( 0.4636 )
        Week 16, n= 23, 11, 14
    -0.052 ( 0.5814 )
    -0.127 ( 0.4880 )
    0.121 ( 0.5494 )
        Week 20, n=22, 8, 12
    0.018 ( 0.5712 )
    -0.238 ( 0.4138 )
    0.300 ( 0.3536 )
        Week 24, n=21, 9, 6
    0.157 ( 0.5006 )
    -0.100 ( 0.4138 )
    0.017 ( 0.5193 )
        Week 28, n=17, 7, 5
    -0.094 ( 0.4956 )
    -0.529 ( 0.4751 )
    0.300 ( 0.3536 )
        Week 32, n=16, 8, 3
    -0.156 ( 0.6077 )
    -0.237 ( 0.2134 )
    0.000 ( 0.2000 )
        Week 36, n=13, 7, 3
    -0.215 ( 0.5728 )
    -0.129 ( 0.3946 )
    0.533 ( 0.3786 )
        Week 40, n=11, 7, 2
    0.045 ( 0.4634 )
    -0.314 ( 0.1952 )
    0.450 ( 0.9192 )
        Week 44, n=11, 6, 2
    -0.182 ( 0.4729 )
    -0.217 ( 0.3920 )
    0.250 ( 0.0707 )
        Week 48, n=11, 6, 1
    -0.109 ( 0.4571 )
    -0.200 ( 0.1414 )
    0.300 ( 999 )
        Week 52, n=9, 5, 0
    -0.222 ( 1.0616 )
    -0.340 ( 0.3286 )
    0 ( 0 )
        Week 56, n=9, 5, 0
    0.111 ( 0.6489 )
    -0.240 ( 0.6427 )
    999 ( 999 )
        Week 60, n=10, 4, 0
    -0.070 ( 0.5889 )
    -0.225 ( 0.2754 )
    999 ( 999 )
        Week 64, n=10, 4, 0
    -0.080 ( 0.4662 )
    -0.150 ( 0.1732 )
    999 ( 999 )
        Week 68, n=7, 2, 0
    0.286 ( 0.6744 )
    -0.550 ( 0.0707 )
    999 ( 999 )
        Week 72, n=7, 1, 0
    0.057 ( 0.7390 )
    -0.400 ( 999 )
    999 ( 999 )
        Week 76, n=6, 0, 0
    0.017 ( 0.4834 )
    999 ( 999 )
    999 ( 999 )
        Week 80, n=6, 0, 0
    -0.150 ( 0.6442 )
    999 ( 999 )
    999 ( 999 )
        Week 84, n=6, 0, 0
    0.067 ( 0.5610 )
    999 ( 999 )
    999 ( 999 )
        Week 88, n=6, 0, 0
    -0.267 ( 0.4131 )
    999 ( 999 )
    999 ( 999 )
        Week 92, n=5, 0, 0
    -0.200 ( 0.8155 )
    999 ( 999 )
    999 ( 999 )
        Week 96, n=4, 0, 0
    -0.125 ( 0.4573 )
    999 ( 999 )
    999 ( 999 )
        Week 100, n=5, 0, 0
    -0.100 ( 0.9083 )
    999 ( 999 )
    999 ( 999 )
        Week 104, n=5, 0, 0
    -0.160 ( 0.7436 )
    999 ( 999 )
    999 ( 999 )
        Week 108, n=4, 0, 0
    0.080 ( 0.6099 )
    999 ( 999 )
    999 ( 999 )
        Week 112, n=4, 0, 0
    0.050 ( 0.5000 )
    999 ( 999 )
    999 ( 999 )
        Week 116, n=3, 0, 0
    0.250 ( 0.6403 )
    999 ( 999 )
    999 ( 999 )
        Week 120, n=3, 0, 0
    0.200 ( 0.4359 )
    999 ( 999 )
    999 ( 999 )
        Week 124, n=3, 0, 0
    0.167 ( 0.8083 )
    999 ( 999 )
    999 ( 999 )
        Week 128, n=2, 0, 0
    0.200 ( 1.4142 )
    999 ( 999 )
    999 ( 999 )
        Week 132, n=2, 0, 0
    -0.150 ( 1.2021 )
    999 ( 999 )
    999 ( 999 )
        Week 136, n=2, 0, 0
    0.000 ( 1.2728 )
    999 ( 999 )
    999 ( 999 )
        Week 140, n=2, 0, 0
    0.450 ( 1.3435 )
    999 ( 999 )
    999 ( 999 )
        Week 144, n=1, 0, 0
    1.300 ( 999 )
    999 ( 999 )
    999 ( 999 )
        Week 148, n=1, 0, 0
    0.700 ( 999 )
    999 ( 999 )
    999 ( 999 )
        Withdrawal/Study Conclusion, n=23, 10, 8
    -0.083 ( 0.6833 )
    -0.020 ( 0.4367 )
    0.237 ( 0.5999 )
        30 Day Follow-up, n=25, 9, 5
    -0.092 ( 0.6238 )
    -0.400 ( 0.5074 )
    0.140 ( 0.5320 )
    No statistical analyses for this end point

    Primary: Number of participants with at least 1 event of left ventricular ejection fraction decrease with the indicated characteristics

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    End point title
    		 Number of participants with at least 1 event of left ventricular ejection fraction decrease with the indicated characteristics [14]
    End point description
    Events of left ventricular ejection fraction (LVEF) decrease were characterized as serious, related to investigational product, leading to withdrawal from the study and fatal. A participant could have been counted in more than one category.
    End point type
    Primary
    End point timeframe
    Baseline and every 8 weeks thereafter up to withdrawal/study completion and 30 day follow-up, up to approx. 3.5 years
    Notes
    [14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: no statistical analysis was planned for this endpoint
    End point values
    		 Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
    Number of subjects analysed
    29
    14
    20 [15]
    Units: Participants
    8
    2
    0
    Notes
    [15] - no patients analyzed in this arm had an LVEF decrease event
    No statistical analyses for this end point

