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    Clinical Trial Results:
    An Open-Label, Phase 2 Basket Study of Neratinib in Patients with Solid Tumors with Somatic Activating HER Mutations

    Summary
    EudraCT number
    		 2013-002872-42
    Trial protocol
    		 ES   IT   FI   GB   DK   BE   FR   IE  
    Global end of trial date
    02 Jan 2023

    Results information
    Results version number
    		 v2(current)
    This version publication date
    27 Apr 2024
    First version publication date
    06 Jan 2024
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    The study was terminated to align with the sponsor's current development plans for neratinib. The decision was not based on any new efficacy or safety data for neratinib.

    Trial information

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    Trial identification
    Sponsor protocol code
    PUMA-NER-5201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01953926
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Puma Biotechnology, Inc.
    Sponsor organisation address
    10880 Wilshire Blvd, Suite 2150, Los Angeles, United States, 90024
    Public contact
    Clinical Trials Information Desk, Puma Biotechnology, Inc., 1 4242486500, clinicaltrials@pumabiotechnology.com
    Scientific contact
    Clinical Trials Information Desk, Puma Biotechnology, Inc., 1 4242486500, clinicaltrials@pumabiotechnology.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
    02 Jan 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Jan 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To determine the objective response rate at 8 weeks (ORR8) following treatment with neratinib in patients with solid tumors that test positive for somatic human epidermal growth factor receptor mutations in the ERBB gene family (EGFR, HER2, and/or HER3) or EGFR gene amplification.
    Protection of trial subjects
    Study commencement required prior written approval of a properly constituted Institutional Review Board (IRB) or Independent Ethics Committee (IEC). Clinical trial data were monitored at regular intervals by the Sponsor or their representative throughout the study to verify compliance to study protocol, completeness, accuracy and consistency of the data and adherence to local regulations on the conduct of clinical research. Patients were discontinued from investigational product(s) (IP) prior to study closure in the following circumstances: disease progression, unacceptable toxicity, and withdrawal of consent.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Sep 2013
    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
    Australia: 10
    Country: Number of subjects enrolled
    Canada: 5
    Country: Number of subjects enrolled
    Israel: 24
    Country: Number of subjects enrolled
    Korea, Republic of: 4
    Country: Number of subjects enrolled
    Serbia: 3
    Country: Number of subjects enrolled
    United States: 346
    Country: Number of subjects enrolled
    Spain: 113
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    Belgium: 14
    Country: Number of subjects enrolled
    Denmark: 15
    Country: Number of subjects enrolled
    France: 23
    Country: Number of subjects enrolled
    Ireland: 8
    Country: Number of subjects enrolled
    Italy: 13
    Worldwide total number of subjects
    582
    EEA total number of subjects
    186
    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)
    359
    From 65 to 84 years
    216
    85 years and over
    7

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Patients will be assigned to cohorts based on tumors harboring somatic mutations in EGFR or HER2 identified through previously documented mutation testing performed prior to screening and by the tumor type. If a tumor harbors more than one qualifying aberration/mutation, then the patient will be assigned to the appropriate tumor-specific cohort.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Neratinib
    Arm description
    		 Neratinib 240 mg PO QD
    Arm type
    		 Experimental

    Investigational medicinal product name
    Neratinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    240 mg PO QD

    Arm title
    		 Neratinib + Fulvestrant
    Arm description
    		 Neratinib 240 mg PO QD + Fulvestrant 500 mg IM on days 1, 15, 29, then every 28 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    500 mg IM on Days 1, 15, 29, then once every 28 days thereafter.

    Investigational medicinal product name
    Neratinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    240 mg PO QD

    Arm title
    		 Neratinib + Paclitaxel
    Arm description
    		 Neratinib 240 mg PO QD + Paclitaxel 80 mg/m^2 on Days 1, 8, 15 of every 4-week cycle
    Arm type
    		 Experimental

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravascular use
    Dosage and administration details
    80 mg/m^2 on Days 1, 8, 15 of every 4-week cycle

    Investigational medicinal product name
    Neratinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    240 mg PO QD

    Arm title
    		 Neratinib + Trastuzumab
    Arm description
    		 Neratinib 240 mg PO QD + Trastuzumab 8 mg/kg once then 6 mg/kg every 3 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    8 mg/kg once then 6 mg/kg every 3 weeks

    Investigational medicinal product name
    Neratinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    240 mg PO QD

    Arm title
    		 Neratinib + Fulvestrant + Trastuzumab
    Arm description
    		 Neratinib 240 mg PO QD + Fulvestrant 500 mg IM on days 1, 15, 29, then every 28 days + Trastuzumab 8 mg/kg once then 6 mg/kg every 3 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Neratinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    240 mg PO QD

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    8 mg/kg once then 6 mg/kg every 3 weeks

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    500 mg IM on Days 1, 15, 29, then once every 28 days thereafter.

    Arm title
    		 Fulvestrant
    Arm description
    		 Fulvestrant 500 mg IM on days 1, 15, 29, then every 28 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    500 mg IM on Days 1, 15, 29, then once every 28 days thereafter.

    Arm title
    		 Fulvestrant + Trastuzumab
    Arm description
    		 Fulvestrant 500 mg IM on days 1, 15, 29, then every 28 days + Trastuzumab 8 mg/kg once then 6 mg/kg every 3 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    8 mg/kg once then 6 mg/kg every 3 weeks

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    500 mg IM on Days 1, 15, 29, then once every 28 days thereafter.

    Arm title
    		 Not treated
    Arm description
    		 Subjects who were assigned a cohort but not treated
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Neratinib Neratinib + Fulvestrant Neratinib + Paclitaxel Neratinib + Trastuzumab Neratinib + Fulvestrant + Trastuzumab Fulvestrant Fulvestrant + Trastuzumab Not treated
    Started
    317
    45
    22
    92
    90
    7
    7
    2
    Treated
    317
    45
    22
    92
    90
    7
    7
    0
    Completed
    231
    31
    14
    70
    32
    2
    0
    0
    Not completed
    86
    14
    8
    22
    58
    5
    7
    2
         Consent withdrawn by subject
    23
    3
    3
    5
    6
    -
    1
    -
         Physician decision
    1
    -
    -
    -
    2
    -
    -
    -
         Never received study drug
    -
    -
    -
    -
    -
    -
    -
    2
         Discontinuation of study by sponsor
    41
    7
    5
    12
    46
    5
    6
    -
         Lost to follow-up
    18
    3
    -
    5
    3
    -
    -
    -
         Disease Progression
    2
    1
    -
    -
    1
    -
    -
    -
         Protocol deviation
    1
    -
    -
    -
    -
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Neratinib
    Reporting group description
    		 Neratinib 240 mg PO QD

    Reporting group title
    Neratinib + Fulvestrant
    Reporting group description
    		 Neratinib 240 mg PO QD + Fulvestrant 500 mg IM on days 1, 15, 29, then every 28 days

    Reporting group title
    Neratinib + Paclitaxel
    Reporting group description
    		 Neratinib 240 mg PO QD + Paclitaxel 80 mg/m^2 on Days 1, 8, 15 of every 4-week cycle

    Reporting group title
    Neratinib + Trastuzumab
    Reporting group description
    		 Neratinib 240 mg PO QD + Trastuzumab 8 mg/kg once then 6 mg/kg every 3 weeks.

    Reporting group title
    Neratinib + Fulvestrant + Trastuzumab
    Reporting group description
    		 Neratinib 240 mg PO QD + Fulvestrant 500 mg IM on days 1, 15, 29, then every 28 days + Trastuzumab 8 mg/kg once then 6 mg/kg every 3 weeks

    Reporting group title
    Fulvestrant
    Reporting group description
    		 Fulvestrant 500 mg IM on days 1, 15, 29, then every 28 days

    Reporting group title
    Fulvestrant + Trastuzumab
    Reporting group description
    		 Fulvestrant 500 mg IM on days 1, 15, 29, then every 28 days + Trastuzumab 8 mg/kg once then 6 mg/kg every 3 weeks

    Reporting group title
    Not treated
    Reporting group description
    		 Subjects who were assigned a cohort but not treated

    Reporting group values
    		 Neratinib Neratinib + Fulvestrant Neratinib + Paclitaxel Neratinib + Trastuzumab Neratinib + Fulvestrant + Trastuzumab Fulvestrant Fulvestrant + Trastuzumab Not treated Total
    Number of subjects
    		 317 45 22 92 90 7 7 2 582
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 201 28 4 57 59 6 3 1 359
        From 65-84 years
    		 112 15 17 35 31 1 4 1 216
        85 years and over
    		 4 2 1 0 0 0 0 0 7
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 59.4 ± 13.1 60.6 ± 11.5 69.4 ± 9.4 60.4 ± 11.1 59.2 ± 11.6 58.3 ± 11.2 62.0 ± 12.4 63.5 ± 4.9 -
    Gender categorical
    Units: Subjects
        Female
    		 188 45 5 58 89 7 7 1 400
        Male
    		 129 0 17 34 1 0 0 1 182

    End points

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    End points reporting groups
    Reporting group title
    Neratinib
    Reporting group description
    		 Neratinib 240 mg PO QD

    Reporting group title
    Neratinib + Fulvestrant
    Reporting group description
    		 Neratinib 240 mg PO QD + Fulvestrant 500 mg IM on days 1, 15, 29, then every 28 days

    Reporting group title
    Neratinib + Paclitaxel
    Reporting group description
    		 Neratinib 240 mg PO QD + Paclitaxel 80 mg/m^2 on Days 1, 8, 15 of every 4-week cycle

    Reporting group title
    Neratinib + Trastuzumab
    Reporting group description
    		 Neratinib 240 mg PO QD + Trastuzumab 8 mg/kg once then 6 mg/kg every 3 weeks.

    Reporting group title
    Neratinib + Fulvestrant + Trastuzumab
    Reporting group description
    		 Neratinib 240 mg PO QD + Fulvestrant 500 mg IM on days 1, 15, 29, then every 28 days + Trastuzumab 8 mg/kg once then 6 mg/kg every 3 weeks

    Reporting group title
    Fulvestrant
    Reporting group description
    		 Fulvestrant 500 mg IM on days 1, 15, 29, then every 28 days

    Reporting group title
    Fulvestrant + Trastuzumab
    Reporting group description
    		 Fulvestrant 500 mg IM on days 1, 15, 29, then every 28 days + Trastuzumab 8 mg/kg once then 6 mg/kg every 3 weeks

    Reporting group title
    Not treated
    Reporting group description
    		 Subjects who were assigned a cohort but not treated

    Primary: Confirmed Objective Response Rate (ORR) Central Assessment (Breast Cancer With Prior CDK46i Cohort)

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    End point title
    		 Confirmed Objective Response Rate (ORR) Central Assessment (Breast Cancer With Prior CDK46i Cohort) [1] [2]
    End point description
    Percentage of participants who are confirmed by independent central review to have achieved complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
    End point type
    Primary
    End point timeframe
    From enrollment until PD or death due to any cause, assessed up to 58 months.
    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: Only the arms represented here were treated in this cohort of patients
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib + Fulvestrant + Trastuzumab Fulvestrant Fulvestrant + Trastuzumab
    Number of subjects analysed
    59
    7
    7
    Units: Percent
    number (confidence interval 95%)
        ORR by central assessment
    40.7 (28.1 to 54.3)
    0 (0.0 to 41)
    14.3 (0.4 to 57.9)
    No statistical analyses for this end point

    Primary: Confirmed Objective Response Rate (ORR) Cervical Cohort

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    End point title
    		 Confirmed Objective Response Rate (ORR) Cervical Cohort [3] [4]
    End point description
    Overall objective response is defined as either a complete or partial response. A complete or partial response that is confirmed no less than 4-weeks after the criteria for response are initially met; taking results from RECIST over PERCIST.
    End point type
    Primary
    End point timeframe
    From first treatment date until PD or death due to any cause, assessed up to 58 months.
    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: Only the arms represented here were treated in this cohort of patients
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    22
    Units: percent
        number (confidence interval 95%)
    18.2 (5.2 to 40.3)
    No statistical analyses for this end point

    Secondary: ORR at Week 8 Lung HER2-mutant Cohort

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    End point title
    		 ORR at Week 8 Lung HER2-mutant Cohort [5]
    End point description
    Percentage of participants who achieve CR or PR per Response Evaluation Criteria in Sold Tumors Criteria (RECIST) v1.1, or other defined response criteria, at the first scheduled tumor assessment, per RECIST or PERCIST, taking better results from RECIST or PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date to Complete or Partial Response, up to 8 weeks or 9 weeks.
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib Neratinib + Trastuzumab
    Number of subjects analysed
    26
    52
    Units: percent
    number (confidence interval 95%)
        Objective Response Rate (ORR) at week 8
    3.8 (0.1 to 19.6)
    15.4 (6.9 to 28.1)
    No statistical analyses for this end point

    Secondary: Objective Response Rate (ORR) at Week 8 (Other Breast Cancer Cohorts)

