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    Clinical Trial Results:
    A Phase II Study of Lapatinib for Brain Metastases in Subjects with ErbB2-Positive Breast Cancer Following Trastuzumab-based Systemic Therapy and Cranial Radiotherapy

    Summary
    EudraCT number
    		 2005-003944-68
    Trial protocol
    		 SE   AT   DE   GB   BE   ES   GR   IT  
    Global end of trial date
    15 Mar 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Mar 2019
    First version publication date
    30 Mar 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    EGF105084
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00263588
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Novartis: CLAP016A2202
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Study Lead, Novartis Pharma AG, 41 +613241111, novartis.email@novartis.com
    Scientific contact
    Study Director, 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
    11 Mar 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Mar 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Determine central nervous system (CNS) objective response rate to lapatinib monotherapy in subjects with progressive brain metastases from human epidermal growth factor receptor 2 (HER2/ErbB2)-overexpressing breast cancer
    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
    02 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
    Austria: 8
    Country: Number of subjects enrolled
    Belgium: 10
    Country: Number of subjects enrolled
    Canada: 7
    Country: Number of subjects enrolled
    France: 26
    Country: Number of subjects enrolled
    Germany: 18
    Country: Number of subjects enrolled
    Greece: 10
    Country: Number of subjects enrolled
    Australia: 18
    Country: Number of subjects enrolled
    India: 2
    Country: Number of subjects enrolled
    Italy: 9
    Country: Number of subjects enrolled
    Japan: 6
    Country: Number of subjects enrolled
    Poland: 4
    Country: Number of subjects enrolled
    Spain: 8
    Country: Number of subjects enrolled
    Sweden: 4
    Country: Number of subjects enrolled
    Switzerland: 5
    Country: Number of subjects enrolled
    Taiwan: 5
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    United States: 92
    Worldwide total number of subjects
    242
    EEA total number of subjects
    107
    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)
    220
    From 65 to 84 years
    21
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 The Intent-to-Treat (ITT) Population: all subjects who received at least one dose of study medication Modified ITT (MITT) Population: all subjects who received at least four doses (750 mg lapatinib twice daily for two days) of study medication and who had measurable brain metastases (≥1 cm in diameter) at baseline assessment

    Pre-assignment
    Screening details
    		 Main phase: ITT 95 in Cohort A, 147 in Cohort B. MITT, 94 in Cohort A, and 143 subjects in Cohort B Optional open-label extension phase: 51 subjects. Long-term follow up (LTFU) Protocol amendment added on 15-Apr-2013

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort A
    Arm description
    		 750mg lapatinib administered orally twice daily. Cohort A subjects had Eastern Cooperative Oncology Group (ECOG) performance status 0-1, and one or two prior trastuzumab-containing regimens, in total, for treatment of breast cancer in adjuvant and/or metastatic settings
    Arm type
    		 Experimental

    Investigational medicinal product name
    lapatinib
    Investigational medicinal product code
    EGF105
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Cohort A subjects had Eastern Cooperative Oncology Group (ECOG) performance status 0-1

    Arm title
    		 Cohort B
    Arm description
    		 750mg lapatinib administered orally twice daily. Cohort B subjects had ECOG performance status 2 or more than 2 prior trastuzumab-containing regimens for treatment of breast cancer in the adjuvant and/or metastatic settings.
    Arm type
    		 Experimental

    Investigational medicinal product name
    laptinib
    Investigational medicinal product code
    EGF105
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    750mg laptinib administered orally twice daily. Cohort B subjects had ECOG performance status 2 or more than 2 prior trastuzumab-containing regimens

    Number of subjects in period 1
    		Cohort A Cohort B
    Started
    95
    147
    Completed
    14
    15
    Not completed
    81
    132
         Adverse event, serious fatal
    54
    90
         sponsor terminated study
    -
    1
         Consent withdrawn by subject
    3
    4
         coma; disease progression; unknown
    10
    11
         Investigator decision
    7
    15
         Lost to follow-up
    7
    10
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Study
    Reporting group description
    		 -