    Primary: Number of participants with the indicated eastern cooperative oncology group (ECOG) performance status value

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    End point title
    		 Number of participants with the indicated eastern cooperative oncology group (ECOG) performance status value [16]
    End point description
    The Eastern Cooperative Oncology Group (ECOG) performance status scales and grades/criteria are used to assess how a participant's disease is progressing, to assess how the disease affects the daily living abilities of the participant, and to determine appropriate treatment and prognosis. Grade 0, fully active, able to carry on all pre-disease performance without restriction. Grade 1, restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. Grade 2, ambulatory and capable of all selfcare, but unable to carry out any work activities; up and about more than 50% of waking hours. Grade 3, capable of only limited selfcare; confined to bed or chair more than 50% of waking hours. Grade 4, completely disabled; cannot carry on any selfcare; totally confined to bed or chair. Grade 5, dead.
    End point type
    Primary
    End point timeframe
    Baseline and every 4 weeks thereafter up to withdrawal/study completion and 30 day follow-up, up to approx. 3.5 years
    Notes
    [16] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: no statistical analysis was planned for this endpoint
    End point values
    		 Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
    Number of subjects analysed
    29
    14
    20
    Units: Participants
        Screening, Grade 3
    0
    0
    0
        Screening, Grade 4
    0
    0
    0
        Screening, Grade 5
    0
    0
    0
        Day 1 pre-dose, Grade 3, n=29, 13, 20
    0
    0
    0
        Day 1 pre-dose, Grade 4, n=29, 13, 20
    0
    0
    0
        Day 1 pre-dose, Grade 5, n=29, 13, 20
    0
    0
    0
        Week 4, Grade 3, n=28, 12, 18
    0
    0
    0
        Week 4, Grade 4, n=28, 12, 18
    0
    0
    0
        Week 4, Grade 5, n=28, 12, 18
    0
    0
    0
        Week 8, Grade 3, n=27, 13, 16
    0
    0
    0
        Week 8, Grade 4, n=27, 13, 16
    0
    0
    0
        Week 8, Grade 5, n=27, 13, 16
    0
    0
    0
        Week 12, Grade 3, n=24, 12, 16
    0
    0
    0
        Week 12, Grade 4, n=24, 12, 16
    0
    0
    0
        Week 12, Grade 5, n=24, 12, 16
    0
    0
    0
        Week 16, Grade 3, n=22, 11, 15
    0
    0
    0
        Week 16, Grade 4, n=22, 11, 15
    0
    0
    0
        Week 16, Grade 5, n=22, 11, 15
    0
    0
    0
        Week 20, Grade 3, n=24, 10, 11
    0
    0
    0
        Week 20, Grade 4, n=24, 10, 11
    0
    0
    0
        Week 20, Grade 5, n=24, 10, 11
    0
    0
    0
        Week 24, Grade 3, n=21, 10, 6
    0
    0
    0
        Week 24, Grade 4, n=21, 10, 6
    0
    0
    0
        Week 24, Grade 5, n=21, 10, 6
    0
    0
    0
        Week 28, Grade 3, n=17, 8, 4
    0
    0
    0
        Week 28, Grade 4, n=17, 8, 4
    0
    0
    0
        Week 28, Grade 5, n=17, 8, 4
    0
    0
    0
        Week 32, Grade 3, n=16, 8, 3
    0
    0
    0
        Week 32, Grade 4, n=16, 8, 3
    0
    0
    0
        Week 32, Grade 5, n=16, 8, 3
    0
    0
    0
        Week 36, Grade 3, n=12, 7, 3
    0
    0
    0
        Week 36, Grade 4, n=12, 7, 3
    0
    0
    0
        Week 36, Grade 5, n=12, 7, 3
    0
    0
    0
        Week 40, Grade 3, n=12, 7, 2
    0
    0
    0
        Week 40, Grade 4, n=12, 7, 2
    0
    0
    0
        Week 40, Grade 5, n=12, 7, 2
    0
    0
    0
        Week 44, Grade 3, n=11, 6, 2
    0
    0
    0
        Week 44, Grade 4, n=11, 6, 2
    0
    0
    0
        Week 44, Grade 5, n=11, 6, 2
    0
    0
    0
        Week 48, Grade 3, n=10, 6, 1
    0
    0
    0
        Week 48, Grade 4, n=10, 6, 1
    0
    0
    0
        Week 48, Grade 5, n=10, 6, 1
    0
    0
    0
        Week 52, Grade3 , n=9, 5, 0
    0
    0
    0
        Week 52, Grade4 , n=9, 5, 0
    0
    0
    0
        Week 52, Grade5 , n=9, 5, 0
    0
    0
    0
        Week 56, Grade 3, n=8, 4, 0
    0
    0
    0
        Week 56, Grade 4, n=8, 4, 0