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    End point title
    		 Objective Response Rate (ORR) at Week 8 (Other Breast Cancer Cohorts) [6]
    End point description
    First Objective response is defined as complete responses (CR) or partial responses (PR) at 8 weeks or 9 weeks of study therapy, which corresponds to the first scheduled tumor assessment; taking better results from RECIST or PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date to Complete or Partial Response, up to 8 weeks or 9 weeks.
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib Neratinib + Fulvestrant Neratinib + Trastuzumab Neratinib + Fulvestrant + Trastuzumab
    Number of subjects analysed
    36
    45
    21
    31
    Units: Percent
        number (confidence interval 95%)
    36.1 (20.8 to 53.8)
    42.2 (27.7 to 57.8)
    33.3 (14.6 to 57.0)
    48.4 (30.2 to 66.9)
    No statistical analyses for this end point

    Secondary: ORR at Week 8 Lung EGFR-mutant Cohort

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    End point title
    		 ORR at Week 8 Lung EGFR-mutant Cohort [7]
    End point description
    First Objective response is defined as complete responses (CR) or partial responses (PR) at 8 weeks or 9 weeks of study therapy, which corresponds to the first scheduled tumor assessment; taking better results from RECIST or PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date to Complete or Partial Response, up to 8 weeks.
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    31
    Units: percentage
        number (confidence interval 95%)
    19.4 (7.5 to 37.5)
    No statistical analyses for this end point

    Secondary: ORR at Week 8 Biliary tract Cohort

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    End point title
    		 ORR at Week 8 Biliary tract Cohort [8]
    End point description
    First Objective response is defined as complete responses (CR) or partial responses (PR) at 8 weeks or 9 weeks of study therapy, which corresponds to the first scheduled tumor assessment; taking better results from RECIST or PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date to Complete or Partial Response, up to 8 weeks.
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    25
    Units: percent
        number (confidence interval 95%)
    12.0 (2.5 to 31.2)
    No statistical analyses for this end point

    Secondary: ORR at Week 4 Brain Cohort

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    End point title
    		 ORR at Week 4 Brain Cohort [9]
    End point description
    First Objective response is defined as complete responses (CR) or partial responses (PR) at 4 weeks of study therapy, which corresponds to the first scheduled tumor assessment according to Macdonald Criteria.
    End point type
    Secondary
    End point timeframe
    From first treatment date to Complete or Partial Response, up to 4 weeks.
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    25
    Units: percent
        number (confidence interval 95%)
    0 (0.0 to 9.3)
    No statistical analyses for this end point

    Secondary: ORR at Week 8 Colorectal Cohort

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    End point title
    		 ORR at Week 8 Colorectal Cohort [10]
    End point description
    First Objective response is defined as complete responses (CR) or partial responses (PR) at 8 weeks or 9 weeks of study therapy, which corresponds to the first scheduled tumor assessment; taking better results from RECIST or PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date to Complete or Partial Response, up to 8 weeks or 9 weeks.
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib Neratinib + Trastuzumab
    Number of subjects analysed
    12
    19
    Units: percent
        number (confidence interval 95%)
    0.0 (0.0 to 26.5)
    5.3 (0.1 to 26.0)
    No statistical analyses for this end point

    Secondary: ORR at Week 8 Bladder/Urinary tract Cohort

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    End point title
    		 ORR at Week 8 Bladder/Urinary tract Cohort [11]
    End point description
    First Objective response is defined as complete responses (CR) or partial responses (PR) at 8 weeks or 9 weeks of study therapy, which corresponds to the first scheduled tumor assessment; taking better results from RECIST or PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib Neratinib + Paclitaxel
    Number of subjects analysed
    16
    22
    Units: percent
        number (confidence interval 95%)
    0.0 (0.0 to 20.6)
    13.6 (2.9 to 34.9)
    No statistical analyses for this end point

    Secondary: ORR at Week 8 Salivary gland Cohort

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    End point title
    		 ORR at Week 8 Salivary gland Cohort [12]
    End point description
    First Objective response is defined as complete responses (CR) or partial responses (PR) at 8 weeks or 9 weeks of study therapy, which corresponds to the first scheduled tumor assessment; taking better results from RECIST or PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date to Complete or Partial Response, up to 8 weeks.
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    11
    Units: percent
        number (confidence interval 95%)
    36.4 (10.9 to 69.2)
    No statistical analyses for this end point

    Secondary: ORR at Week 8 Ovarian Cohort

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    End point title
    		 ORR at Week 8 Ovarian Cohort [13]
    End point description
    First Objective response is defined as complete responses (CR) or partial responses (PR) at 8 weeks or 9 weeks of study therapy, which corresponds to the first scheduled tumor assessment; taking better results from RECIST or PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date to Complete or Partial Response, up to 8 weeks.
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    10
    Units: percent
        number (confidence interval 95%)
    0 (0.0 to 30.8)
    No statistical analyses for this end point

    Secondary: ORR at Week 8 Fibrolamellar carcinoma (FLC) Cohort

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    End point title
    		 ORR at Week 8 Fibrolamellar carcinoma (FLC) Cohort [14]
    End point description
    First Objective response is defined as complete responses (CR) or partial responses (PR) at 8 weeks or 9 weeks of study therapy, which corresponds to the first scheduled tumor assessment; taking better results from RECIST or PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date to Complete or Partial Response, up to 8 weeks.
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    15
    Units: percent
        number (confidence interval 95%)
    0 (0.0 to 21.8)
    No statistical analyses for this end point

    Secondary: ORR at Week 8 Gastroesophageal Cohort

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    End point title
    		 ORR at Week 8 Gastroesophageal Cohort [15]
    End point description
    First Objective response is defined as complete responses (CR) or partial responses (PR) at 8 weeks or 9 weeks of study therapy, which corresponds to the first scheduled tumor assessment; taking better results from RECIST or PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date to Complete or Partial Response, up to 8 weeks.
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    7
    Units: percent
        number (confidence interval 95%)
    0 (0.0 to 41.0)
    No statistical analyses for this end point

    Secondary: ORR at Week 8 Endometrial Cohort

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    End point title
    		 ORR at Week 8 Endometrial Cohort [16]
    End point description
    First Objective response is defined as complete responses (CR) or partial responses (PR) at 8 weeks or 9 weeks of study therapy, which corresponds to the first scheduled tumor assessment; taking better results from RECIST or PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date to Complete or Partial Response, up to 8 weeks.
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    7
    Units: percent
        number (confidence interval 95%)
    0 (0.0 to 41.0)
    No statistical analyses for this end point

    Secondary: ORR at Week 8 HER3 NOS Cohort

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    End point title
    		 ORR at Week 8 HER3 NOS Cohort [17]
    End point description
    First Objective response is defined as complete responses (CR) or partial responses (PR) at 8 weeks or 9 weeks of study therapy, which corresponds to the first scheduled tumor assessment; taking better results from RECIST or PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date to Complete or Partial Response, up to 8 weeks.
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    16
    Units: percent
        number (confidence interval 95%)
    0.0 (0.0 to 20.6)
    No statistical analyses for this end point

    Secondary: ORR at Week 8 HER4 NOS Cohort

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    End point title
    		 ORR at Week 8 HER4 NOS Cohort [18]
    End point description
    First Objective response is defined as complete responses (CR) or partial responses (PR) at 8 weeks or 9 weeks of study therapy, which corresponds to the first scheduled tumor assessment; taking better results from RECIST or PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date to Complete or Partial Response, up to 8 weeks.
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    3
    Units: percent
        number (confidence interval 95%)
    0.0 (0.0 to 70.8)
    No statistical analyses for this end point

    Secondary: Confirmed Objective Response Rate (ORR) (Breast Cancer With Prior CDK46i Cohort)

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    End point title
    		 Confirmed Objective Response Rate (ORR) (Breast Cancer With Prior CDK46i Cohort) [19]
    End point description
    Percentage of participants who are confirmed by Investigator assessment to have achieved complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
    End point type
    Secondary
    End point timeframe
    From enrollment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib + Fulvestrant + Trastuzumab Fulvestrant Fulvestrant + Trastuzumab
    Number of subjects analysed
    59
    7
    7
    Units: percent
        number (confidence interval 95%)
    39.0 (26.5 to 52.6)
    0 (0 to 41.0)
    0 (0 to 41.0)
    No statistical analyses for this end point

    Secondary: ORR at Week 8 HER2 NOS Cohort

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    End point title
    		 ORR at Week 8 HER2 NOS Cohort [20]
    End point description
    First Objective response is defined as complete responses (CR) or partial responses (PR) at 8 weeks or 9 weeks of study therapy, which corresponds to the first scheduled tumor assessment; taking better results from RECIST or PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date to Complete or Partial Response, up to 8 weeks.
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    42
    Units: percent
        number (confidence interval 95%)
    4.8 (0.6 to 16.2)
    No statistical analyses for this end point

    Secondary: Confirmed ORR (Other Breast Cancer Cohorts)

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    End point title
    		 Confirmed ORR (Other Breast Cancer Cohorts) [21]
    End point description
    Overall objective response is defined as either a complete or partial response. A complete or partial response that is confirmed no less than 4-weeks after the criteria for response are initially met; taking results from RECIST over PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib Neratinib + Fulvestrant Neratinib + Trastuzumab Neratinib + Fulvestrant + Trastuzumab
    Number of subjects analysed
    36
    45
    21
    31
    Units: percent
        number (confidence interval 95%)
    25.0 (12.1 to 42.2)
    28.9 (16.4 to 44.3)
    33.3 (14.6 to 57.0)
    35.5 (19.2 to 54.6)
    No statistical analyses for this end point

    Secondary: Confirmed ORR Lung HER2-mutant Cohort

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    End point title
    		 Confirmed ORR Lung HER2-mutant Cohort [22]
    End point description
    Overall objective response is defined as either a complete or partial response. A complete or partial response that is confirmed no less than 4-weeks after the criteria for response are initially met; taking results from RECIST over PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib Neratinib + Trastuzumab
    Number of subjects analysed
    26
    52
    Units: percent
        number (confidence interval 95%)
    3.8 (0.1 to 19.6)
    9.6 (3.2 to 21.0)
    No statistical analyses for this end point

    Secondary: Confirmed ORR Lung EGFR-mutant Cohort

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    End point title
    		 Confirmed ORR Lung EGFR-mutant Cohort [23]
    End point description
    Overall objective response is defined as either a complete or partial response. A complete or partial response that is confirmed no less than 4-weeks after the criteria for response are initially met; taking results from RECIST over PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    31
    Units: percent
        number (confidence interval 95%)
    32.3 (16.7 to 51.4)
    No statistical analyses for this end point

    Secondary: Confirmed ORR Biliary tract Cohort

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    End point title
    		 Confirmed ORR Biliary tract Cohort [24]
    End point description
    Overall objective response is defined as either a complete or partial response. A complete or partial response that is confirmed no less than 4-weeks after the criteria for response are initially met; taking results from RECIST over PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    25
    Units: percent
        number (confidence interval 95%)
    16.0 (4.5 to 36.1)
    No statistical analyses for this end point

    Secondary: Confirmed ORR Bladder/Urinary tract Cohort

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    End point title
    		 Confirmed ORR Bladder/Urinary tract Cohort [25]
    End point description
    Overall objective response is defined as either a complete or partial response. A complete or partial response that is confirmed no less than 4-weeks after the criteria for response are initially met; taking results from RECIST over PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib Neratinib + Paclitaxel
    Number of subjects analysed
    16
    22
    Units: percent
        number (confidence interval 95%)
    0 (0 to 20.6)
    13.6 (2.9 to 34.9)
    No statistical analyses for this end point

    Secondary: Confirmed ORR Brain Cohort

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    End point title
    		 Confirmed ORR Brain Cohort [26]
    End point description
    Overall objective response is defined as either a complete or partial response. A complete or partial response that is confirmed no less than 4-weeks after the criteria for response are initially met. Brain tumor assessment is based on Macdonald Criteria.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    38
    Units: percent
        number (confidence interval 95%)
    2.6 (0.1 to 13.8)
    No statistical analyses for this end point

    Secondary: Confirmed ORR Colorectal Cohort

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    End point title
    		 Confirmed ORR Colorectal Cohort [27]
    End point description
    Overall objective response is defined as either a complete or partial response. A complete or partial response that is confirmed no less than 4-weeks after the criteria for response are initially met; taking results from RECIST over PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib Neratinib + Trastuzumab
    Number of subjects analysed
    12
    19
    Units: percent
        number (confidence interval 95%)
    0 (0 to 26.5)
    5.3 (0.1 to 26.0)
    No statistical analyses for this end point

    Secondary: Confirmed ORR Ovarian Cohort

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    End point title
    		 Confirmed ORR Ovarian Cohort [28]
    End point description
    Overall objective response is defined as either a complete or partial response. A complete or partial response that is confirmed no less than 4-weeks after the criteria for response are initially met; taking results from RECIST over PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    10
    Units: percent
        number (confidence interval 95%)
    0 (0 to 30.8)
    No statistical analyses for this end point