    Reporting group values
    		 Overall Study Total
    Number of subjects
    		 242 242
    Age, Customized
    Units: Subjects
        <18|242
    		 0 0
        18-64 years|242
    		 220 220
        65-84 years|242
    		 21 21
        >85 years|242
    		 1 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 49.7 ( 10.56 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 241 241
        Male
    		 1 1
    Race/Ethnicity, Customized
    Units: Subjects
        African American/African
    		 7 7
        American Indian/Alaskan Native
    		 1 1
        Asian – Central/South
    		 3 3
        Asian – Japanese
    		 6 6
        Asian - South-East Asian
    		 3 3
        Asia - East
    		 5 5
        Native Hawaiian or other Pacific Islander
    		 1 1
        White - Arabic/North African
    		 2 2
        White - White/ Caucasian/European
    		 212 212
        Mixed race
    		 1 1
        Other
    		 1 1
    Subject analysis sets

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The Intent-to-Treat (ITT) Population: all subjects who received at least one dose of study medication

    Subject analysis set title
    MITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Modified ITT (MITT) Population: all subjects who received at least four doses (750 mg lapatinib twice daily for two days) of study medication and who had measurable brain metastases (≥1 cm in diameter) at baseline assessment

    Subject analysis sets values
    		 ITT MITT
    Number of subjects
    242
    241
    Age, Customized
    Units: Subjects
        <18|242
    0
        18-64 years|242
    220
        65-84 years|242
    21
        >85 years|242
    1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    49.7 ( 10.56 )
    0 ( 0 )
    Sex: Female, Male
    Units: Subjects
        Female
    241
        Male
    1
    Race/Ethnicity, Customized
    Units: Subjects
        African American/African
    7
        American Indian/Alaskan Native
    1
        Asian – Central/South
    3
        Asian – Japanese
    6
        Asian - South-East Asian
    3
        Asia - East
    5
        Native Hawaiian or other Pacific Islander
    1
        White - Arabic/North African
    2
        White - White/ Caucasian/European
    212
        Mixed race
    1
        Other
    1

    End points

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    End points reporting groups
    Reporting group title
    Cohort A
    Reporting group description
    		 750mg lapatinib administered orally twice daily. Cohort A subjects had Eastern Cooperative Oncology Group (ECOG) performance status 0-1, and one or two prior trastuzumab-containing regimens, in total, for treatment of breast cancer in adjuvant and/or metastatic settings

    Reporting group title
    Cohort B
    Reporting group description
    		 750mg lapatinib administered orally twice daily. Cohort B subjects had ECOG performance status 2 or more than 2 prior trastuzumab-containing regimens for treatment of breast cancer in the adjuvant and/or metastatic settings.

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The Intent-to-Treat (ITT) Population: all subjects who received at least one dose of study medication

    Subject analysis set title
    MITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Modified ITT (MITT) Population: all subjects who received at least four doses (750 mg lapatinib twice daily for two days) of study medication and who had measurable brain metastases (≥1 cm in diameter) at baseline assessment

    Primary: Central nervous system (CNS) objective response rate

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    End point title
    		 Central nervous system (CNS) objective response rate [1]
    End point description
    Summary of CNS Objective Response (Lapatinib Monotherapy - MITT Population) Response to lapatinib in patients with progressive brain metastases from ErbB2-overexpressing breast cancer. The primary indicator of drug efficacy was CNS objective response rate. A CNS objective response was defined as either a Complete response (CR) or Partial response (PR), as assessed by volumetric analysis of brain Magnetic resonance imaging (MRI), provided there was no progression of systemic disease outside of the CNS, increasing steroid requirements, or worsening of Neurological signs and symptoms (NSS) A CNS objective response rate was defined as a 50% volumetric reduction in sum of CNS target lesions, with no new or progressive CNS or non-CNS lesions, no increases in tumor-related steroid requirements and no worsening of neurological signs or symptoms
    End point type
    Primary
    End point timeframe
    time from baseline to data cutoff (25 Sept 2007); approximately 2 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 analyses were planned for primary endpoint
    End point values
    		 Cohort A Cohort B
    Number of subjects analysed
    94
    143
    Units: participants
        Complete response (CR)
    0
    0
        Partial response (PR)
    6
    9
        Stable disease (SD)
    40
    46
        Progressive disease (PD)
    40
    70
        Unknown
    8
    18
    No statistical analyses for this end point

    Primary: Central nervous system (CNS) objective response rate - Response Rate (CR + PR), a percentage