    0
    0
    0
        Week 56, Grade 5, n=8, 4, 0
    0
    0
    0
        Week 60, Grade 3, n=10, 4, 0
    0
    0
    0
        Week 60, Grade 4, n=10, 4, 0
    0
    0
    0
        Week 60, Grade 5, n=10, 4, 0
    0
    0
    0
        Week 64, Grade 3, n=9, 4, 0
    0
    0
    0
        Week 64, Grade 4, n=9, 4, 0
    0
    0
    0
        Week 64, Grade 5, n=9, 4, 0
    0
    0
    0
        Week 68, Grade3 , n=8, 2, 0
    0
    0
    0
        Week 68, Grade4 , n=8, 2, 0
    0
    0
    0
        Week 68, Grade5 , n=8, 2, 0
    0
    0
    0
        Week 72, Grade 3, n=7, 1, 0
    0
    0
    0
        Week 72, Grade 4, n=7, 1, 0
    0
    0
    0
        Week 72, Grade 5, n=7, 1, 0
    0
    0
    0
        Week 76, Grade3 , n=6, 0, 0
    0
    0
    0
        Week 76, Grade4 , n=6, 0, 0
    0
    0
    0
        Week 76, Grade5 , n=6, 0, 0
    0
    0
    0
        Week 80, Grade 3, n=6, 0, 0
    0
    0
    0
        Week 80, Grade 4, n=6, 0, 0
    0
    0
    0
        Week 80, Grade 5, n=6, 0, 0
    0
    0
    0
        Week 84, Grade 3, n=6, 0, 0
    0
    0
    0
        Week 84, Grade 4, n=6, 0, 0
    0
    0
    0
        Week 84, Grade 5, n=6, 0, 0
    0
    0
    0
        Week 88, Grade 3, n=6, 0, 0
    0
    0
    0
        Week 88, Grade 4, n=6, 0, 0
    0
    0
    0
        Week 88, Grade 5, n=6, 0, 0
    0
    0
    0
        Week 92, Grade 3, n=5, 0, 0
    0
    0
    0
        Week 92, Grade 4, n=5, 0, 0
    0
    0
    0
        Week 92, Grade 5, n=5, 0, 0
    0
    0
    0
        Week 96, Grade 3, n=4, 0, 0
    0
    0
    0
        Week 96, Grade 4, n=4, 0, 0
    0
    0
    0
        Week 96, Grade 5, n=4, 0, 0
    0
    0
    0
        Week 100, Grade 3, n=5, 0, 0
    0
    0
    0
        Week 100, Grade 4, n=5, 0, 0
    0
    0
    0
        Week 100, Grade 5, n=5, 0, 0
    0
    0
    0
        Week 104, Grade 3, n=5, 0, 0
    0
    0
    0
        Week 104, Grade 4, n=5, 0, 0
    0
    0
    0
        Week 104, Grade 5, n=5, 0, 0
    0
    0
    0
        Week 108, Grade 3, n=5, 0, 0
    0
    0
    0
        Week 108, Grade 4, n=5, 0, 0
    0
    0
    0
        Week 108, Grade 5, n=5, 0, 0
    0
    0
    0
        Week 112, Grade 3, n=4, 0, 0
    0
    0
    0
        Week 112, Grade 4, n=4, 0, 0
    0
    0
    0
        Week 112, Grade 5, n=4, 0, 0
    0
    0
    0
        Week 116, Grade 3, n=4, 0, 0
    0
    0
    0
        Week 116, Grade 4, n=4, 0, 0
    0
    0
    0
        Week 116, Grade 5, n=4, 0, 0
    0
    0
    0
        Week 120, Grade 3, n=3, 0, 0
    0
    0
    0
        Week 120, Grade 4, n=3, 0, 0
    0
    0
    0
        Week 120, Grade 5, n=3, 0, 0
    0
    0
    0
        Week 124, Grade 3, n=3, 0, 0
    0
    0
    0
        Week 124, Grade 4, n=3, 0, 0
    0
    0
    0
        Week 124, Grade 5, n=3, 0, 0
    0
    0
    0
        Week 128, Grade 3, n=2, 0, 0
    0
    0
    0
        Week 128, Grade 4, n=2, 0, 0
    0
    0
    0
        Week 128, Grade 5, n=2, 0, 0
    0
    0
    0
        Week 132, Grade 3, n=2, 0, 0
    0
    0
    0
        Week 132, Grade 4, n=2, 0, 0
    0
    0
    0
        Week 132, Grade 5, n=2, 0, 0
    0
    0
    0
        Week 136, Grade 3, n=2, 0, 0
    0
    0
    0
        Week 136, Grade 4, n=2, 0, 0
    0
    0
    0
        Week 136, Grade 5, n=2, 0, 0
    0
    0
    0
        Week 140, Grade 3, n=2, 0, 0
    2
    0
    0
        Week 140, Grade 4, n=2, 0, 0
    0
    0
    0
        Week 140, Grade 5, n=2, 0, 0
    0
    0
    0
        Week 144, Grade 3, n=1, 0, 0
    0
    0
    0
        Week 144, Grade 4, n=1, 0, 0
    0
    0
    0
        Week 144, Grade 5, n=1, 0, 0
    0
    0
    0
        Week 148, Grade 3, n=1, 0, 0
    0
    0
    0
        Week 148, Grade 4, n=1, 0, 0
    0
    0
    0
        Week 148, Grade 5, n=1, 0, 0
    0
    0
    0
        Withdrawal/Study conclusion, Grade 3, n=22, 10, 7
    0
    0
    0
        Withdrawal/Study conclusion, Grade 4, n=22, 10, 7
    0
    0
    0
        Withdrawal/Study conclusion, Grade 5, n=22, 10, 7
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of participants who received any concomitant medications during the study period