    Secondary: Confirmed ORR Fibrolamellar carcinoma (FLC) Cohort

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    End point title
    		 Confirmed ORR Fibrolamellar carcinoma (FLC) Cohort [29]
    End point description
    Overall objective response is defined as either a complete or partial response. A complete or partial response that is confirmed no less than 4-weeks after the criteria for response are initially met; taking results from RECIST over PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    15
    Units: percent
        number (confidence interval 95%)
    0 (0 to 21.8)
    No statistical analyses for this end point

    Secondary: Confirmed ORR Gastroesophageal Cohort

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    End point title
    		 Confirmed ORR Gastroesophageal Cohort [30]
    End point description
    Overall objective response is defined as either a complete or partial response. A complete or partial response that is confirmed no less than 4-weeks after the criteria for response are initially met; taking results from RECIST over PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    7
    Units: percent
        number (confidence interval 95%)
    0 (0 to 41.0)
    No statistical analyses for this end point

    Secondary: Confirmed ORR Salivary gland Cohort

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    End point title
    		 Confirmed ORR Salivary gland Cohort [31]
    End point description
    Overall objective response is defined as either a complete or partial response. A complete or partial response that is confirmed no less than 4-weeks after the criteria for response are initially met; taking results from RECIST over PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [31] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    11
    Units: percent
        number (confidence interval 95%)
    9.1 (0.2 to 41.3)
    No statistical analyses for this end point

    Secondary: Confirmed ORR Endometrial Cohort

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    End point title
    		 Confirmed ORR Endometrial Cohort [32]
    End point description
    Overall objective response is defined as either a complete or partial response. A complete or partial response that is confirmed no less than 4-weeks after the criteria for response are initially met; taking results from RECIST over PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    7
    Units: percent
        number (confidence interval 95%)
    0 (0 to 41.0)
    No statistical analyses for this end point

    Secondary: Confirmed ORR HER2 NOS Cohort

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    End point title
    		 Confirmed ORR HER2 NOS Cohort [33]
    End point description
    Overall objective response is defined as either a complete or partial response. A complete or partial response that is confirmed no less than 4-weeks after the criteria for response are initially met; taking results from RECIST over PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    42
    Units: percent
        number (confidence interval 95%)
    2.4 (0.1 to 12.6)
    No statistical analyses for this end point

    Secondary: Confirmed ORR HER3 NOS Cohort

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    End point title
    		 Confirmed ORR HER3 NOS Cohort [34]
    End point description
    Overall objective response is defined as either a complete or partial response. A complete or partial response that is confirmed no less than 4-weeks after the criteria for response are initially met; taking results from RECIST over PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    16
    Units: percent
        number (confidence interval 95%)
    0 (0 to 20.6)
    No statistical analyses for this end point

    Secondary: Confirmed ORR HER4 NOS Cohort

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    End point title
    		 Confirmed ORR HER4 NOS Cohort [35]
    End point description
    Overall objective response is defined as either a complete or partial response. A complete or partial response that is confirmed no less than 4-weeks after the criteria for response are initially met; taking results from RECIST over PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [35] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    3
    Units: percent
        number (confidence interval 95%)
    0 (0 to 70.8)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) Central Assessment (Breast Cancer With Prior CDK46i Cohort)

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    End point title
    		 Duration of Response (DOR) Central Assessment (Breast Cancer With Prior CDK46i Cohort) [36]
    End point description
    Duration of response was defined as the time (in months) from the date of the first documented objective response of CR or PR, confirmed at least 4 weeks later to the date of the first documented PD or date of death, whichever occurred first. PD was assessed as per RECIST version 1.1.
    End point type
    Secondary
    End point timeframe
    From enrollment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib + Fulvestrant + Trastuzumab Fulvestrant Fulvestrant + Trastuzumab
    Number of subjects analysed
    24
    0 [37]
    1
    Units: month
        median (full range (min-max))
    13.14 (2.3 to 23.7)
    ( to )
    1.4 (1.4 to 1.4)
    Notes
    [37] - There were no responders in this arm.
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) Investigator Assessment (Breast Cancer With Prior CDK46i Cohort)

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    End point title
    		 Duration of Response (DOR) Investigator Assessment (Breast Cancer With Prior CDK46i Cohort) [38]
    End point description
    Duration of response was defined as the time (in months) from the date of the first documented objective response of CR or PR, confirmed at least 4 weeks later to the date of the first documented PD or date of death, whichever occurred first. Disease progression was assessed as per RECIST version 1.1.
    End point type
    Secondary
    End point timeframe
    From enrollment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib + Fulvestrant + Trastuzumab Fulvestrant Fulvestrant + Trastuzumab
    Number of subjects analysed
    23
    0 [39]
    0 [40]
    Units: month
        median (full range (min-max))
    14.4 (2.1 to 31.4)
    ( to )
    ( to )
    Notes
    [39] - There were no responders in this arm.
    [40] - There were no responders in this arm.
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) Cervical Cohort

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    End point title
    		 Duration of Response (DOR) Cervical Cohort [41]
    End point description
    Duration of response was defined as the time (in months) from the date of the first documented objective response of CR or PR, confirmed at least 4 weeks later to the date of the first documented PD or date of death, whichever occurred first. Disease progression assessed by RECIST criteria, or for PERCIST for those participants who did not have RECIST performed.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [41] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    4
    Units: month
        median (full range (min-max))
    7.62 (5.6 to 12.3)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) (Other Breast Cancer Cohorts)

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    End point title
    		 Duration of Response (DOR) (Other Breast Cancer Cohorts) [42]
    End point description
    Duration of response was defined as the time (in months) from the date of the first documented objective response of CR or PR, confirmed at least 4 weeks later to the date of the first documented PD or date of death, whichever occurred first. Disease progression assessed by RECIST criteria, or for PERCIST for those participants who did not have RECIST performed.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [42] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib Neratinib + Fulvestrant Neratinib + Trastuzumab Neratinib + Fulvestrant + Trastuzumab
    Number of subjects analysed
    9
    13
    7
    11
    Units: month
        median (full range (min-max))
    4.76 (1.9 to 16.6)
    9.23 (3.9 to 55.0)
    7.28 (1.9 to 14.5)
    9.17 (4.0 to 55.9)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) Lung HER2-mutant Cohort

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    End point title
    		 Duration of Response (DOR) Lung HER2-mutant Cohort [43]
    End point description
    Duration of response was defined as the time (in months) from the date of the first documented objective response of CR or PR, confirmed at least 4 weeks later to the date of the first documented PD or date of death, whichever occurred first. Disease progression assessed by RECIST criteria, or for PERCIST for those participants who did not have RECIST performed.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [43] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib Neratinib + Trastuzumab
    Number of subjects analysed
    1
    5
    Units: month
        median (full range (min-max))
    9.23 (9.2 to 9.23)
    6.80 (4.2 to 47.5)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) Lung EGFR-mutant Cohort

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    End point title
    		 Duration of Response (DOR) Lung EGFR-mutant Cohort [44]
    End point description
    Duration of response was defined as the time (in months) from the date of the first documented objective response of CR or PR, confirmed at least 4 weeks later to the date of the first documented PD or date of death, whichever occurred first. Disease progression assessed by RECIST criteria, or for PERCIST for those participants who did not have RECIST performed.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [44] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    10
    Units: month
        median (full range (min-max))
    22.24 (4.0 to 30.0)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) Biliary tract Cohort

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    End point title
    		 Duration of Response (DOR) Biliary tract Cohort [45]
    End point description
    Duration of response was defined as the time (in months) from the date of the first documented objective response of CR or PR, confirmed at least 4 weeks later to the date of the first documented PD or date of death, whichever occurred first. Disease progression assessed by RECIST criteria, or for PERCIST for those participants who did not have RECIST performed.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [45] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    4
    Units: month
        median (full range (min-max))
    3.75 (3.0 to 4.7)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) Bladder/Urinary tract Cohort

    		 Close Top of page
    End point title
    		 Duration of Response (DOR) Bladder/Urinary tract Cohort [46]
    End point description
    Duration of response was defined as the time (in months) from the date of the first documented objective response of CR or PR, confirmed at least 4 weeks later to the date of the first documented PD or date of death, whichever occurred first. Disease progression assessed by RECIST criteria, or for PERCIST for those participants who did not have RECIST performed.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [46] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib Neratinib + Paclitaxel
    Number of subjects analysed
    0 [47]
    3
    Units: month
        median (full range (min-max))
    ( to )
    7.20 (2.8 to 7.6)
    Notes
    [47] - There were no responders in this arm.
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) Brain Cohort

    		 Close Top of page
    End point title
    		 Duration of Response (DOR) Brain Cohort [48]
    End point description
    Duration of response was defined as the time (in months) from the date of the first documented objective response of CR or PR, confirmed at least 4 weeks later to the date of the first documented PD or date of death, whichever occurred first. Disease progression assessed by RECIST criteria, or for PERCIST for those participants who did not have RECIST performed.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [48] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    1
    Units: month
        median (full range (min-max))
    19.94 (19.9 to 19.94)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) Colorectal Cohort

    		 Close Top of page
    End point title
    		 Duration of Response (DOR) Colorectal Cohort [49]
    End point description
    Duration of response was defined as the time (in months) from the date of the first documented objective response of CR or PR, confirmed at least 4 weeks later to the date of the first documented PD or date of death, whichever occurred first. Disease progression assessed by RECIST criteria, or for PERCIST for those participants who did not have RECIST performed.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [49] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib Neratinib + Trastuzumab
    Number of subjects analysed
    0 [50]
    1
    Units: month
        median (full range (min-max))
    ( to )
    12.19 (12.19 to 12.2)
    Notes
    [50] - There were no responders in this arm.
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) Salivary gland Cohort

    		 Close Top of page
    End point title
    		 Duration of Response (DOR) Salivary gland Cohort [51]
    End point description
    Duration of response was defined as the time (in months) from the date of the first documented objective response of CR or PR, confirmed at least 4 weeks later to the date of the first documented PD or date of death, whichever occurred first. Disease progression assessed by RECIST criteria, or for PERCIST for those participants who did not have RECIST performed.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [51] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    1
    Units: month
        median (full range (min-max))
    5.4 (5.4 to 5.4)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) HER2 NOS Cohort

    		 Close Top of page
    End point title
    		 Duration of Response (DOR) HER2 NOS Cohort [52]
    End point description
    Duration of response was defined as the time (in months) from the date of the first documented objective response of CR or PR, confirmed at least 4 weeks later to the date of the first documented PD or date of death, whichever occurred first. Disease progression assessed by RECIST criteria, or for PERCIST for those participants who did not have RECIST performed.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [52] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    1
    Units: month
        median (full range (min-max))
    3.71 (3.7 to 3.71)
    No statistical analyses for this end point

    Secondary: Clinical Benefit Rate (CBR) Central Assessment (Breast Cancer With Prior CDK46i Cohort)

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    End point title
    		 Clinical Benefit Rate (CBR) Central Assessment (Breast Cancer With Prior CDK46i Cohort) [53]
    End point description
    The Clinical Benefit Rate (CBR) is defined as the percent of patients who achieve overall tumor response (CR or PR) or SD for at least 16 weeks (at least 24 weeks for the breast cancer cohorts). Tumor assessment based on RECIST version 1.1.
    End point type
    Secondary
    End point timeframe
    From enrollment until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [53] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib + Fulvestrant + Trastuzumab Fulvestrant Fulvestrant + Trastuzumab
    Number of subjects analysed
    59
    7
    7
    Units: month
        number (confidence interval 95%)
    49.2 (35.9 to 62.5)
    0 (0 to 41.0)
    14.3 (0.4 to 57.9)
    No statistical analyses for this end point

    Secondary: Clinical Benefit Rate (CBR) Investigator Assessment (Breast Cancer With Prior CDK46i Cohort)

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    End point title
    		 Clinical Benefit Rate (CBR) Investigator Assessment (Breast Cancer With Prior CDK46i Cohort) [54]
    End point description
    The Clinical Benefit Rate (CBR) is defined as the percent of patients who achieve overall tumor response (CR or PR) or SD for at least 16 weeks (at least 24 weeks for the breast cancer cohorts). Tumor assessment based on RECIST version 1.1.
    End point type
    Secondary
    End point timeframe
    From enrollment until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [54] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib + Fulvestrant + Trastuzumab Fulvestrant Fulvestrant + Trastuzumab
    Number of subjects analysed
    59
    7
    7
    Units: month
        number (confidence interval 95%)
    54.2 (40.8 to 67.3)
    0 (0 to 41.0)
    0 (0 to 41.0)
    No statistical analyses for this end point

    Secondary: Clinical Benefit Rate (CBR) Cervical Cohort

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    End point title
    		 Clinical Benefit Rate (CBR) Cervical Cohort [55]
    End point description
    The Clinical Benefit Rate (CBR) is defined as the percent of patients who achieve overall tumor response (CR or PR) or SD for at least 16 weeks (at least 24 weeks for the breast cancer cohorts). Tumor assessment taking results from RECIST over PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [55] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    22
    Units: month
        number (confidence interval 95%)
    45.5 (24.4 to 67.8)
    No statistical analyses for this end point