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    End point title
    		 Central nervous system (CNS) objective response rate - Response Rate (CR + PR), a percentage [2]
    End point description
    Summary of CNS Objective Response (the Complete Response + Partial Response)
    End point type
    Primary
    End point timeframe
    baseline to time of best response to treatment
    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 analyses were planned for End Point: Central nervous system (CNS) objective response rate
    End point values
    		 Cohort A Cohort B
    Number of subjects analysed
    94
    143
    Units: percentage
        number (confidence interval 95%)
    6 (2.4 to 13.4)
    6 (2.9 to 11.6)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Improvement in neurological signs and symptoms (NSS) measured using the Neurological Examination Worksheet

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    End point title
    		 Percentage of Participants with Improvement in neurological signs and symptoms (NSS) measured using the Neurological Examination Worksheet
    End point description
    Physician-reported NSS worksheet is derived from 13 AEs and measured by NCI CTCAE v3.0 grouped into 7 categories: level of consciousness, neurological symptoms, cranial nerves, language, strength, sensation, and ataxia. Improvement of NSS required all of the following: Decrease by 1 or more grades from baseline of any tumor-related NSS, with confirmation at least 4 wks later, No development or worsening in any tumor-related NSS during interval, No radiographic evidence of CNS progression (assessed by volumetric MRI) or systemic (non-CNS) progression (assessed by RECIST) during interval, Stable or decreasing steroids during interval as defined by GSK equivalent doses of an alternative corticosteroid or a dose increase for non-tumor related reasons (e.g., asthma) didn’t constitute a steroid increase. Improvement in any non-tumor associated NSS didn’t constitute improvement in NSS. Neurological exam, using Neurological Examination Worksheet was assessed at baseline and each 4 weeks
    End point type
    Secondary
    End point timeframe
    time from baseline to data cutoff (25 Sept 2007); approximately 2 years
    End point values
    		 ITT
    Number of subjects analysed
    237
    Units: percentage of participants
    number (confidence interval 95%)
        % with NSS at Baseline
    12.1 (7.9 to 17.5)
        % with NSS at Baseline with 20% volume reduction
    23.5 (10.7 to 41.2)
        % w NSS at Baseline & any volume reduction
    23.7 (13.6 to 36.6)
        % with NSS at Baseline & volume increase of w/drew
    7.2 (3.3 to 13.2)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with a CNS Objective Response or Improvement in Baseline neurological signs and symptoms (NSS)

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    End point title
    		 Percentage of Subjects with a CNS Objective Response or Improvement in Baseline neurological signs and symptoms (NSS)
    End point description
    Summary of Proportion of Subjects with a CNS Objective Response or Improvement in Baseline NSS
    End point type
    Secondary
    End point timeframe
    baseline and weeks 8, 16, 24, 32, 40, 48
    End point values
    		 Cohort A Cohort B
    Number of subjects analysed
    94
    143
    Units: percentage of participants
    number (confidence interval 95%)
        week 8
    23 (14.1 to 33.6)
    14 (7.8 to 21.5)
        week 16
    2 (0.1 to 12.3)
    8 (2.2 to 19.2)
        week 24
    8 (0.2 to 38.5)
    11 (1.3 to 33.1)
        week 32
    17 (0.4 to 64.1)
    0.0 (0.0 to 0.0)
        week 40
    0.0 (0.0 to 0.0)
    0.0 (0.0 to 0.0)
        week 48
    0.0 (0.0 to 0.0)
    0.0 (0.0 to 0.0)
    No statistical analyses for this end point

    Secondary: Duration of Central Nervous System (CNS) objective response

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    End point title
    		 Duration of Central Nervous System (CNS) objective response
    End point description
    The duration of CNS objective response, defined as the time from first CNS Objective response until tumor progression at any site or death due to any cause. A CNS objective response was defined as either a Complete Response (CR) or Partial Response (PR), as assessed by volumetric analysis of magnetic resonance imaging (MRI), provided there was no progression of systemic disease outside of the CNS, increasing steroid requirements, or worsening of tumor-related neurological signs or symptoms. 9.9999999999 =upper limit Not evaluable (Due to the low number of CNS responders, a meaningful interpretation of duration of response is not possible). This is only a placeholder
    End point type
    Secondary
    End point timeframe
    time from baseline to data cutoff (25 Sept 2007); approximately 2 years
    End point values
    		 Cohort A Cohort B
    Number of subjects analysed
    94
    143
    Units: duration in months
        number (confidence interval 95%)
    2.43 (0.99 to 9.9999)
    1.58 (0.99 to 3.55)
    No statistical analyses for this end point