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    End point title
    		 Number of participants who received any concomitant medications during the study period [17]
    End point description
    Number of participants who received any concomitant medication along with study drugs (lapatinib, trastuzumab and paclitaxel) were counted during the treatment period.
    End point type
    Primary
    End point timeframe
    withdrawal/study completion, up to approx. 3.5 years
    Notes
    [17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: no statistical analysis was planned for this endpoint
    End point values
    		 Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
    Number of subjects analysed
    29
    14
    20
    Units: Participants
    29
    14
    20
    No statistical analyses for this end point

    Primary: Overall Response (OR): Percentage of participants with a best overall response (OR) of confirmed complete response (CR) or confirmed partial response (PR) as assessed by the investigator

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    End point title
    		 Overall Response (OR): Percentage of participants with a best overall response (OR) of confirmed complete response (CR) or confirmed partial response (PR) as assessed by the investigator [18]
    End point description
    OR is defined as the number of participants achieving either a CR or PR, per Response Evaluation Criteria in Solid Tumors (RECIST). The best OR is defined as the best response recorded from the start of treatment until progressive disease (PD)/recurrence. CR is defined as the disappearance of all target lesions (TLs) and non-TLs. PR is defined as at least a 30% decrease in the sum of the longest diameters (LD) of TLs, taking as a reference the Baseline sum LD and no PD, or complete resolution of TLs and the persistence of one or more non-TL(s), as assessed by the IRC. PD is defined as at least a 20% increase in the sum of the LD of TLs, taking as a reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions or unequivocal progression of existing non-TLs. Responses were confirmed at subsequent assessments made >=28 days after the original response. Participants with an unknown or missing response are treated as non-responders.
    End point type
    Primary
    End point timeframe
    From the date of the first dose of investigational product to end of study, up to approx. 7 years
    Notes
    [18] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: no statistical analysis was planned for this endpoint
    End point values
    		 Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
    Number of subjects analysed
    29
    14
    20
    Units: Percentage of participants
        number (confidence interval 95%)
    79.3 (64.6 to 94.1)
    71.4 (47.8 to 95.1)
    70.0 (49.9 to 90.1)
    No statistical analyses for this end point

    Secondary: Time to response as assessed by the investigator

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    End point title
    		 Time to response as assessed by the investigator
    End point description
    Time to response is defined as the time from randomization until the first documented evidence of a PR or CR (whichever status is recorded first). Analysis was based on responses confirmed at a repeat assessment made at least 4 weeks after the initial response, with the time to response taken as the first time the response was observed, not the confirmation assessment. Participants who withdraw with no tumor response were censored at the date of withdrawal from the study. CR is defined as the disappearance of all TLs and non-TLs. PR is defined as at least a 30% decrease in the sum of the LD of TLs, taking as a reference the Baseline sum LD and no PD, or complete resolution of TLs and the persistence of one or more non-TL(s). PD is defined as at least a 20% increase in the sum of the LD of TLs, taking as a reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions or unequivocal progression of existing non-TLs.
    End point type
    Secondary
    End point timeframe
    From the date of the first dose of investigational product until the first documented evidence of a PR or CR, up to approx. 7 years
    End point values
    		 Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
    Number of subjects analysed
    23
    10
    14
    Units: Participants
        Week 8
    15
    8
    8
        Week 12
    5
    1
    1
        Week 16
    2
    1
    3
        Week 20
    0
    0
    1
        Week 24
    1
    0
    0
        Week 28
    0
    0
    1
    No statistical analyses for this end point

    Secondary: Duration of response (DoR), as assessed by the investigator

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    End point title
    		 Duration of response (DoR), as assessed by the investigator
    End point description
    DoR is defined for the subset of participants who had a confirmed CR (disappearance of all TLs and non-TLs) or PR (>=30% decrease in the sum of the LD of TLs, taking as a reference the Baseline sum LD and no PD, or complete resolution of TLs and the persistence of one or more non-TL[s]) as the time from the first documented evidence of a CR or PR until the first documentation of radiological PD or death due to breast cancer, if sooner. PD is defined as >=20% increase in the sum of the LD of TLs, taking as a reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions or unequivocal progression of existing non-TLs. For participants who did not progress or die, DoR was censored on the date of the last radiological scan. If a participant had only a Baseline visit or did not have a date of a radiological scan that was later than the date of initiation of anti-cancer therapy, DoR was censored at the start date of treatment.
    End point type
    Secondary
    End point timeframe
    From the first documented evidence of a PR or CR until the earlier of the date of disease progression or the date of death due to breast cancer, up to approx. 7 years
    End point values
    		 Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
    Number of subjects analysed
    29
    14
    20
    Units: Weeks
        median (inter-quartile range (Q1-Q3))
    56.6 (27.6 to 117.7)
    59.0 (33.1 to 88.7)
    70.6 (31.4 to 103.1)
    No statistical analyses for this end point

    Secondary: Percentage of participants with clinical benefit (complete response (CR), partial response (PR), and stable disease [SD] for at least 24 weeks) as assessed by investigator

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    End point title
    		 Percentage of participants with clinical benefit (complete response (CR), partial response (PR), and stable disease [SD] for at least 24 weeks) as assessed by investigator
    End point description
    Clinical benefit is defined as the percentage of participants achieving either a CR or PR or SD (neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (at least a 20% increase in the sum of the LD of target lesions, taking as a reference, the smallest sum LD recorded since the treatment started or the appearance of 1 or more new lesions), taking as reference, the smallest sum LD since the treatment started) for at least 24 weeks. This was based on confirmed responses from the investigator assessment of clinical benefit.
    End point type
    Secondary
    End point timeframe
    From the date of the first dose of investigational product until the first documented evidence of a PR or CR or SD until the earlier of the date of disease progression or the date of death due to breast cancer, up to approx. 7 years
    End point values
    		 Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
    Number of subjects analysed
    29
    14
    20
    Units: Percentage of Participants
        number (confidence interval 95%)
    79.3 (64.6 to 94.1)
    71.4 (47.8 to 95.1)
    70.0 (49.9 to 90.1)
    No statistical analyses for this end point

    Secondary: Progression-free survival as assessed by the investigator

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    End point title
    		 Progression-free survival as assessed by the investigator
    End point description
    Progression-free survival is defined as the time from randomization until the earliest date of disease progression or death due to any cause, if sooner. Disease progression was based on the investigator's assessments of the objective evidence (e.g., radiological scans and medical photographs). For participants who do not progress, or die, progression-free survival was censored at the time of the last investigator assessed radiological scan preceding the initiation of any alternative anti-cancer therapy. Progression-free survival was summarized using Kaplan-Meier curves.
    End point type
    Secondary
    End point timeframe
    From the date of the first dose of investigational product until the earlier of the date of disease progression or death due to any cause, up to approx. 7 years
    End point values
    		 Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
    Number of subjects analysed
    29
    14
    20
    Units: Weeks
        median (confidence interval 95%)
    64.7 (33.1 to 117)
    55.0 (20.4 to 96.1)
    78.4 (31.9 to 111)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Timeframe for AE
    Adverse event reporting additional description
    AE additional description
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    1000 mg Lapatinib / 80 mg/m2 Paclitaxel/ 2 mg Trastuzumab
    Reporting group description
    		 1000 mg Lapatinib / 80 mg/m2 Paclitaxel/ 2 mg Trastuzumab