    Secondary: Clinical Benefit Rate (CBR) (Other Breast Cancer Cohorts)

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    End point title
    		 Clinical Benefit Rate (CBR) (Other Breast Cancer Cohorts) [56]
    End point description
    The Clinical Benefit Rate (CBR) is defined as the percent of patients who achieve overall tumor response (CR or PR) or SD for at least 16 weeks (at least 24 weeks for the breast cancer cohorts). Tumor assessment taking results from RECIST over PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [56] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib Neratinib + Fulvestrant Neratinib + Trastuzumab Neratinib + Fulvestrant + Trastuzumab
    Number of subjects analysed
    36
    45
    21
    31
    Units: month
        number (confidence interval 95%)
    33.3 (18.6 to 51.0)
    42.2 (27.7 to 57.8)
    42.9 (21.8 to 66.0)
    54.8 (36.0 to 72.7)
    No statistical analyses for this end point

    Secondary: Clinical Benefit Rate (CBR) Lung HER2-mutant Cohort

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    End point title
    		 Clinical Benefit Rate (CBR) Lung HER2-mutant Cohort [57]
    End point description
    The Clinical Benefit Rate (CBR) is defined as the percent of patients who achieve overall tumor response (CR or PR) or SD for at least 16 weeks (at least 24 weeks for the breast cancer cohorts). Tumor assessment taking results from RECIST over PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [57] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib Neratinib + Trastuzumab
    Number of subjects analysed
    26
    52
    Units: month
        number (confidence interval 95%)
    38.5 (20.2 to 59.4)
    30.8 (18.7 to 45.1)
    No statistical analyses for this end point

    Secondary: Clinical Benefit Rate (CBR) Lung EGFR-mutant Cohort

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    End point title
    		 Clinical Benefit Rate (CBR) Lung EGFR-mutant Cohort [58]
    End point description
    The Clinical Benefit Rate (CBR) is defined as the percent of patients who achieve overall tumor response (CR or PR) or SD for at least 16 weeks (at least 24 weeks for the breast cancer cohorts). Tumor assessment taking results from RECIST over PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [58] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    31
    Units: month
        number (confidence interval 95%)
    48.4 (30.2 to 66.9)
    No statistical analyses for this end point

    Secondary: Clinical Benefit Rate (CBR) Biliary tract Cohort

    		 Close Top of page
    End point title
    		 Clinical Benefit Rate (CBR) Biliary tract Cohort [59]
    End point description
    The Clinical Benefit Rate (CBR) is defined as the percent of patients who achieve overall tumor response (CR or PR) or SD for at least 16 weeks (at least 24 weeks for the breast cancer cohorts). Tumor assessment taking results from RECIST over PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [59] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    25
    Units: month
        number (confidence interval 95%)
    24.0 (9.4 to 45.1)
    No statistical analyses for this end point

    Secondary: Clinical Benefit Rate (CBR) Bladder/Urinary tract Cohort

    		 Close Top of page
    End point title
    		 Clinical Benefit Rate (CBR) Bladder/Urinary tract Cohort [60]
    End point description
    The Clinical Benefit Rate (CBR) is defined as the percent of patients who achieve overall tumor response (CR or PR) or SD for at least 16 weeks (at least 24 weeks for the breast cancer cohorts). Tumor assessment taking results from RECIST over PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [60] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib Neratinib + Paclitaxel
    Number of subjects analysed
    16
    22
    Units: month
        number (confidence interval 95%)
    18.8 (4.0 to 45.6)
    31.8 (13.9 to 54.9)
    No statistical analyses for this end point

    Secondary: Clinical Benefit Rate (CBR) Brain Cohort

    		 Close Top of page
    End point title
    		 Clinical Benefit Rate (CBR) Brain Cohort [61]
    End point description
    The Clinical Benefit Rate (CBR) is defined as the percent of patients who achieve overall tumor response (CR or PR) or SD for at least 16 weeks (at least 24 weeks for the breast cancer cohorts). Tumor was assessed per Macdonald Criteria.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [61] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    38
    Units: month
        number (confidence interval 95%)
    10.5 (2.9 to 24.8)
    No statistical analyses for this end point

    Secondary: Clinical Benefit Rate (CBR) Colorectal Cohort

    		 Close Top of page
    End point title
    		 Clinical Benefit Rate (CBR) Colorectal Cohort [62]
    End point description
    The Clinical Benefit Rate (CBR) is defined as the percent of patients who achieve overall tumor response (CR or PR) or SD for at least 16 weeks (at least 24 weeks for the breast cancer cohorts). Tumor assessment taking results from RECIST over PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [62] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib Neratinib + Trastuzumab
    Number of subjects analysed
    12
    19
    Units: month
        number (confidence interval 95%)
    8.3 (0.2 to 38.5)
    21.1 (6.1 to 45.6)
    No statistical analyses for this end point

    Secondary: Clinical Benefit Rate (CBR) Ovarian Cohort

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    End point title
    		 Clinical Benefit Rate (CBR) Ovarian Cohort [63]
    End point description
    The Clinical Benefit Rate (CBR) is defined as the percent of patients who achieve overall tumor response (CR or PR) or SD for at least 16 weeks (at least 24 weeks for the breast cancer cohorts). Tumor assessment taking results from RECIST over PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [63] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    10
    Units: month
        number (confidence interval 95%)
    20.0 (2.5 to 55.6)
    No statistical analyses for this end point

    Secondary: Clinical Benefit Rate (CBR) Fibrolamellar carcinoma (FLC) Cohort

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    End point title
    		 Clinical Benefit Rate (CBR) Fibrolamellar carcinoma (FLC) Cohort [64]
    End point description
    The Clinical Benefit Rate (CBR) is defined as the percent of patients who achieve overall tumor response (CR or PR) or SD for at least 16 weeks (at least 24 weeks for the breast cancer cohorts). Tumor assessment taking results from RECIST over PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [64] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    15
    Units: month
        number (confidence interval 95%)
    13.3 (1.7 to 40.5)
    No statistical analyses for this end point

    Secondary: Clinical Benefit Rate (CBR) Gastroesophageal Cohort

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    End point title
    		 Clinical Benefit Rate (CBR) Gastroesophageal Cohort [65]
    End point description
    The Clinical Benefit Rate (CBR) is defined as the percent of patients who achieve overall tumor response (CR or PR) or SD for at least 16 weeks (at least 24 weeks for the breast cancer cohorts). Tumor assessment taking results from RECIST over PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [65] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    7
    Units: month
        number (confidence interval 95%)
    0 (0 to 41.0)
    No statistical analyses for this end point

    Secondary: Clinical Benefit Rate (CBR) Salivary gland Cohort

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    End point title
    		 Clinical Benefit Rate (CBR) Salivary gland Cohort [66]
    End point description
    The Clinical Benefit Rate (CBR) is defined as the percent of patients who achieve overall tumor response (CR or PR) or SD for at least 16 weeks (at least 24 weeks for the breast cancer cohorts). Tumor assessment taking results from RECIST over PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [66] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    11
    Units: month
        number (confidence interval 95%)
    54.5 (23.4 to 83.3)
    No statistical analyses for this end point

    Secondary: Clinical Benefit Rate (CBR) Endometrial Cohort

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    End point title
    		 Clinical Benefit Rate (CBR) Endometrial Cohort [67]
    End point description
    The Clinical Benefit Rate (CBR) is defined as the percent of patients who achieve overall tumor response (CR or PR) or SD for at least 16 weeks (at least 24 weeks for the breast cancer cohorts). Tumor assessment taking results from RECIST over PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [67] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    7
    Units: month
        number (confidence interval 95%)
    14.3 (0.4 to 57.9)
    No statistical analyses for this end point

    Secondary: Clinical Benefit Rate (CBR) HER2 NOS Cohort

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    End point title
    		 Clinical Benefit Rate (CBR) HER2 NOS Cohort [68]
    End point description
    The Clinical Benefit Rate (CBR) is defined as the percent of patients who achieve overall tumor response (CR or PR) or SD for at least 16 weeks (at least 24 weeks for the breast cancer cohorts). Tumor assessment taking results from RECIST over PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [68] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    42
    Units: month
        number (confidence interval 95%)
    19.0 (8.6 to 34.1)
    No statistical analyses for this end point

    Secondary: Clinical Benefit Rate (CBR) HER3 NOS Cohort

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    End point title
    		 Clinical Benefit Rate (CBR) HER3 NOS Cohort [69]
    End point description
    The Clinical Benefit Rate (CBR) is defined as the percent of patients who achieve overall tumor response (CR or PR) or SD for at least 16 weeks (at least 24 weeks for the breast cancer cohorts). Tumor assessment taking results from RECIST over PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [69] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    16
    Units: month
        number (confidence interval 95%)
    6.3 (0.2 to 30.2)
    No statistical analyses for this end point

    Secondary: Clinical Benefit Rate (CBR) HER4 NOS Cohort

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    End point title
    		 Clinical Benefit Rate (CBR) HER4 NOS Cohort [70]
    End point description
    The Clinical Benefit Rate (CBR) is defined as the percent of patients who achieve overall tumor response (CR or PR) or SD for at least 16 weeks (at least 24 weeks for the breast cancer cohorts). Tumor assessment taking results from RECIST over PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [70] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    3
    Units: month
        number (confidence interval 95%)
    0 (0 to 70.8)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS) Central Assessment (Breast Cancer With Prior CDK46i Cohort)

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    End point title
    		 Progression-Free Survival (PFS) Central Assessment (Breast Cancer With Prior CDK46i Cohort) [71]
    End point description
    PFS was defined as the time (in months) from enrollment to the earlier date of the documented PD or death due to any cause. PD was assessed based on RECIST version 1.1.
    End point type
    Secondary
    End point timeframe
    From enrollment until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [71] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib + Fulvestrant + Trastuzumab Fulvestrant Fulvestrant + Trastuzumab
    Number of subjects analysed
    59
    7
    7
    Units: month
        number (confidence interval 95%)
    8.11 (6.01 to 16.39)
    2.27 (1.61 to 2.7)
    4.11 (1.87 to 4.11)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS) Investigator Assessment (Breast Cancer With Prior CDK46i Cohort)

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    End point title
    		 Progression-Free Survival (PFS) Investigator Assessment (Breast Cancer With Prior CDK46i Cohort) [72]
    End point description
    PFS was defined as the time (in months) from enrollment to the earlier date of the documented PD or death due to any cause. PD was assessed based on RECIST version 1.1.
    End point type
    Secondary
    End point timeframe
    From enrollment until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [72] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib + Fulvestrant + Trastuzumab Fulvestrant Fulvestrant + Trastuzumab
    Number of subjects analysed
    59
    7
    7
    Units: month
        number (confidence interval 95%)
    8.3 (6.0 to 12.7)
    4.1 (1.6 to 4.1)
    3.9 (1.9 to 4.1)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS) Cervical Cohort

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    End point title
    		 Progression-Free Survival (PFS) Cervical Cohort [73]
    End point description
    PFS was defined as the time (in months) from the first treatment date to the earlier date of the documented PD or death due to any cause. PD was assessed taking results from RECIST over PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [73] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    22
    Units: month
        number (confidence interval 95%)
    5.09 (1.74 to 7.23)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS) (Other Breast Cancer Cohorts)

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    End point title
    		 Progression-Free Survival (PFS) (Other Breast Cancer Cohorts) [74]
    End point description
    PFS was defined as the time (in months) from the first treatment date to the earlier date of the documented PD or death due to any cause. PD was assessed taking results from RECIST over PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [74] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib Neratinib + Fulvestrant Neratinib + Trastuzumab Neratinib + Fulvestrant + Trastuzumab
    Number of subjects analysed
    36
    45
    21
    31
    Units: month
        number (confidence interval 95%)
    3.48 (1.94 to 3.88)
    5.36 (3.71 to 9.23)
    6.24 (2.10 to 10.25)
    8.21 (4.07 to 11.01)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS) Lung HER2-mutant Cohort

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    End point title
    		 Progression-Free Survival (PFS) Lung HER2-mutant Cohort [75]
    End point description
    PFS was defined as the time (in months) from the first treatment date to the earlier date of the documented PD or death due to any cause. PD was assessed taking results from RECIST over PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [75] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib Neratinib + Trastuzumab
    Number of subjects analysed
    26
    52
    Units: month
        number (confidence interval 95%)
    4.17 (1.87 to 8.80)
    4.01 (2.10 to 4.57)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS) Lung EGFR-mutant Cohort

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    End point title
    		 Progression-Free Survival (PFS) Lung EGFR-mutant Cohort [76]
    End point description
    PFS was defined as the time (in months) from the first treatment date to the earlier date of the documented PD or death due to any cause. PD was assessed taking results from RECIST over PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [76] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    31
    Units: month
        number (confidence interval 95%)
    5.75 (2.27 to 9.23)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS) Biliary tract Cohort