    Secondary: Percentage of patients with CNS disease control (complete response, partial response or stable disease) at 6 months of lapatinib therapy

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    End point title
    		 Percentage of patients with CNS disease control (complete response, partial response or stable disease) at 6 months of lapatinib therapy
    End point description
    The CNS disease control rate, defined as the percentage of subjects with CR, PR or stable disease at Week 24
    End point type
    Secondary
    End point timeframe
    from Start of lapatinib to 6 months
    End point values
    		 Cohort A Cohort B
    Number of subjects analysed
    94
    143
    Units: percentage of participants
        number (confidence interval 95%)
    9 (3.7 to 16.1)
    2 (0.4 to 6.0)
    No statistical analyses for this end point

    Secondary: Time to progression (TTP) at any site

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    End point title
    		 Time to progression (TTP) at any site
    End point description
    Summary of Kaplan-Meier Estimates for Progression Free Survival at Any Site
    End point type
    Secondary
    End point timeframe
    time from baseline to data cutoff (25 Sept 2007); approximately 2 years
    End point values
    		 Cohort A Cohort B
    Number of subjects analysed
    94
    143
    Units: months
        median (confidence interval 95%)
    2.60 (1.87 to 3.25)
    1.87 (1.84 to 2.63)
    No statistical analyses for this end point

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    Overall survival (OS) defined as the time from initiation of investigational product to death due to any cause.
    End point type
    Secondary
    End point timeframe
    time from baseline to data cutoff (25 Sept 2007); approximately 2 years
    End point values
    		 Cohort A Cohort B
    Number of subjects analysed
    94
    143
    Units: months
        median (confidence interval 95%)
    10.78 (7.95 to 12.68)
    5.82 (4.78 to 7.89)
    No statistical analyses for this end point

    Secondary: Summary of site of first progression

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    End point title
    		 Summary of site of first progression
    End point description
    Overall survival (OS) defined as the time from initiation of investigational product to death due to any cause.
    End point type
    Secondary
    End point timeframe
    time from baseline to data cutoff (25 Sept 2007); approximately 2 years
    End point values
    		 Cohort A Cohort B
    Number of subjects analysed
    94
    143
    Units: participants
        CNS progression
    69
    72
        Non-CNS prgression
    1
    10
        CNS and Non-CNS progression
    12
    36
    No statistical analyses for this end point

    Secondary: Primary cause of death

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    End point title
    		 Primary cause of death
    End point description
    Primary causes of death as reported by investigator
    End point type
    Secondary
    End point timeframe
    time from baseline to data cutoff (25 Sept 2007); approximately 2 years
    End point values
    		 Cohort A Cohort B
    Number of subjects analysed
    95
    147
    Units: participants
        Disease under study
    74
    124
        Other
    4
    4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV).  All Adverse events are reported in this record from First Patient First Treatment until Last Patient Last Visit.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    EGF105084/Cohort B
    Reporting group description
    		 EGF105084/Cohort B

    Reporting group title
    EGF105084/Cohort A
    Reporting group description
    		 EGF105084/Cohort A