    Reporting group title
    750 mg Lapatinib / 80 mg/m2 Paclitaxel 2 mg Trastuzumab
    Reporting group description
    		 750 mg Lapatinib / 80 mg/m2 Paclitaxel 2 mg Trastuzumab

    Reporting group title
    1000 mg Lapatinib/ 70 mg/m2 Paclitaxel / 2 mg Trastuzumab
    Reporting group description
    		 1000 mg Lapatinib/ 70 mg/m2 Paclitaxel / 2 mg Trastuzumab

    Serious adverse events
    		 1000 mg Lapatinib / 80 mg/m2 Paclitaxel/ 2 mg Trastuzumab 750 mg Lapatinib / 80 mg/m2 Paclitaxel 2 mg Trastuzumab 1000 mg Lapatinib/ 70 mg/m2 Paclitaxel / 2 mg Trastuzumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    14 / 29 (48.28%)
    5 / 20 (25.00%)
    6 / 14 (42.86%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvic pain
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Ejection fraction decreased
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Compression fracture
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Left ventricular dysfunction
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Guillain-Barre syndrome
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 20 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 20 (5.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 20 (5.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    2 / 14 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis streptococcal
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infectious colitis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    5 / 29 (17.24%)
    1 / 20 (5.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    4 / 5
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 20 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 1000 mg Lapatinib / 80 mg/m2 Paclitaxel/ 2 mg Trastuzumab 750 mg Lapatinib / 80 mg/m2 Paclitaxel 2 mg Trastuzumab 1000 mg Lapatinib/ 70 mg/m2 Paclitaxel / 2 mg Trastuzumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    29 / 29 (100.00%)
    20 / 20 (100.00%)
    13 / 14 (92.86%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to bone
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    2
    0
    1
    Vascular disorders
    Flushing
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 20 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    0
    Hot flush
         subjects affected / exposed
    5 / 29 (17.24%)
    3 / 20 (15.00%)
    2 / 14 (14.29%)
         occurrences all number
    5
    4
    4
    Hypotension
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 20 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    0
    Lymphoedema
         subjects affected / exposed
    4 / 29 (13.79%)
    1 / 20 (5.00%)
    1 / 14 (7.14%)
         occurrences all number
    4
    1
    1
    Surgical and medical procedures
    Prophylaxis
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Mastectomy
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 20 (10.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    2
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 20 (5.00%)
    1 / 14 (7.14%)
         occurrences all number
    2
    1
    1
    Chest pain
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    3
    0
    1
    Chills
         subjects affected / exposed
    4 / 29 (13.79%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    7
    0
    1
    Fatigue
         subjects affected / exposed
    21 / 29 (72.41%)
    13 / 20 (65.00%)
    12 / 14 (85.71%)
         occurrences all number
    102
    14
    23
    Mucosal inflammation
         subjects affected / exposed
    8 / 29 (27.59%)
    2 / 20 (10.00%)
    6 / 14 (42.86%)
         occurrences all number
    9
    3
    9
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 20 (10.00%)
    4 / 14 (28.57%)
         occurrences all number
    0
    2
    6
    Oedema peripheral
         subjects affected / exposed
    5 / 29 (17.24%)
    0 / 20 (0.00%)
    4 / 14 (28.57%)
         occurrences all number
    13
    0
    5
    Peripheral swelling
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    1
    0
    1
    Pain
         subjects affected / exposed
    4 / 29 (13.79%)
    4 / 20 (20.00%)
    3 / 14 (21.43%)
         occurrences all number
    4
    4
    5
    Pyrexia
         subjects affected / exposed
    6 / 29 (20.69%)
    5 / 20 (25.00%)
    5 / 14 (35.71%)
         occurrences all number
    13
    5
    7
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 20 (10.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    2
    0
    Hypersensitivity
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 20 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    4
    0
    3
    Seasonal allergy
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    1
    0
    1
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    2
    0
    5
    Vaginal discharge
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 20 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    5 / 29 (17.24%)
    4 / 20 (20.00%)
    6 / 14 (42.86%)
         occurrences all number
    7
    4
    11
    Cough
         subjects affected / exposed
    12 / 29 (41.38%)
    4 / 20 (20.00%)
    3 / 14 (21.43%)
         occurrences all number
    27
    5
    8
    Lower respiratory tract congestion
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Dyspnoea exertional
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 20 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    0
    Epistaxis
         subjects affected / exposed
    10 / 29 (34.48%)
    1 / 20 (5.00%)
    2 / 14 (14.29%)
         occurrences all number
    13
    1
    2
    Oropharyngeal pain
         subjects affected / exposed
    9 / 29 (31.03%)
    5 / 20 (25.00%)
    2 / 14 (14.29%)
         occurrences all number
    11
    9
    2
    Nasal congestion
         subjects affected / exposed
    6 / 29 (20.69%)
    1 / 20 (5.00%)
    3 / 14 (21.43%)
         occurrences all number
    8
    1
    6
    Pleuritic pain
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Productive cough
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 20 (5.00%)
    2 / 14 (14.29%)
         occurrences all number
    1
    2
    3
    Sinus congestion
         subjects affected / exposed
    3 / 29 (10.34%)
    1 / 20 (5.00%)
    1 / 14 (7.14%)
         occurrences all number
    5
    1
    1
    Upper respiratory tract congestion
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Upper-airway cough syndrome
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    4
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 20 (10.00%)
    3 / 14 (21.43%)
         occurrences all number
    2
    2
    4
    Depression
         subjects affected / exposed
    3 / 29 (10.34%)
    1 / 20 (5.00%)
    3 / 14 (21.43%)
         occurrences all number
    3
    1
    4
    Confusional state
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 20 (5.00%)
    1 / 14 (7.14%)
         occurrences all number