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    End point title
    		 Progression-Free Survival (PFS) Biliary tract Cohort [77]
    End point description
    PFS was defined as the time (in months) from the first treatment date to the earlier date of the documented PD or death due to any cause. PD was assessed taking results from RECIST over PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [77] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    25
    Units: month
        number (confidence interval 95%)
    2.76 (1.05 to 3.75)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS) Bladder/Urinary tract Cohort

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    End point title
    		 Progression-Free Survival (PFS) Bladder/Urinary tract Cohort [78]
    End point description
    PFS was defined as the time (in months) from the first treatment date to the earlier date of the documented PD or death due to any cause. PD was assessed taking results from RECIST over PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [78] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib Neratinib + Paclitaxel
    Number of subjects analysed
    16
    22
    Units: month
        number (confidence interval 95%)
    1.77 (1.68 to 3.55)
    3.75 (1.87 to 5.62)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS) Brain Cohort

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    End point title
    		 Progression-Free Survival (PFS) Brain Cohort [79]
    End point description
    PFS was defined as the time (in months) from the first treatment date to the earlier date of the documented PD or death due to any cause. PD was assessed per Macdonald Criteria.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [79] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    38
    Units: month
        number (confidence interval 95%)
    1.81 (1.02 to 2.69)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS) Colorectal Cohort

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    End point title
    		 Progression-Free Survival (PFS) Colorectal Cohort [80]
    End point description
    PFS was defined as the time (in months) from the first treatment date to the earlier date of the documented PD or death due to any cause. PD was assessed taking results from RECIST over PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [80] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib Neratinib + Trastuzumab
    Number of subjects analysed
    12
    19
    Units: month
        number (confidence interval 95%)
    1.71 (1.45 to 1.87)
    2.04 (1.81 to 3.48)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS) Ovarian Cohort

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    End point title
    		 Progression-Free Survival (PFS) Ovarian Cohort [81]
    End point description
    PFS was defined as the time (in months) from the first treatment date to the earlier date of the documented PD or death due to any cause. PD was assessed taking results from RECIST over PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [81] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    10
    Units: month
        number (confidence interval 95%)
    2.37 (1.48 to 7.36)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS) Fibrolamellar carcinoma (FLC) Cohort

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    End point title
    		 Progression-Free Survival (PFS) Fibrolamellar carcinoma (FLC) Cohort [82]
    End point description
    PFS was defined as the time (in months) from the first treatment date to the earlier date of the documented PD or death due to any cause. PD was assessed taking results from RECIST over PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [82] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    15
    Units: month
        number (confidence interval 95%)
    3.58 (1.84 to 3.71)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS) Gastroesophageal Cohort

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    End point title
    		 Progression-Free Survival (PFS) Gastroesophageal Cohort [83]
    End point description
    PFS was defined as the time (in months) from the first treatment date to the earlier date of the documented PD or death due to any cause. PD was assessed taking results from RECIST over PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [83] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    7
    Units: month
        number (confidence interval 95%)
    1.74 (0.82 to 2.23)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS) Salivary gland Cohort

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    End point title
    		 Progression-Free Survival (PFS) Salivary gland Cohort [84]
    End point description
    PFS was defined as the time (in months) from the first treatment date to the earlier date of the documented PD or death due to any cause. PD was assessed taking results from RECIST over PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [84] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    11
    Units: month
        number (confidence interval 95%)
    5.32 (1.81 to 9.26)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS) Endometrial Cohort

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    End point title
    		 Progression-Free Survival (PFS) Endometrial Cohort [85]
    End point description
    PFS was defined as the time (in months) from the first treatment date to the earlier date of the documented PD or death due to any cause. PD was assessed taking results from RECIST over PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [85] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    7
    Units: month
        number (confidence interval 95%)
    1.87 (1.61 to 6.87)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS) HER2 NOS Cohort

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    End point title
    		 Progression-Free Survival (PFS) HER2 NOS Cohort [86]
    End point description
    PFS was defined as the time (in months) from the first treatment date to the earlier date of the documented PD or death due to any cause. PD was assessed taking results from RECIST over PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [86] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    42
    Units: month
        number (confidence interval 95%)
    1.84 (1.74 to 2.07)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS) HER3 NOS Cohort

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    End point title
    		 Progression-Free Survival (PFS) HER3 NOS Cohort [87]
    End point description
    PFS was defined as the time (in months) from the first treatment date to the earlier date of the documented PD or death due to any cause. PD was assessed taking results from RECIST over PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [87] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    16
    Units: month
        number (confidence interval 95%)
    1.69 (1.41 to 2.04)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS) HER4 NOS Cohort

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    End point title
    		 Progression-Free Survival (PFS) HER4 NOS Cohort [88]
    End point description
    PFS was defined as the time (in months) from the first treatment date to the earlier date of the documented PD or death due to any cause. PD was assessed taking results from RECIST over PERCIST.
    End point type
    Secondary
    End point timeframe
    From first treatment date until disease progression or death due to any cause, assessed up to 58 months.
    Notes
    [88] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the arms represented here were treated in this cohort of patients
    End point values
    		 Neratinib
    Number of subjects analysed
    3
    Units: month
        number (confidence interval 95%)
    1.71 (1.12 to 1.74)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    1st dose through 28 days after last dose
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Neratinib Monotherapy
    Reporting group description
    		 Neratinib Monotherapy

    Reporting group title
    Neratinib + Fulvestrant
    Reporting group description
    		 Neratinib + Fulvestrant

    Reporting group title
    Neratinib + Paclitaxel
    Reporting group description
    		 Neratinib + Paclitaxel

    Reporting group title
    Fulvestrant + Trastuzumab
    Reporting group description
    		 Fulvestrant + Trastuzumab

    Reporting group title
    Neratinib + Fulvestrant + Trastuzumab
    Reporting group description
    		 Neratinib + Fulvestrant + Trastuzumab

    Reporting group title
    Fulvestrant Monotherapy
    Reporting group description
    		 Fulvestrant Monotherapy

    Reporting group title
    Neratinib + Trastuzumab
    Reporting group description
    		 Neratinib + Trastuzumab