    Serious adverse events
    		 EGF105084/Cohort B EGF105084/Cohort A
    Total subjects affected by serious adverse events
         subjects affected / exposed
    52 / 147 (35.37%)
    36 / 95 (37.89%)
         number of deaths (all causes)
    48
    20
         number of deaths resulting from adverse events
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Malignant pleural effusion
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    2 / 147 (1.36%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Complication associated with device
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 147 (0.68%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Performance status decreased
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 147 (0.68%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 147 (1.36%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    4 / 147 (2.72%)
    5 / 95 (5.26%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Psychiatric disorders
    Completed suicide
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Depression
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 147 (0.00%)
    2 / 95 (2.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood phosphorus increased
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    4 / 147 (2.72%)
    2 / 95 (2.11%)
         occurrences causally related to treatment / all
    4 / 4
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Altered state of consciousness
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aphasia
         subjects affected / exposed
    1 / 147 (0.68%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dizziness
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 147 (0.00%)
    2 / 95 (2.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 147 (0.68%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukoencephalopathy
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraplegia
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    5 / 147 (3.40%)
    3 / 95 (3.16%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    4 / 147 (2.72%)
    6 / 95 (6.32%)
         occurrences causally related to treatment / all
    3 / 4
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 147 (1.36%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    3 / 147 (2.04%)
    3 / 95 (3.16%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal perforation
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vomiting
         subjects affected / exposed
    5 / 147 (3.40%)
    3 / 95 (3.16%)
         occurrences causally related to treatment / all
    2 / 5
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct obstruction
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Exfoliative rash
         subjects affected / exposed
    1 / 147 (0.68%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myopathy
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acinetobacter infection
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    3 / 147 (2.04%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis bacterial
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Necrotising fasciitis
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal candidiasis
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 147 (0.68%)
    2 / 95 (2.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary tuberculosis
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    4 / 147 (2.72%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 147 (1.36%)
    4 / 95 (4.21%)
         occurrences causally related to treatment / all
    2 / 2
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 147 (0.68%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 EGF105084/Cohort B EGF105084/Cohort A
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    131 / 147 (89.12%)
    90 / 95 (94.74%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    13 / 147 (8.84%)
    4 / 95 (4.21%)
         occurrences all number
    13
    4
    Blood bilirubin increased
         subjects affected / exposed
    1 / 147 (0.68%)
    7 / 95 (7.37%)
         occurrences all number
    1
    9
    Weight decreased
         subjects affected / exposed
    11 / 147 (7.48%)
    5 / 95 (5.26%)
         occurrences all number
    12
    6
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    5 / 147 (3.40%)
    8 / 95 (8.42%)
         occurrences all number
    5
    11
    Dysgeusia
         subjects affected / exposed
    5 / 147 (3.40%)
    5 / 95 (5.26%)
         occurrences all number
    5
    5
    Headache
         subjects affected / exposed
    29 / 147 (19.73%)
    23 / 95 (24.21%)
         occurrences all number
    40
    31
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    7 / 147 (4.76%)
    5 / 95 (5.26%)
         occurrences all number
    8
    6
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    15 / 147 (10.20%)
    9 / 95 (9.47%)
         occurrences all number
    18
    9
    Fatigue
         subjects affected / exposed
    29 / 147 (19.73%)
    30 / 95 (31.58%)
         occurrences all number
    33
    31
    Oedema peripheral
         subjects affected / exposed
    16 / 147 (10.88%)
    6 / 95 (6.32%)
         occurrences all number
    18
    6
    Pyrexia
         subjects affected / exposed
    6 / 147 (4.08%)
    5 / 95 (5.26%)
         occurrences all number
    7
    6
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 147 (2.72%)
    5 / 95 (5.26%)
         occurrences all number
    5
    5
    Constipation
         subjects affected / exposed
    16 / 147 (10.88%)
    9 / 95 (9.47%)
         occurrences all number
    19
    10
    Diarrhoea
         subjects affected / exposed
    92 / 147 (62.59%)
    71 / 95 (74.74%)
         occurrences all number
    153
    113
    Dry mouth
         subjects affected / exposed
    6 / 147 (4.08%)
    6 / 95 (6.32%)
         occurrences all number
    7
    7
    Dyspepsia
         subjects affected / exposed
    9 / 147 (6.12%)
    3 / 95 (3.16%)
         occurrences all number
    10
    3
    Nausea
         subjects affected / exposed
    47 / 147 (31.97%)
    29 / 95 (30.53%)
         occurrences all number
    58
    42
    Vomiting
         subjects affected / exposed
    39 / 147 (26.53%)
    24 / 95 (25.26%)
         occurrences all number
    50
    37
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 147 (5.44%)
    5 / 95 (5.26%)
         occurrences all number
    9
    6
    Dyspnoea
         subjects affected / exposed
    11 / 147 (7.48%)
    6 / 95 (6.32%)
         occurrences all number
    12
    8
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    11 / 147 (7.48%)
    6 / 95 (6.32%)
         occurrences all number
    12
    8
    Dermatitis acneiform
         subjects affected / exposed
    10 / 147 (6.80%)
    6 / 95 (6.32%)
         occurrences all number
    10
    8
    Dry skin
         subjects affected / exposed
    15 / 147 (10.20%)
    7 / 95 (7.37%)
         occurrences all number
    16
    9
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    21 / 147 (14.29%)
    16 / 95 (16.84%)
         occurrences all number
    27
    16
    Pruritus
         subjects affected / exposed
    13 / 147 (8.84%)
    8 / 95 (8.42%)
         occurrences all number
    13
    9
    Rash
         subjects affected / exposed
    37 / 147 (25.17%)
    40 / 95 (42.11%)
         occurrences all number
    44
    48
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    7 / 147 (4.76%)
    5 / 95 (5.26%)
         occurrences all number
    10
    6
    Back pain
         subjects affected / exposed
    6 / 147 (4.08%)
    6 / 95 (6.32%)
         occurrences all number
    6
    6
    Bone pain
         subjects affected / exposed
    8 / 147 (5.44%)
    2 / 95 (2.11%)
         occurrences all number
    8
    2
    Pain in extremity
         subjects affected / exposed
    7 / 147 (4.76%)
    8 / 95 (8.42%)
         occurrences all number
    8
    9
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 147 (1.36%)
    5 / 95 (5.26%)
         occurrences all number
    2
    6
    Urinary tract infection
         subjects affected / exposed
    8 / 147 (5.44%)
    7 / 95 (7.37%)
         occurrences all number
    9
    8
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    28 / 147 (19.05%)
    16 / 95 (16.84%)
         occurrences all number
    29
    17
    Hypokalaemia
         subjects affected / exposed
    11 / 147 (7.48%)
    5 / 95 (5.26%)
         occurrences all number
    14
    8