    1
    1
    1
    Insomnia
         subjects affected / exposed
    6 / 29 (20.69%)
    3 / 20 (15.00%)
    7 / 14 (50.00%)
         occurrences all number
    7
    3
    9
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    7
    0
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 20 (5.00%)
    1 / 14 (7.14%)
         occurrences all number
    3
    1
    4
    Blood alkaline phosphatase increased
         subjects affected / exposed
    4 / 29 (13.79%)
    1 / 20 (5.00%)
    0 / 14 (0.00%)
         occurrences all number
    6
    1
    0
    Blood creatinine increased
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 20 (5.00%)
    1 / 14 (7.14%)
         occurrences all number
    7
    1
    1
    Blood potassium decreased
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 20 (5.00%)
    0 / 14 (0.00%)
         occurrences all number
    2
    1
    0
    Ejection fraction decreased
         subjects affected / exposed
    6 / 29 (20.69%)
    1 / 20 (5.00%)
    1 / 14 (7.14%)
         occurrences all number
    6
    1
    2
    Blood pressure decreased
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Haemoglobin decreased
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 20 (10.00%)
    0 / 14 (0.00%)
         occurrences all number
    6
    2
    0
    Neutrophil count decreased
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 20 (5.00%)
    1 / 14 (7.14%)
         occurrences all number
    3
    2
    2
    Lymphocyte count decreased
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 20 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    0
    Weight decreased
         subjects affected / exposed
    7 / 29 (24.14%)
    0 / 20 (0.00%)
    3 / 14 (21.43%)
         occurrences all number
    8
    0
    8
    White blood cell count decreased
         subjects affected / exposed
    3 / 29 (10.34%)
    3 / 20 (15.00%)
    1 / 14 (7.14%)
         occurrences all number
    3
    5
    1
    Weight increased
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    1
    0
    1
    White blood cell count increased
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 20 (5.00%)
    0 / 14 (0.00%)
         occurrences all number
    4
    1
    0
    Injury, poisoning and procedural complications
    Postoperative wound complication
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Sunburn
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Cardiac disorders
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    1
    0
    1
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Dizziness
         subjects affected / exposed
    5 / 29 (17.24%)
    4 / 20 (20.00%)
    3 / 14 (21.43%)
         occurrences all number
    6
    7
    6
    Dysgeusia
         subjects affected / exposed
    3 / 29 (10.34%)
    2 / 20 (10.00%)
    1 / 14 (7.14%)
         occurrences all number
    3
    4
    1
    Headache
         subjects affected / exposed
    8 / 29 (27.59%)
    5 / 20 (25.00%)
    5 / 14 (35.71%)
         occurrences all number
    21
    6
    7
    Hypoaesthesia
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 20 (5.00%)
    1 / 14 (7.14%)
         occurrences all number
    2
    1
    3
    Neuropathy peripheral
         subjects affected / exposed
    5 / 29 (17.24%)
    4 / 20 (20.00%)
    6 / 14 (42.86%)
         occurrences all number
    6
    6
    14
    Hyperaesthesia
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Paraesthesia
         subjects affected / exposed
    7 / 29 (24.14%)
    5 / 20 (25.00%)
    1 / 14 (7.14%)
         occurrences all number
    23
    8
    8
    Peripheral sensory neuropathy
         subjects affected / exposed
    6 / 29 (20.69%)
    3 / 20 (15.00%)
    2 / 14 (14.29%)
         occurrences all number
    6
    4
    2
    Toxic neuropathy
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Syncope
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    1
    0
    1
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    1
    0
    1
    Eosinophilia
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Anaemia
         subjects affected / exposed
    11 / 29 (37.93%)
    3 / 20 (15.00%)
    2 / 14 (14.29%)
         occurrences all number
    24
    3
    24
    Leukopenia
         subjects affected / exposed
    5 / 29 (17.24%)
    1 / 20 (5.00%)
    0 / 14 (0.00%)
         occurrences all number
    17
    2
    0
    Neutropenia
         subjects affected / exposed
    4 / 29 (13.79%)
    4 / 20 (20.00%)
    1 / 14 (7.14%)
         occurrences all number
    9
    8
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 20 (10.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    3
    0
    Vertigo
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    1
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    3 / 29 (10.34%)
    2 / 20 (10.00%)
    0 / 14 (0.00%)
         occurrences all number
    3
    3
    0
    Eye irritation
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 20 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    3
    0
    0
    Ocular hyperaemia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    1
    0
    1
    Vision blurred
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 20 (5.00%)
    1 / 14 (7.14%)
         occurrences all number
    5
    1
    1
    Visual impairment
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 20 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    4
    0
    0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Abdominal pain
         subjects affected / exposed
    5 / 29 (17.24%)
    3 / 20 (15.00%)
    1 / 14 (7.14%)
         occurrences all number
    7
    3
    5
    Abdominal pain upper
         subjects affected / exposed
    4 / 29 (13.79%)
    1 / 20 (5.00%)
    3 / 14 (21.43%)
         occurrences all number
    6
    2
    8
    Constipation
         subjects affected / exposed
    7 / 29 (24.14%)
    5 / 20 (25.00%)
    7 / 14 (50.00%)
         occurrences all number
    11
    5
    9
    Cheilitis
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    0
    0
    3
    Dyspepsia
         subjects affected / exposed
    7 / 29 (24.14%)
    2 / 20 (10.00%)
    3 / 14 (21.43%)
         occurrences all number
    9
    2
    9
    Diarrhoea
         subjects affected / exposed
    28 / 29 (96.55%)
    15 / 20 (75.00%)
    13 / 14 (92.86%)
         occurrences all number
    351
    41
    94
    Dysphagia
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 20 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    3
    0
    0
    Eructation
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Gastritis
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Flatulence
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 20 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    2
    0
    2
    Gastrooesophageal reflux disease
         subjects affected / exposed
    4 / 29 (13.79%)