    Serious adverse events
    		 Neratinib Monotherapy Neratinib + Fulvestrant Neratinib + Paclitaxel Fulvestrant + Trastuzumab Neratinib + Fulvestrant + Trastuzumab Fulvestrant Monotherapy Neratinib + Trastuzumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    144 / 317 (45.43%)
    12 / 45 (26.67%)
    13 / 22 (59.09%)
    0 / 7 (0.00%)
    28 / 90 (31.11%)
    5 / 7 (71.43%)
    45 / 92 (48.91%)
         number of deaths (all causes)
    231
    31
    14
    0
    32
    2
    71
         number of deaths resulting from adverse events
    16
    1
    2
    0
    0
    0
    6
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to meninges
         subjects affected / exposed
    1 / 317 (0.32%)
    1 / 45 (2.22%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour associated fever
         subjects affected / exposed
    0 / 317 (0.00%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-Hodgkin's lymphoma
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    0 / 317 (0.00%)
    2 / 45 (4.44%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasm malignant
         subjects affected / exposed
    0 / 317 (0.00%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    1 / 90 (1.11%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Embolism
         subjects affected / exposed
    2 / 317 (0.63%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    3 / 317 (0.95%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    1 / 90 (1.11%)
    0 / 7 (0.00%)
    2 / 92 (2.17%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic thrombosis
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    2 / 317 (0.63%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Mammoplasty
         subjects affected / exposed
    0 / 317 (0.00%)
    1 / 45 (2.22%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain management
         subjects affected / exposed
    0 / 317 (0.00%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 317 (0.95%)
    0 / 45 (0.00%)
    1 / 22 (4.55%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    2 / 317 (0.63%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    2 / 317 (0.63%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    1 / 7 (14.29%)
    2 / 92 (2.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    3 / 317 (0.95%)
    0 / 45 (0.00%)
    1 / 22 (4.55%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Pyrexia
         subjects affected / exposed
    7 / 317 (2.21%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    1 / 90 (1.11%)
    1 / 7 (14.29%)
    3 / 92 (3.26%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Testicular pain
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic pain
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    0 / 317 (0.00%)
    1 / 45 (2.22%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    1 / 22 (4.55%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Dyspnoea
         subjects affected / exposed
    8 / 317 (2.52%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    3 / 90 (3.33%)
    0 / 7 (0.00%)
    2 / 92 (2.17%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 0
    0 / 0
    0 / 0
    0 / 4
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    Productive cough
         subjects affected / exposed
    0 / 317 (0.00%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 317 (0.00%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    3 / 317 (0.95%)
    2 / 45 (4.44%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 317 (0.00%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    1 / 90 (1.11%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    3 / 317 (0.95%)
    0 / 45 (0.00%)
    1 / 22 (4.55%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Pulmonary embolism
         subjects affected / exposed
    3 / 317 (0.95%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Disorientation
         subjects affected / exposed
    0 / 317 (0.00%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    1 / 7 (14.29%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug abuse
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    3 / 317 (0.95%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Agitation
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device malfunction
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 317 (0.63%)
    0 / 45 (0.00%)
    1 / 22 (4.55%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    2 / 92 (2.17%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 317 (1.26%)
    0 / 45 (0.00%)
    1 / 22 (4.55%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    2 / 92 (2.17%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    2 / 317 (0.63%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphocyte count decreased
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    4 / 317 (1.26%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    2 / 90 (2.22%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 0
    0 / 0
    0 / 0
    2 / 3
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Troponin I increased
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 317 (0.00%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    1 / 90 (1.11%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    2 / 317 (0.63%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    1 / 90 (1.11%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 317 (0.00%)
    2 / 45 (4.44%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 317 (0.00%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    1 / 22 (4.55%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    0 / 317 (0.00%)
    1 / 45 (2.22%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 317 (0.00%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 317 (0.00%)
    1 / 45 (2.22%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural bile leak
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Tracheo-oesophageal fistula
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    3 / 317 (0.95%)
    2 / 45 (4.44%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 317 (0.00%)
    0 / 45 (0.00%)
    1 / 22 (4.55%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 317 (0.00%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    1 / 90 (1.11%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    0 / 317 (0.00%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    1 / 90 (1.11%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 317 (0.00%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 317 (0.00%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Cardiac tamponade
         subjects affected / exposed
    0 / 317 (0.00%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aphasia
         subjects affected / exposed
    0 / 317 (0.00%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    1 / 7 (14.29%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    3 / 317 (0.95%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    3 / 317 (0.95%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 317 (0.00%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    2 / 92 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    0 / 317 (0.00%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    1 / 90 (1.11%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    2 / 317 (0.63%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neurological decompensation
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 317 (0.63%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    0 / 317 (0.00%)
    0 / 45 (0.00%)
    1 / 22 (4.55%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 317 (0.63%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    2 / 92 (2.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Leukocytosis
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 317 (0.00%)
    0 / 45 (0.00%)
    1 / 22 (4.55%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    3 / 317 (0.95%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Diplopia
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    2 / 317 (0.63%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    17 / 317 (5.36%)
    0 / 45 (0.00%)
    3 / 22 (13.64%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    1 / 7 (14.29%)
    3 / 92 (3.26%)
         occurrences causally related to treatment / all
    2 / 20
    0 / 0
    1 / 3
    0 / 0
    0 / 0
    0 / 2
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    4 / 317 (1.26%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    4 / 317 (1.26%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    30 / 317 (9.46%)
    1 / 45 (2.22%)
    6 / 22 (27.27%)
    0 / 7 (0.00%)
    6 / 90 (6.67%)
    3 / 7 (42.86%)
    12 / 92 (13.04%)
         occurrences causally related to treatment / all
    34 / 35
    1 / 1
    6 / 6
    0 / 0
    7 / 7
    3 / 3
    15 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 317 (0.00%)
    1 / 45 (2.22%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 317 (0.00%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    1 / 90 (1.11%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    2 / 317 (0.63%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    2 / 317 (0.63%)
    0 / 45 (0.00%)
    2 / 22 (9.09%)
    0 / 7 (0.00%)
    2 / 90 (2.22%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 3
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestinal haemorrhage
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    1 / 7 (14.29%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 317 (0.00%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    1 / 90 (1.11%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    9 / 317 (2.84%)
    0 / 45 (0.00%)
    1 / 22 (4.55%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    2 / 92 (2.17%)
         occurrences causally related to treatment / all
    5 / 9
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Obstruction gastric
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    3 / 317 (0.95%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    14 / 317 (4.42%)
    1 / 45 (2.22%)
    2 / 22 (9.09%)
    0 / 7 (0.00%)
    3 / 90 (3.33%)
    0 / 7 (0.00%)
    6 / 92 (6.52%)
         occurrences causally related to treatment / all
    10 / 16
    1 / 1
    2 / 2
    0 / 0
    4 / 4
    0 / 0
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    2 / 317 (0.63%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    4 / 317 (1.26%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis acute
         subjects affected / exposed
    0 / 317 (0.00%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Biliary obstruction
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bile duct stone
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute hepatic failure
         subjects affected / exposed
    0 / 317 (0.00%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 317 (0.00%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant biliary obstruction
         subjects affected / exposed
    2 / 317 (0.63%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gallbladder obstruction
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug eruption
         subjects affected / exposed
    0 / 317 (0.00%)
    1 / 45 (2.22%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    1 / 22 (4.55%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    5 / 317 (1.58%)
    0 / 45 (0.00%)
    4 / 22 (18.18%)
    0 / 7 (0.00%)
    4 / 90 (4.44%)
    0 / 7 (0.00%)
    6 / 92 (6.52%)
         occurrences causally related to treatment / all
    3 / 7
    0 / 0
    2 / 4
    0 / 0
    3 / 5
    0 / 0
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    1 / 90 (1.11%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    1 / 90 (1.11%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    1 / 22 (4.55%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    4 / 317 (1.26%)
    0 / 45 (0.00%)
    2 / 22 (9.09%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    1 / 90 (1.11%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    1 / 90 (1.11%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 317 (0.63%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sacral pain
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 317 (0.00%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    1 / 7 (14.29%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    0 / 317 (0.00%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Arthritis bacterial
         subjects affected / exposed
    0 / 317 (0.00%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    1 / 90 (1.11%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal infection
         subjects affected / exposed
    2 / 317 (0.63%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 317 (0.00%)
    1 / 45 (2.22%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 317 (0.63%)
    1 / 45 (2.22%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    1 / 90 (1.11%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    1 / 22 (4.55%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    0 / 317 (0.00%)
    0 / 45 (0.00%)
    1 / 22 (4.55%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Kidney infection
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphangitis
         subjects affected / exposed
    0 / 317 (0.00%)
    1 / 45 (2.22%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Perirectal abscess
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    2 / 317 (0.63%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 317 (0.95%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    1 / 90 (1.11%)
    0 / 7 (0.00%)
    4 / 92 (4.35%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 317 (0.00%)
    1 / 45 (2.22%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    6 / 317 (1.89%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular device infection
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    8 / 317 (2.52%)
    0 / 45 (0.00%)
    2 / 22 (9.09%)
    0 / 7 (0.00%)
    3 / 90 (3.33%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 0
    0 / 3
    0 / 0
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Failure to thrive
         subjects affected / exposed
    0 / 317 (0.00%)
    1 / 45 (2.22%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    1 / 90 (1.11%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 317 (0.00%)
    1 / 45 (2.22%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    3 / 317 (0.95%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cachexia
         subjects affected / exposed
    0 / 317 (0.00%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    1 / 90 (1.11%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    10 / 317 (3.15%)
    0 / 45 (0.00%)
    1 / 22 (4.55%)
    0 / 7 (0.00%)
    3 / 90 (3.33%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    5 / 10
    0 / 0
    2 / 2
    0 / 0
    1 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    3 / 317 (0.95%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    2 / 317 (0.63%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 317 (0.63%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Neratinib Monotherapy Neratinib + Fulvestrant Neratinib + Paclitaxel Fulvestrant + Trastuzumab Neratinib + Fulvestrant + Trastuzumab Fulvestrant Monotherapy Neratinib + Trastuzumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    304 / 317 (95.90%)
    45 / 45 (100.00%)
    20 / 22 (90.91%)
    7 / 7 (100.00%)
    89 / 90 (98.89%)
    7 / 7 (100.00%)
    92 / 92 (100.00%)
    Vascular disorders
    Lymphoedema
         subjects affected / exposed
    3 / 317 (0.95%)
    3 / 45 (6.67%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    1 / 90 (1.11%)
    1 / 7 (14.29%)
    2 / 92 (2.17%)
         occurrences all number
    3
    3
    0
    0
    1
    1
    2
    Hot flush
         subjects affected / exposed
    4 / 317 (1.26%)
    5 / 45 (11.11%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    8 / 90 (8.89%)
    1 / 7 (14.29%)
    0 / 92 (0.00%)
         occurrences all number
    4
    5
    0
    0
    10
    1
    0
    Hypertension
         subjects affected / exposed
    19 / 317 (5.99%)
    3 / 45 (6.67%)
    1 / 22 (4.55%)
    2 / 7 (28.57%)
    10 / 90 (11.11%)
    0 / 7 (0.00%)
    8 / 92 (8.70%)
         occurrences all number
    23
    3
    1
    4
    24
    0
    10
    Haematoma
         subjects affected / exposed
    0 / 317 (0.00%)
    1 / 45 (2.22%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    1 / 7 (14.29%)
    0 / 92 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    98 / 317 (30.91%)
    12 / 45 (26.67%)
    10 / 22 (45.45%)
    1 / 7 (14.29%)
    33 / 90 (36.67%)
    2 / 7 (28.57%)
    33 / 92 (35.87%)
         occurrences all number
    122
    20
    25
    1
    61
    5
    52
    Chills
         subjects affected / exposed
    10 / 317 (3.15%)
    0 / 45 (0.00%)
    2 / 22 (9.09%)
    1 / 7 (14.29%)
    9 / 90 (10.00%)
    1 / 7 (14.29%)
    5 / 92 (5.43%)
         occurrences all number
    11
    0
    2
    1
    9
    1
    7
    Asthenia
         subjects affected / exposed
    26 / 317 (8.20%)
    4 / 45 (8.89%)
    4 / 22 (18.18%)
    0 / 7 (0.00%)
    17 / 90 (18.89%)
    1 / 7 (14.29%)
    11 / 92 (11.96%)
         occurrences all number
    35
    8
    6
    0
    32
    1
    18
    Mass
         subjects affected / exposed
    0 / 317 (0.00%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    1 / 7 (14.29%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Injection site pruritus
         subjects affected / exposed
    0 / 317 (0.00%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    1 / 7 (14.29%)
    0 / 92 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Induration
         subjects affected / exposed
    0 / 317 (0.00%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    1 / 7 (14.29%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Oedema peripheral
         subjects affected / exposed
    21 / 317 (6.62%)
    8 / 45 (17.78%)
    1 / 22 (4.55%)
    0 / 7 (0.00%)
    10 / 90 (11.11%)
    0 / 7 (0.00%)
    8 / 92 (8.70%)
         occurrences all number
    23
    10
    2
    0
    13
    0
    9
    Pyrexia
         subjects affected / exposed
    27 / 317 (8.52%)
    5 / 45 (11.11%)
    3 / 22 (13.64%)
    1 / 7 (14.29%)
    7 / 90 (7.78%)
    1 / 7 (14.29%)
    15 / 92 (16.30%)
         occurrences all number
    33
    5
    4
    2
    9
    1
    22
    Pain
         subjects affected / exposed
    10 / 317 (3.15%)
    1 / 45 (2.22%)
    2 / 22 (9.09%)
    0 / 7 (0.00%)
    5 / 90 (5.56%)
    1 / 7 (14.29%)
    1 / 92 (1.09%)
         occurrences all number
    18
    1
    2
    0
    5
    1
    3
    Immune system disorders
    Food allergy
         subjects affected / exposed
    0 / 317 (0.00%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    1 / 7 (14.29%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Reproductive system and breast disorders
    Breast mass
         subjects affected / exposed
    0 / 317 (0.00%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    1 / 7 (14.29%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    24 / 317 (7.57%)
    7 / 45 (15.56%)
    3 / 22 (13.64%)
    1 / 7 (14.29%)
    8 / 90 (8.89%)
    0 / 7 (0.00%)
    12 / 92 (13.04%)
         occurrences all number
    30
    7
    3
    1
    11
    0
    14
    Nasal congestion
         subjects affected / exposed
    8 / 317 (2.52%)
    4 / 45 (8.89%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    4 / 90 (4.44%)
    0 / 7 (0.00%)
    2 / 92 (2.17%)
         occurrences all number
    8
    4
    0
    0
    4
    0
    2
    Epistaxis
         subjects affected / exposed
    9 / 317 (2.84%)
    1 / 45 (2.22%)
    2 / 22 (9.09%)
    0 / 7 (0.00%)
    6 / 90 (6.67%)
    0 / 7 (0.00%)
    6 / 92 (6.52%)
         occurrences all number
    9
    2
    4
    0
    6
    0
    7
    Cough
         subjects affected / exposed
    20 / 317 (6.31%)
    4 / 45 (8.89%)
    2 / 22 (9.09%)
    0 / 7 (0.00%)
    8 / 90 (8.89%)
    0 / 7 (0.00%)
    10 / 92 (10.87%)
         occurrences all number
    25
    5
    2
    0
    10
    0
    11
    Hiccups
         subjects affected / exposed
    0 / 317 (0.00%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    1 / 7 (14.29%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    Psychiatric disorders
    Disorientation
         subjects affected / exposed
    0 / 317 (0.00%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    1 / 7 (14.29%)
    0 / 92 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Anxiety
         subjects affected / exposed
    13 / 317 (4.10%)
    0 / 45 (0.00%)
    1 / 22 (4.55%)
    0 / 7 (0.00%)
    4 / 90 (4.44%)
    1 / 7 (14.29%)
    4 / 92 (4.35%)
         occurrences all number
    14
    0
    1
    0
    5
    1
    4
    Insomnia
         subjects affected / exposed
    12 / 317 (3.79%)
    6 / 45 (13.33%)
    3 / 22 (13.64%)
    0 / 7 (0.00%)
    5 / 90 (5.56%)
    1 / 7 (14.29%)
    5 / 92 (5.43%)
         occurrences all number
    12
    9
    3
    0
    5
    2
    5
    Depression
         subjects affected / exposed
    7 / 317 (2.21%)
    1 / 45 (2.22%)
    2 / 22 (9.09%)
    0 / 7 (0.00%)