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Oct 2005
    Amendment 01 (13-Oct-2005) - Country specific amendment for Germany and Poland to remove the requirement for specialized radiological assessments using positron emission tomography (PET).
    21 Dec 2005
    Amendment 02 (21-Dec-2005) – Country specific amendment for Japan to (1) add a pharmacokinetic component to the protocol (2) add a Go/No Go decision based on dose limiting toxicities in first 6 Japanese subjects (3) remove option to enroll into an open-label extension phase (lapatinib combination therapy) and (4) elect as an option, on a site basis, the specialized radiological assessments using positron emission tomography (PET)
    19 Jun 2006
    Amendment 03 (19-Jun-2006) – Optional protocol extension added for subjects on monotherapy lapatinib who develop disease progression in the CNS, to receive the combinationof lapatinib and capecitabine, protocol clarifications added throughout.
    22 Jan 2007
    Amendment 04 (22-Jan-2007) – Country specific amendment for Japan, to allow the trial to remain open in Japan beyond the full-enrollment closure globally, in order to allow the participation of at least 6 Japanese subjects and the collection of PK and safety data.
    29 May 2008
    Amendment 05 (29-May-2008) –Additional safety information and treatment guidelines related to hepatotoxicity added.
    29 Aug 2012
    Amendment 06 (29-Aug-2012)  - Discontinuation of many specific efficacy and safety assessments. The study was stopped for subjects in post treatment follow up. Continued access to study treatment lapatinib was permitted for subject ongoing at the time of implementation of this amendment. - Update to Prohibited Medications was added - Extension phases of the study were removed This amendment was not circulated outside Sponsor (GSK) and later replaced by Protocol Amendment 07 which re-instated the extension phase of the study.
    15 Apr 2013
    Protocol Amendment 07 was implemented to discontinue collection of many study-specific assessments while allowing the one subject receiving treatment to have continued access to the treatment until the occurrence of unacceptable toxicity or disease progression (as determined by the investigator). Amendment 07 (15-Apr-2013), introduced the following changes:  - Re-instated the Extension phase of the study  - Continued access to treatment under one of the extension phases permitted. - Reduced the number of study assessments in the extension phases. - Updated information on LAP016A2305/EGF111438 results added to align with Supplement 01 of Lapatinib Investigator’s Brochure version 13 - Updated safety guidelines - Addition of the efficacy results of the Study EGF111438 interim analysis (CSR dated 16-Oct-2012) Amendment 08 (03-Oct-2016), introduced the following changes:  - Deleted or replaced references to GSK or its staff with that of Novartis and its authorized agents.  - Administrative changes 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.
    3 objectives not in protocol were initially registered in error. There was no analysis of these outcomes and there should not have been 2 participants were counted twice when they moved from one site to another. 1 iJapan and 1 in US. Actual global
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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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