    3 / 20 (15.00%)
    1 / 14 (7.14%)
         occurrences all number
    5
    3
    1
    Gingival bleeding
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Nausea
         subjects affected / exposed
    16 / 29 (55.17%)
    13 / 20 (65.00%)
    11 / 14 (78.57%)
         occurrences all number
    59
    15
    45
    Oesophagitis
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Oral pain
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 20 (10.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    2
    0
    Stomatitis
         subjects affected / exposed
    8 / 29 (27.59%)
    6 / 20 (30.00%)
    3 / 14 (21.43%)
         occurrences all number
    34
    11
    4
    Rectal haemorrhage
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    1
    0
    1
    Toothache
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 20 (5.00%)
    0 / 14 (0.00%)
         occurrences all number
    4
    1
    0
    Vomiting
         subjects affected / exposed
    17 / 29 (58.62%)
    4 / 20 (20.00%)
    6 / 14 (42.86%)
         occurrences all number
    31
    7
    11
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    22 / 29 (75.86%)
    11 / 20 (55.00%)
    8 / 14 (57.14%)
         occurrences all number
    25
    13
    11
    Dermatitis contact
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    1
    0
    2
    Dry skin
         subjects affected / exposed
    5 / 29 (17.24%)
    3 / 20 (15.00%)
    3 / 14 (21.43%)
         occurrences all number
    5
    3
    5
    Nail disorder
         subjects affected / exposed
    7 / 29 (24.14%)
    3 / 20 (15.00%)
    6 / 14 (42.86%)
         occurrences all number
    9
    3
    10
    Hyperhidrosis
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    0
    0
    2
    Nail discolouration
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    1
    0
    3
    Nail ridging
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Pain of skin
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    1
    Rash
         subjects affected / exposed
    25 / 29 (86.21%)
    17 / 20 (85.00%)
    9 / 14 (64.29%)
         occurrences all number
    75
    27
    29
    Photosensitivity reaction
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Pruritus
         subjects affected / exposed
    6 / 29 (20.69%)
    3 / 20 (15.00%)
    5 / 14 (35.71%)
         occurrences all number
    7
    4
    5
    Skin discolouration
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 20 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    4
    0
    0
    Rash follicular
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Rash papular
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 20 (5.00%)
    1 / 14 (7.14%)
         occurrences all number
    1
    1
    1
    Telangiectasia
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Skin fissures
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 20 (5.00%)
    1 / 14 (7.14%)
         occurrences all number
    1
    1
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    3
    0
    1
    Ureteric stenosis
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    6 / 29 (20.69%)
    6 / 20 (30.00%)
    1 / 14 (7.14%)
         occurrences all number
    10
    8
    2
    Back pain
         subjects affected / exposed
    5 / 29 (17.24%)
    3 / 20 (15.00%)
    3 / 14 (21.43%)
         occurrences all number
    7
    3
    8
    Bone pain
         subjects affected / exposed
    3 / 29 (10.34%)
    1 / 20 (5.00%)
    0 / 14 (0.00%)
         occurrences all number
    5
    1
    0
    Muscle twitching
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    1
    0
    2
    Muscle spasms
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 20 (5.00%)
    2 / 14 (14.29%)
         occurrences all number
    2
    1
    4
    Muscular weakness
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    4
    0
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    3 / 29 (10.34%)
    3 / 20 (15.00%)
    0 / 14 (0.00%)
         occurrences all number
    4
    3
    0
    Musculoskeletal pain
         subjects affected / exposed
    4 / 29 (13.79%)
    1 / 20 (5.00%)
    2 / 14 (14.29%)
         occurrences all number
    27
    1
    2
    Myalgia
         subjects affected / exposed
    11 / 29 (37.93%)
    4 / 20 (20.00%)
    3 / 14 (21.43%)
         occurrences all number
    26
    5
    6
    Neck pain
         subjects affected / exposed
    5 / 29 (17.24%)
    1 / 20 (5.00%)
    2 / 14 (14.29%)
         occurrences all number
    5
    2
    2
    Pain in extremity
         subjects affected / exposed
    7 / 29 (24.14%)
    5 / 20 (25.00%)
    3 / 14 (21.43%)
         occurrences all number
    9
    7
    6
    Trismus
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Infections and infestations
    Angular cheilitis
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Bronchitis
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 20 (5.00%)
    0 / 14 (0.00%)
         occurrences all number
    2
    1
    0
    Candida infection
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 20 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    0
    Cellulitis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    1
    0
    3
    Conjunctivitis
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    2
    Ear infection
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 20 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    2
    0
    2
    Cystitis
         subjects affected / exposed
    3 / 29 (10.34%)
    1 / 20 (5.00%)
    1 / 14 (7.14%)
         occurrences all number
    3
    1
    1
    Fungal skin infection
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    1
    0
    1
    Gastroenteritis viral
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 20 (10.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    3
    1
    Herpes zoster
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    2
    1
    Infection
         subjects affected / exposed
    3 / 29 (10.34%)
    1 / 20 (5.00%)
    1 / 14 (7.14%)
         occurrences all number
    3
    1
    1
    Laryngitis
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 20 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    0
    Localised infection
         subjects affected / exposed
    5 / 29 (17.24%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    9
    0
    1
    Nail infection
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 20 (5.00%)
    0 / 14 (0.00%)
         occurrences all number
    2
    2
    0
    Paronychia
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 20 (5.00%)
    0 / 14 (0.00%)
         occurrences all number
    6
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 20 (10.00%)
    0 / 14 (0.00%)
         occurrences all number
    2
    3
    0
    Sinusitis
         subjects affected / exposed
    3 / 29 (10.34%)
    1 / 20 (5.00%)