    5 / 90 (5.56%)
    0 / 7 (0.00%)
    2 / 92 (2.17%)
         occurrences all number
    9
    1
    2
    0
    6
    0
    2
    Daydreaming
         subjects affected / exposed
    0 / 317 (0.00%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    1 / 7 (14.29%)
    0 / 92 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Mood swings
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    1 / 7 (14.29%)
    0 / 92 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    27 / 317 (8.52%)
    2 / 45 (4.44%)
    1 / 22 (4.55%)
    0 / 7 (0.00%)
    5 / 90 (5.56%)
    0 / 7 (0.00%)
    6 / 92 (6.52%)
         occurrences all number
    40
    3
    2
    0
    7
    0
    7
    Blood creatinine increased
         subjects affected / exposed
    14 / 317 (4.42%)
    1 / 45 (2.22%)
    6 / 22 (27.27%)
    0 / 7 (0.00%)
    9 / 90 (10.00%)
    0 / 7 (0.00%)
    6 / 92 (6.52%)
         occurrences all number
    32
    1
    11
    0
    18
    0
    7
    Ejection fraction decreased
         subjects affected / exposed
    0 / 317 (0.00%)
    1 / 45 (2.22%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    6 / 90 (6.67%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences all number
    0
    1
    0
    0
    6
    0
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    31 / 317 (9.78%)
    4 / 45 (8.89%)
    2 / 22 (9.09%)
    0 / 7 (0.00%)
    8 / 90 (8.89%)
    1 / 7 (14.29%)
    4 / 92 (4.35%)
         occurrences all number
    45
    4
    2
    0
    13
    1
    5
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    1 / 22 (4.55%)
    0 / 7 (0.00%)
    2 / 90 (2.22%)
    1 / 7 (14.29%)
    1 / 92 (1.09%)
         occurrences all number
    1
    0
    1
    0
    2
    1
    1
    Neutrophil count decreased
         subjects affected / exposed
    5 / 317 (1.58%)
    1 / 45 (2.22%)
    2 / 22 (9.09%)
    0 / 7 (0.00%)
    2 / 90 (2.22%)
    0 / 7 (0.00%)
    2 / 92 (2.17%)
         occurrences all number
    5
    1
    4
    0
    4
    0
    3
    Blood alkaline phosphatase increased
         subjects affected / exposed
    19 / 317 (5.99%)
    0 / 45 (0.00%)
    2 / 22 (9.09%)
    0 / 7 (0.00%)
    4 / 90 (4.44%)
    0 / 7 (0.00%)
    4 / 92 (4.35%)
         occurrences all number
    27
    0
    4
    0
    6
    0
    4
    Lymphocyte count decreased
         subjects affected / exposed
    7 / 317 (2.21%)
    1 / 45 (2.22%)
    1 / 22 (4.55%)
    1 / 7 (14.29%)
    2 / 90 (2.22%)
    0 / 7 (0.00%)
    3 / 92 (3.26%)
         occurrences all number
    15
    1
    1
    3
    7
    0
    3
    Weight decreased
         subjects affected / exposed
    34 / 317 (10.73%)
    5 / 45 (11.11%)
    1 / 22 (4.55%)
    1 / 7 (14.29%)
    14 / 90 (15.56%)
    0 / 7 (0.00%)
    15 / 92 (16.30%)
         occurrences all number
    50
    7
    2
    2
    16
    0
    16
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    0 / 317 (0.00%)
    0 / 45 (0.00%)
    1 / 22 (4.55%)
    0 / 7 (0.00%)
    5 / 90 (5.56%)
    0 / 7 (0.00%)
    2 / 92 (2.17%)
         occurrences all number
    0
    0
    1
    0
    5
    0
    2
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    4 / 317 (1.26%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    1 / 90 (1.11%)
    1 / 7 (14.29%)
    0 / 92 (0.00%)
         occurrences all number
    4
    0
    0
    0
    1
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    21 / 317 (6.62%)
    4 / 45 (8.89%)
    4 / 22 (18.18%)
    0 / 7 (0.00%)
    6 / 90 (6.67%)
    1 / 7 (14.29%)
    9 / 92 (9.78%)
         occurrences all number
    25
    4
    8
    0
    8
    2
    10
    Headache
         subjects affected / exposed
    30 / 317 (9.46%)
    8 / 45 (17.78%)
    0 / 22 (0.00%)
    1 / 7 (14.29%)
    17 / 90 (18.89%)
    2 / 7 (28.57%)
    6 / 92 (6.52%)
         occurrences all number
    32
    10
    0
    1
    20
    2
    7
    Paraesthesia
         subjects affected / exposed
    4 / 317 (1.26%)
    3 / 45 (6.67%)
    1 / 22 (4.55%)
    0 / 7 (0.00%)
    5 / 90 (5.56%)
    1 / 7 (14.29%)
    1 / 92 (1.09%)
         occurrences all number
    4
    3
    1
    0
    7
    1
    1
    Dysmetria
         subjects affected / exposed
    0 / 317 (0.00%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    1 / 7 (14.29%)
    0 / 92 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Neuropathy peripheral
         subjects affected / exposed
    5 / 317 (1.58%)
    0 / 45 (0.00%)
    5 / 22 (22.73%)
    0 / 7 (0.00%)
    4 / 90 (4.44%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences all number
    5
    0
    10
    0
    5
    0
    0
    Dysgeusia
         subjects affected / exposed
    18 / 317 (5.68%)
    2 / 45 (4.44%)
    4 / 22 (18.18%)
    1 / 7 (14.29%)
    9 / 90 (10.00%)
    0 / 7 (0.00%)
    5 / 92 (5.43%)
         occurrences all number
    18
    2
    5
    1
    10
    0
    5
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    3 / 317 (0.95%)
    3 / 45 (6.67%)
    2 / 22 (9.09%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences all number
    8
    4
    2
    0
    0
    0
    1
    Anaemia
         subjects affected / exposed
    44 / 317 (13.88%)
    7 / 45 (15.56%)
    4 / 22 (18.18%)
    1 / 7 (14.29%)
    13 / 90 (14.44%)
    1 / 7 (14.29%)
    17 / 92 (18.48%)
         occurrences all number
    77
    16
    12
    1
    30
    1
    29
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    2 / 317 (0.63%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    1 / 7 (14.29%)
    1 / 92 (1.09%)
         occurrences all number
    2
    0
    0
    0
    0
    1
    1
    Eye disorders
    Visual acuity reduced
         subjects affected / exposed
    0 / 317 (0.00%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    1 / 7 (14.29%)
    0 / 92 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Dry eye
         subjects affected / exposed
    2 / 317 (0.63%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    5 / 90 (5.56%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences all number
    2
    0
    0
    0
    6
    0
    0
    Retinal detachment
         subjects affected / exposed
    0 / 317 (0.00%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    1 / 7 (14.29%)
    0 / 92 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    1 / 90 (1.11%)
    1 / 7 (14.29%)
    0 / 92 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    1
    0
    Constipation
         subjects affected / exposed
    111 / 317 (35.02%)
    17 / 45 (37.78%)
    7 / 22 (31.82%)
    3 / 7 (42.86%)
    34 / 90 (37.78%)
    2 / 7 (28.57%)
    28 / 92 (30.43%)
         occurrences all number
    157
    21
    12
    4
    64
    3
    41
    Abdominal distension
         subjects affected / exposed
    13 / 317 (4.10%)
    2 / 45 (4.44%)
    1 / 22 (4.55%)
    0 / 7 (0.00%)
    9 / 90 (10.00%)
    0 / 7 (0.00%)
    4 / 92 (4.35%)
         occurrences all number
    14
    2
    1
    0
    12
    0
    4
    Abdominal pain
         subjects affected / exposed
    60 / 317 (18.93%)
    8 / 45 (17.78%)
    5 / 22 (22.73%)
    1 / 7 (14.29%)
    26 / 90 (28.89%)
    0 / 7 (0.00%)
    12 / 92 (13.04%)
         occurrences all number
    83
    8
    6
    1
    35
    0
    15
    Abdominal pain lower
         subjects affected / exposed
    5 / 317 (1.58%)
    1 / 45 (2.22%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    1 / 7 (14.29%)
    0 / 92 (0.00%)
         occurrences all number
    5
    1
    0
    0
    0
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    9 / 317 (2.84%)
    3 / 45 (6.67%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    8 / 90 (8.89%)
    1 / 7 (14.29%)
    7 / 92 (7.61%)
         occurrences all number
    9
    4
    0
    0
    9
    1
    10
    Diarrhoea
         subjects affected / exposed
    211 / 317 (66.56%)
    39 / 45 (86.67%)
    16 / 22 (72.73%)
    6 / 7 (85.71%)
    82 / 90 (91.11%)
    6 / 7 (85.71%)
    74 / 92 (80.43%)
         occurrences all number
    1225
    421
    61
    8
    1068
    107
    388
    Dry mouth
         subjects affected / exposed
    16 / 317 (5.05%)
    3 / 45 (6.67%)
    2 / 22 (9.09%)
    1 / 7 (14.29%)
    6 / 90 (6.67%)
    1 / 7 (14.29%)
    1 / 92 (1.09%)
         occurrences all number
    18
    4
    2
    1
    6
    1
    1
    Dysphagia
         subjects affected / exposed
    8 / 317 (2.52%)
    1 / 45 (2.22%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    5 / 90 (5.56%)
    0 / 7 (0.00%)
    2 / 92 (2.17%)
         occurrences all number
    8
    1
    0
    0
    6
    0
    3
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    1 / 7 (14.29%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    Nausea
         subjects affected / exposed
    133 / 317 (41.96%)
    19 / 45 (42.22%)
    11 / 22 (50.00%)
    3 / 7 (42.86%)
    59 / 90 (65.56%)
    3 / 7 (42.86%)
    43 / 92 (46.74%)
         occurrences all number
    181
    29
    24
    3
    106
    5
    66
    Gastrooesophageal reflux disease
         subjects affected / exposed
    9 / 317 (2.84%)
    3 / 45 (6.67%)
    2 / 22 (9.09%)
    0 / 7 (0.00%)
    5 / 90 (5.56%)
    0 / 7 (0.00%)
    2 / 92 (2.17%)
         occurrences all number
    9
    3
    2
    0
    5
    0
    3
    Vomiting
         subjects affected / exposed
    105 / 317 (33.12%)
    10 / 45 (22.22%)
    10 / 22 (45.45%)
    2 / 7 (28.57%)
    44 / 90 (48.89%)
    1 / 7 (14.29%)
    42 / 92 (45.65%)
         occurrences all number
    164
    16
    22
    2
    83
    1
    74
    Stomatitis
         subjects affected / exposed
    16 / 317 (5.05%)
    4 / 45 (8.89%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    13 / 90 (14.44%)
    1 / 7 (14.29%)
    12 / 92 (13.04%)
         occurrences all number
    19
    7
    0
    0
    16
    1
    19
    Dyspepsia
         subjects affected / exposed
    14 / 317 (4.42%)
    4 / 45 (8.89%)
    3 / 22 (13.64%)
    0 / 7 (0.00%)
    10 / 90 (11.11%)
    1 / 7 (14.29%)
    8 / 92 (8.70%)
         occurrences all number
    14
    4
    3
    0
    19
    1
    9
    Flatulence
         subjects affected / exposed
    4 / 317 (1.26%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    1 / 7 (14.29%)
    4 / 90 (4.44%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences all number
    4
    0
    0
    1
    4
    0
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    7 / 317 (2.21%)
    3 / 45 (6.67%)
    2 / 22 (9.09%)
    0 / 7 (0.00%)
    4 / 90 (4.44%)
    0 / 7 (0.00%)
    3 / 92 (3.26%)
         occurrences all number
    8
    3
    2
    0
    4
    0
    3
    Onychoclasis
         subjects affected / exposed
    3 / 317 (0.95%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    1 / 7 (14.29%)
    6 / 90 (6.67%)
    0 / 7 (0.00%)
    2 / 92 (2.17%)
         occurrences all number
    3
    0
    0
    1
    7
    0
    2
    Rash
         subjects affected / exposed
    26 / 317 (8.20%)
    7 / 45 (15.56%)
    4 / 22 (18.18%)
    2 / 7 (28.57%)
    13 / 90 (14.44%)
    0 / 7 (0.00%)
    12 / 92 (13.04%)
         occurrences all number
    29
    8
    6
    2
    16
    0
    17
    Rash maculo-papular
         subjects affected / exposed
    11 / 317 (3.47%)
    5 / 45 (11.11%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    6 / 90 (6.67%)
    0 / 7 (0.00%)
    4 / 92 (4.35%)
         occurrences all number
    13
    6
    0
    0
    8
    0
    9
    Nail disorder
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    3 / 22 (13.64%)
    0 / 7 (0.00%)
    4 / 90 (4.44%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences all number
    1
    0
    3
    0
    4
    0
    1
    Pruritus
         subjects affected / exposed
    18 / 317 (5.68%)
    4 / 45 (8.89%)
    1 / 22 (4.55%)
    0 / 7 (0.00%)
    8 / 90 (8.89%)
    0 / 7 (0.00%)
    3 / 92 (3.26%)
         occurrences all number
    20
    4
    1
    0
    9
    0
    4
    Nail ridging
         subjects affected / exposed
    1 / 317 (0.32%)
    1 / 45 (2.22%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    2 / 90 (2.22%)
    1 / 7 (14.29%)
    1 / 92 (1.09%)
         occurrences all number
    1
    1
    0
    0
    2
    1
    1
    Dry skin
         subjects affected / exposed
    20 / 317 (6.31%)
    8 / 45 (17.78%)
    1 / 22 (4.55%)
    1 / 7 (14.29%)
    9 / 90 (10.00%)
    0 / 7 (0.00%)
    4 / 92 (4.35%)
         occurrences all number
    20
    9
    1
    1
    10
    0
    4
    Dermatitis acneiform
         subjects affected / exposed
    11 / 317 (3.47%)
    1 / 45 (2.22%)
    3 / 22 (13.64%)
    0 / 7 (0.00%)
    5 / 90 (5.56%)
    1 / 7 (14.29%)
    11 / 92 (11.96%)
         occurrences all number
    11
    1
    3
    0
    8
    2
    15
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    1 / 7 (14.29%)
    2 / 92 (2.17%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    3
    Urinary tract obstruction
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    2 / 22 (9.09%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences all number
    1
    0
    2
    0
    0
    0
    0
    Pollakiuria
         subjects affected / exposed
    3 / 317 (0.95%)
    2 / 45 (4.44%)
    2 / 22 (9.09%)
    0 / 7 (0.00%)
    3 / 90 (3.33%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences all number
    3
    2
    2
    0
    5
    0
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    1 / 7 (14.29%)
    0 / 92 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    14 / 317 (4.42%)
    5 / 45 (11.11%)
    2 / 22 (9.09%)
    0 / 7 (0.00%)
    12 / 90 (13.33%)
    1 / 7 (14.29%)
    2 / 92 (2.17%)
         occurrences all number
    16
    5
    2
    0
    18
    1
    2
    Back pain
         subjects affected / exposed
    28 / 317 (8.83%)
    8 / 45 (17.78%)
    3 / 22 (13.64%)
    0 / 7 (0.00%)
    7 / 90 (7.78%)
    0 / 7 (0.00%)
    11 / 92 (11.96%)
         occurrences all number
    32
    9
    3
    0
    7
    0
    14
    Arthralgia
         subjects affected / exposed
    23 / 317 (7.26%)
    7 / 45 (15.56%)
    5 / 22 (22.73%)
    2 / 7 (28.57%)
    11 / 90 (12.22%)
    1 / 7 (14.29%)
    12 / 92 (13.04%)
         occurrences all number
    23
    10
    6
    2
    15
    1
    13
    Spinal disorder
         subjects affected / exposed
    0 / 317 (0.00%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    1 / 7 (14.29%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    0 / 92 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Spinal pain
         subjects affected / exposed
    1 / 317 (0.32%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    1 / 7 (14.29%)
    0 / 92 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    Pain in extremity
         subjects affected / exposed
    8 / 317 (2.52%)
    6 / 45 (13.33%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    6 / 90 (6.67%)
    1 / 7 (14.29%)
    8 / 92 (8.70%)
         occurrences all number
    9
    8
    0
    0
    8
    1
    9
    Musculoskeletal chest pain
         subjects affected / exposed
    12 / 317 (3.79%)
    3 / 45 (6.67%)
    1 / 22 (4.55%)
    1 / 7 (14.29%)
    4 / 90 (4.44%)
    1 / 7 (14.29%)
    3 / 92 (3.26%)
         occurrences all number
    13
    3
    1
    1
    6
    1
    3
    Muscle spasms
         subjects affected / exposed
    13 / 317 (4.10%)
    3 / 45 (6.67%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    15 / 90 (16.67%)
    0 / 7 (0.00%)
    5 / 92 (5.43%)
         occurrences all number
    18
    3
    0
    0
    15
    0
    5
    Musculoskeletal pain
         subjects affected / exposed
    4 / 317 (1.26%)
    1 / 45 (2.22%)
    0 / 22 (0.00%)
    1 / 7 (14.29%)
    4 / 90 (4.44%)
    0 / 7 (0.00%)
    2 / 92 (2.17%)
         occurrences all number
    4
    1
    0
    1
    5
    0
    2
    Flank pain
         subjects affected / exposed
    2 / 317 (0.63%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    1 / 90 (1.11%)
    1 / 7 (14.29%)
    4 / 92 (4.35%)
         occurrences all number
    2
    0
    0
    0
    1
    1
    6
    Bone pain
         subjects affected / exposed
    3 / 317 (0.95%)
    2 / 45 (4.44%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    4 / 90 (4.44%)
    1 / 7 (14.29%)
    2 / 92 (2.17%)
         occurrences all number
    5
    3
    0
    0
    5
    1
    2
    Muscular weakness
         subjects affected / exposed
    8 / 317 (2.52%)
    1 / 45 (2.22%)
    2 / 22 (9.09%)
    0 / 7 (0.00%)
    5 / 90 (5.56%)
    1 / 7 (14.29%)
    2 / 92 (2.17%)
         occurrences all number
    10
    1
    2
    0
    6
    1
    2
    Infections and infestations
    Influenza
         subjects affected / exposed
    2 / 317 (0.63%)
    1 / 45 (2.22%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    1 / 7 (14.29%)
    0 / 92 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    1
    0
    Infection
         subjects affected / exposed
    0 / 317 (0.00%)
    0 / 45 (0.00%)
    1 / 22 (4.55%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    1 / 7 (14.29%)
    0 / 92 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    3 / 317 (0.95%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    7 / 90 (7.78%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences all number
    4
    0
    0
    0
    7
    0
    1
    Urinary tract infection
         subjects affected / exposed
    21 / 317 (6.62%)
    3 / 45 (6.67%)
    3 / 22 (13.64%)
    0 / 7 (0.00%)
    12 / 90 (13.33%)
    0 / 7 (0.00%)
    5 / 92 (5.43%)
         occurrences all number
    33
    3
    5
    0
    17
    0
    5
    Respiratory tract infection
         subjects affected / exposed
    1 / 317 (0.32%)
    1 / 45 (2.22%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    1 / 7 (14.29%)
    0 / 92 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    1
    0
    Paronychia
         subjects affected / exposed
    7 / 317 (2.21%)
    4 / 45 (8.89%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    8 / 90 (8.89%)
    0 / 7 (0.00%)
    7 / 92 (7.61%)
         occurrences all number
    7
    4
    0
    0
    12
    0
    12
    Upper respiratory tract infection
         subjects affected / exposed
    8 / 317 (2.52%)
    5 / 45 (11.11%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 90 (0.00%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences all number
    9
    5
    0
    0
    0
    0
    1
    Localised infection
         subjects affected / exposed
    1 / 317 (0.32%)
    1 / 45 (2.22%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    1 / 90 (1.11%)
    1 / 7 (14.29%)
    1 / 92 (1.09%)
         occurrences all number
    1
    1
    0
    0
    1
    1
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    84 / 317 (26.50%)
    13 / 45 (28.89%)
    6 / 22 (27.27%)
    1 / 7 (14.29%)
    34 / 90 (37.78%)
    3 / 7 (42.86%)
    25 / 92 (27.17%)
         occurrences all number
    99
    16
    12
    1
    49
    4
    33
    Hyperglycaemia
         subjects affected / exposed
    9 / 317 (2.84%)
    2 / 45 (4.44%)
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    3 / 90 (3.33%)
    0 / 7 (0.00%)
    5 / 92 (5.43%)
         occurrences all number
    10
    9
    0
    0
    7
    0
    5
    Dehydration
         subjects affected / exposed
    20 / 317 (6.31%)
    2 / 45 (4.44%)
    4 / 22 (18.18%)
    0 / 7 (0.00%)
    7 / 90 (7.78%)
    0 / 7 (0.00%)
    3 / 92 (3.26%)
         occurrences all number
    33
    3
    5
    0
    9
    0
    4
    Hyperkalaemia
         subjects affected / exposed
    8 / 317 (2.52%)
    1 / 45 (2.22%)
    2 / 22 (9.09%)
    0 / 7 (0.00%)
    2 / 90 (2.22%)
    0 / 7 (0.00%)
    1 / 92 (1.09%)
         occurrences all number
    10
    1
    2
    0
    5
    0
    1
    Hypomagnesaemia
         subjects affected / exposed
    11 / 317 (3.47%)
    3 / 45 (6.67%)
    0 / 22 (0.00%)
    1 / 7 (14.29%)
    7 / 90 (7.78%)
    0 / 7 (0.00%)
    5 / 92 (5.43%)
         occurrences all number
    13
    9
    0
    1
    7
    0
    7
    Hyponatraemia
         subjects affected / exposed
    9 / 317 (2.84%)
    2 / 45 (4.44%)
    2 / 22 (9.09%)
    2 / 7 (28.57%)
    4 / 90 (4.44%)
    0 / 7 (0.00%)
    4 / 92 (4.35%)
         occurrences all number
    12
    4
    2
    2
    9
    0
    5
    Hypoalbuminaemia
         subjects affected / exposed
    7 / 317 (2.21%)
    1 / 45 (2.22%)
    1 / 22 (4.55%)
    1 / 7 (14.29%)
    4 / 90 (4.44%)
    0 / 7 (0.00%)
    6 / 92 (6.52%)
         occurrences all number
    13
    2
    1
    1
    8
    0
    6
    Hypocalcaemia
         subjects affected / exposed
    6 / 317 (1.89%)
    4 / 45 (8.89%)
    1 / 22 (4.55%)
    0 / 7 (0.00%)
    5 / 90 (5.56%)
    0 / 7 (0.00%)
    5 / 92 (5.43%)
         occurrences all number
    7
    8
    1
    0
    11
    0
    7
    Hypophosphataemia
         subjects affected / exposed
    11 / 317 (3.47%)
    0 / 45 (0.00%)
    1 / 22 (4.55%)
    0 / 7 (0.00%)
    7 / 90 (7.78%)
    0 / 7 (0.00%)
    2 / 92 (2.17%)
         occurrences all number
    13
    0
    2
    0
    15
    0
    2
    Hypokalaemia
         subjects affected / exposed
    15 / 317 (4.73%)
    1 / 45 (2.22%)
    1 / 22 (4.55%)
    0 / 7 (0.00%)
    12 / 90 (13.33%)
    0 / 7 (0.00%)
    7 / 92 (7.61%)
         occurrences all number
    17
    3
    1
    0
    14
    0
    15