    3 / 14 (21.43%)
         occurrences all number
    5
    1
    3
    Pneumonia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    1
    0
    2
    Skin infection
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    1
    Upper respiratory tract infection
         subjects affected / exposed
    8 / 29 (27.59%)
    3 / 20 (15.00%)
    6 / 14 (42.86%)
         occurrences all number
    13
    6
    7
    Urinary tract infection
         subjects affected / exposed
    5 / 29 (17.24%)
    2 / 20 (10.00%)
    3 / 14 (21.43%)
         occurrences all number
    12
    3
    9
    Vulvovaginal mycotic infection
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    4
    0
    2
    Vaginal infection
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 20 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    3
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    8 / 29 (27.59%)
    3 / 20 (15.00%)
    2 / 14 (14.29%)
         occurrences all number
    11
    6
    11
    Dehydration
         subjects affected / exposed
    8 / 29 (27.59%)
    1 / 20 (5.00%)
    2 / 14 (14.29%)
         occurrences all number
    10
    1
    2
    Hyperglycaemia
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    8
    0
    4
    Hyperkalaemia
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Hypoalbuminaemia
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 20 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    3
    0
    0
    Hypocalcaemia
         subjects affected / exposed
    5 / 29 (17.24%)
    1 / 20 (5.00%)
    0 / 14 (0.00%)
         occurrences all number
    14
    2
    0
    Hypomagnesaemia
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 20 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    8
    0
    0
    Hypokalaemia
         subjects affected / exposed
    12 / 29 (41.38%)
    2 / 20 (10.00%)
    3 / 14 (21.43%)
         occurrences all number
    24
    3
    7
    Hyponatraemia
         subjects affected / exposed
    4 / 29 (13.79%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    6
    0
    1
    Hypophosphataemia
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 20 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    6
    0
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Aug 2006
    Applied to all centers. An IDMC was incorporated to monitor subject safety during the randomized phase of the study. Diarrhea management guidelines were added to the protocol to encourage proactive management of diarrhea during the study and thus avoid more serious complications. The efficacy data from the ongoing lapatinib clinical program showed clinical activity and benefit. Therefore, for the randomized phase, the primary efficacy analysis population was changed to the ITT population. Clinical disease assessment for palpable or visual lesions was preformed 4 weekly rather than 8 weekly and the list of prohibited medications was also updated.
    22 Feb 2007
    Applied to all centers. Due to a high rate of diarrhea observed in the initial open label safety cohort (cohort 1), the safety cohort was extended to investigate a lower dose of paclitaxel (70 mg/m2) when combined with 1000 mg once daily of lapatinib plus standard weekly dose of trastuzumab (cohort 2). Following a review of the data from cohort 2, the possibility of conducting an additional cohort in the open label phase to investigate a lower dose of lapatinib (750 mg once daily) plus 80 mg/m2 paclitaxel plus standard weekly dose of trastuzumab (cohort 3) was included. Primary prophylactic antidiarrheal treatment was also incorporated into the protocol. Pharmacokinetic sampling was introduced into the extended safety cohort and the open label secondary objectives were updated to explore any correlations between lapatinib and paclitaxel plasma concentrations and safety. The sample size was updated to reflect the extension of the safety cohort.
    07 Dec 2007
    This amendment was country specific for all centers in Belgium, and other future European countries included after the amendment, to allow the use of locally sourced Taxol or generic paclitaxel. The description of the vial size of tastuzumab was also updated to included 150 mg vials.
    06 Jun 2008
    Applied to all centers. Following a review of all hepatobiliary events reported across the lapatinib clinical program, a causal relationship between hepatobiliary disorders and lapatinib could not be excluded. Therefore, changes to the exclusion criteria, lapatinib stopping criteria and follow up criteria, and definition of an SAE due to potential liver toxicity, were made.
    17 Nov 2008
    Applied to all centers. The addition of PK sampling to the follow up assessment of subjects with a severe liver toxicity while on study medication was made to enable an accurate attribution of causality of the liver event to the study medication. To reduce the burden on the subject and center, the collection of serum samples for analysis of the extracellular domain of ErbB1 and ErbB2 was removed from the protocol. Similarly, the independent review of radiological scans was removed from the protocol. Only the investigator assessment of the subject’s radiological scans was to be used in the analysis.
    22 Jun 2010
    This amendment stopped the survival follow-up for subjects who had discontinued study treatment and stopped the follow-up for progression for subjects who had withdrawn from study treatment prematurely. Sites in North America were allowed to use local Laboratory results for hematology and chemistry assessments instead the central laboratory.
    19 Mar 2013
    Applied to all centers. Randomized Phase III part of the study was cancelled due to recruitment challenges. Long-term follow up phase of the study was added. Continued access to clinical trial material was allowed for subjects ongoing at the time of implementation of this amendment. Many study specific efficacy and safety assessments were discontinued. Information regarding use of proton pump inhibitors was updated. Subjects were allowed to switch to a 3-weekly trastuzumab (6 mg/kg trastuzumab) schedule in the maintenance phase of their treatment (i.e. lapatinib plus trastuzumab) based on investigator’s clinical judgment. Information regarding diarrhea management for all grades was updated.
    16 Mar 2016
    Applied to all centers. References to GlaxoSmithKline or its staff were deleted or replaced with that of Novartis and its authorized agents to align with the change of sponsorship. Administrative changes were made to align with Novartis processes and procedures.

    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.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.nov for complete trial results.
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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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