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Nov 2013
    Amendment 1 key changes included primary and secondary objectives, including the primary objective was changed from “HER2-mutation positive solid tumors” to “solid tumors that test positive for somatic human epidermal growth factor receptor mutations in the ERBB gene family (EGFR, HER2, and/or HER3) or EGFR gene amplification”, secondary objective #1 was revised from “HER2-mutation positive solid tumors” to “tumors that test positive for somatic human epidermal growth factor receptor mutations (EGFR, HER2, HER3) in the ERBB gene family (EGFR, HER2, and/or HER3) or EGFR gene amplification”, secondary objective #2 changed the clinical benefit rate starting from “date of enrollment” to “C1D1”. Changes were made to the exploratory objectives. In study design, the safety follow up was revised from “28 to 35 days” to “28 days (+14 days)”, two new cohorts of patients with solid tumors were added, for a total of 8 cohorts of patients organized in two groups (HER2 mutation positive and HER3 mutation positive). Additional changes included inclusion and exclusion criteria, study assessments, and clarifications to the study analysis plan.
    02 Apr 2014
    Amendment 2 key changes included the addition of a HER2-mutant breast cancer cohort, for a total of nine cohorts organized in two groups (HER2 mutation and HER3 mutation). The number of patients and study centers was increased. Modified PERCIST (mPERCIST) was included with clarification of resistance mechanism to drug and exploratory objectives. The Primary Efficacy Endpoint (Objective Response Rate at 8 weeks) was defined as the proportion of patients who achieved confirmed Complete Response or Partial Response per RECIST version 1.1 or other defined response criteria. Additional changes were made to the study analysis section and known HER2 mutations.
    17 Mar 2015
    Amendment 3 key changes included increase in number of patients and study duration, and the addition of five new cohorts, for a total of 14 cohorts organized by mutations (ERBB2, EGFR, and ERBB3), clarified that mutation testing will be centrally evaluated retrospectively, clarifications to the primary and secondary endpoints, addition of new inclusion and exclusion criteria, secondary endpoints, exploratory objectives and clarifications to study analysis methods and treatment timelines. Additional changes to study design included the addition of new combination of regimens, concomitant medications and study assessments.
    20 May 2016
    Amendment 4 key changes included an increase in the number of centers and study duration, clarifications to the primary objective of the study, introduction of a new treatment cohort with combination treatment of neratinib with paclitaxel in bladder/urinary tract cancer. The following cohorts were closed to enrollment: bladder/urinary tract monotherapy, colorectal monotherapy, breast HR positive monotherapy, lung (NSCLC) monotherapy, primary brain monotherapy, and solid tumors (NOS) ERBB3-mutant monotherapy cohorts. Additional changes included inclusion and exclusion criteria, study assessments, study analysis, and instructions on combination treatment dosing administration and concomitant medications.
    04 Oct 2017
    Amendment 5 key changes included an increase in the number of centers, number of patients, and study duration. The primary objective of the study was clarified. A new treatment cohort was added: patients with ERBB2-mutant cervical cancer treated with neratinib monotherapy; patients with ERBB4-mutant solid tumors treated with neratinib monotherapy; patients with EGFR exon 18 mutant lung cancer treated with neratinib monotherapy; and patients with ERBB2-mutant breast, lung, or colorectal cancer treated with neratinib + trastuzumab ± fulvestrant combination therapy. The following cohorts were closed to enrollment: ERBB2-mutant bladder/urinary tract monotherapy, ERBB2-mutant HR positive breast monotherapy, ERBB2-mutant HR positive breast combination with fulvestrant, ERBB2-mutant HR negative breast monotherapy, ERBB2-mutant colorectal monotherapy, ERBB2-mutant endometrial monotherapy, ERBB2-mutant lung monotherapy, EGFR-mutant or amplified primary brain monotherapy, and ERBB3-mutant solid tumor (NOS) monotherapy cohorts. Additional changes included inclusion and exclusion criteria, study assessments, study analysis, and instructions on dose adjustment due to toxicity and combination treatment regimens.
    21 Jan 2020
    Amendment 6 key changes included an increase in the number of centers, number of patients, and study duration, and updates to primary, secondary and exploratory objectives of the study. The following cohorts were closed to enrollment: colorectal cancer combination therapy with neratinib + trastuzumab, lung cancer HER2-mutant combination therapy with neratinib + trastuzumab, esophageal cancer monotherapy, biliary cancer monotherapy, ovarian cancer monotherapy, solid tumors (not otherwise specified) HER4-mutant, and fibrolamellar carcinoma. The overall design and plan of the study was revised to accommodate changes to procedures and schedule of events specific to hormone receptor positive, HER2 negative metastatic breast cancer and metastatic cervical cancer cohort and by removal of information applicable to discontinued cohorts. Randomization procedures were added for patients in the HER2-negative, HER2-mutant, HR positive breast cancer cohort with RECIST measurable tumors who were previously treated with CDK4/6 inhibitors. Additional changes included inclusion and exclusion criteria, study assessments, study analysis, and instructions on combination treatment regimens and concomitant therapies.
    03 Feb 2021
    Amendment 7 key changes included increase in study duration and exploratory objectives. The following cohorts were closed to enrollment: solid tumors (NOS) HER2-mutant monotherapy and bladder/urinary HER2-mutant combination therapy of neratinib + paclitaxel, clarifications related to these closures were included. Additional changes included inclusion and exclusion criteria and study assessments.

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

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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/29420467
    http://www.ncbi.nlm.nih.gov/pubmed/31806627
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