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    Clinical Trial Results:
    A Phase II Randomized Clinical Trial Evaluating Neoadjuvant Therapy Regimens With Weekly Paclitaxel Plus Neratinib or Trastuzumab or Neratinib and Trastuzumab Followed by Doxorubicin and Cyclophosphamide With Postoperative Trastuzumab in Women With Locally Advanced HER2-Positive Breast Cancer

    Summary
    EudraCT number
    		 2013-004391-35
    Trial protocol
    		 IT   ES   PT  
    Global end of trial date
    25 Nov 2016

    Results information
    Results version number
    		 v1
    This version publication date
    03 Jan 2018
    First version publication date
    03 Jan 2018
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    FB-7
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01008150
    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 Operations Senior Director, Puma Biotechnology, Inc., 1 4242486500, clinicaltrials@pumabiotechnology.com
    Scientific contact
    Clinical Operations Senior Director, 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
    30 Nov 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Nov 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Nov 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    FB-7 is a Phase II, multi-center randomized study of neratinib in combination with weekly paclitaxel with or without trastuzumab followed by doxorubicin and cyclophosphamide (AC) as neoadjuvant therapy for women with HER2-positive locally advanced breast cancer. Patients in the control arm will receive neoadjuvant trastuzumab in combination with weekly paclitaxel followed by AC. The primary aim of the study is to determine the pathologic complete response (pCR) rate in breast and axillary nodes following the neoadjuvant therapy regimens.
    Protection of trial subjects
    The protocol, the investigator’s brochure, and the informed consent form (ICF) for this clinical study were submitted to an independent ethics committee (IEC) or an institutional review board (IRB) for review and written approval. Any subsequent amendments to the protocol or any revisions to the ICF were submitted for IEC or IRB review and written approval. Subjects were to be discontinued from the study for any of the following reasons: disease progression, symptomatic deterioration, unacceptable toxicity, death, or withdrawal of consent. The study was monitored by an independent clinical site monitor evaluating patient and site compliance, patient safety and physician oversight.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Feb 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 11
    Country: Number of subjects enrolled
    Spain: 33
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    United States: 76
    Country: Number of subjects enrolled
    Italy: 16
    Country: Number of subjects enrolled
    Portugal: 2
    Worldwide total number of subjects
    141
    EEA total number of subjects
    54
    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)
    123
    From 65 to 84 years
    18
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 xxx

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Trastuzumab
    Arm description
    		 Trastuzumab + Paclitaxel
    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
    Trastuzumab concurrently with paclitaxel weekly for a total of 16 doses (4 mg/kg loading dose, then 2 mg/kg weekly). Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy).

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    4 cycles of paclitaxel 80 mg/m2 on Days 1, 8, and 15 of a 28-day cycle.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Following trastuzumab/paclitaxel therapy, every 21 days for 4 cycles, at 200 mg/m2/week.

    Investigational medicinal product name
    Adriamycin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Following trastuzumab/paclitaxel therapy, every 21 days for 4 cycles, at 20 mg/m2/week.

    Arm title
    		 Neratinib
    Arm description
    		 Neratinib + Paclitaxel
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Neratinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Neratinib 240 mg orally once daily beginning on Day 1 of paclitaxel and continuing through Day 28 of the final cycle of paclitaxel. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy).

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    4 cycles of paclitaxel 80 mg/m2 on Days 1, 8, and 15 of a 28-day cycle.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Following neratinib/paclitaxel therapy, every 21 days for 4 cycles, at 200 mg/m2/week.

    Investigational medicinal product name
    Adriamycin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Following neratinib/paclitaxel therapy, every 21 days for 4 cycles, at 20 mg/m2/week.

    Arm title
    		 Neratinib + Trastuzumab
    Arm description
    		 Neratinib + Trastuzumab + Paclitaxel
    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
    Trastuzumab concurrently with paclitaxel, weekly for a total of 16 doses (4 mg/kg loading dose, then 2 mg/kg weekly) and Neratinib 200 mg orally once daily beginning on Day 1 of paclitaxel and continuing through Day 28 of the final cycle of paclitaxel. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy).

    Investigational medicinal product name
    Adriamycin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Following paclitaxel/trastuzumab/neratinib therapy, every 21 days for 4 cycles, at 20 mg/m2/week.

    Investigational medicinal product name
    Neratinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Neratinib 200 mg orally once daily beginning on Day 1 of paclitaxel and continuing through Day 28 of the final cycle of paclitaxel. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy).

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Following paclitaxel/trastuzumab/neratinib therapy, every 21 days for 4 cycles, at 200 mg/m2/week.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    4 cycles of paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28 day cycle.

    Arm title
    		 Neratinib + Trastuzumab NR
    Arm description
    		 Neratinib + Trastuzumab + Paclitaxel non randomized group
    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
    Neratinib 200 mg orally once daily beginning on Day 1 of paclitaxel and continuing through Day 28 of the final cycle of paclitaxel. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy).

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    4 cycles of paclitaxel 80 mg/m2 on Days 1, 8, and 15 of a 28-day cycle.

    Investigational medicinal product name
    Adriamycin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Following paclitaxel/trastuzumab/neratinib therapy, every 21 days for 4 cycles, at 20 mg/m2/week.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Following paclitaxel/trastuzumab/neratinib therapy, every 21 days for 4 cycles, at 200 mg/m2/week.

    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
    Trastuzumab concurrently with paclitaxel, weekly for a total of 16 doses (4 mg/kg loading dose, then 2 mg/kg weekly) and Neratinib 200 mg orally once daily beginning on Day 1 of paclitaxel and continuing through Day 28 of the final cycle of paclitaxel. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy).

    Number of subjects in period 1
    		Trastuzumab Neratinib Neratinib + Trastuzumab Neratinib + Trastuzumab NR
    Started
    43
    43
    43
    12
    Completed
    37
    37
    35
    11
    Not completed
    6
    6
    8
    1
         Consent withdrawn by subject
    2
    4
    6
    -
         Physician decision
    1
    -
    1
    1
         Subject Noncompliant
    1
    -
    -
    -
         Adverse event, non-fatal
    -
    -
    1
    -
         Lost to follow-up
    2
    1
    -
    -
         Lack of efficacy
    -
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Trastuzumab
    Reporting group description
    		 Trastuzumab + Paclitaxel

    Reporting group title
    Neratinib
    Reporting group description
    		 Neratinib + Paclitaxel

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

    Reporting group title
    Neratinib + Trastuzumab NR
    Reporting group description
    		 Neratinib + Trastuzumab + Paclitaxel non randomized group

    Reporting group values
    		 Trastuzumab Neratinib Neratinib + Trastuzumab Neratinib + Trastuzumab NR Total
    Number of subjects
    		 43 43 43 12 141
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 41 36 35 11 123
        From 65-84 years
    		 2 7 8 1 18
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 50.5 ± 9.8 54.2 ± 10.1 50.8 ± 12.5 48.6 ± 11.9 -
    Gender categorical
    Units: Subjects
        Female
    		 43 43 43 12 141
        Male
    		 0 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Trastuzumab
    Reporting group description
    		 Trastuzumab + Paclitaxel

    Reporting group title
    Neratinib
    Reporting group description
    		 Neratinib + Paclitaxel

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

    Reporting group title
    Neratinib + Trastuzumab NR
    Reporting group description
    		 Neratinib + Trastuzumab + Paclitaxel non randomized group

    Primary: Pathologic Complete Response in breast and nodes

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    End point title
    		 Pathologic Complete Response in breast and nodes
    End point description
    Pathologic Complete Response in breast and axillary lymph nodes. As measured by no histologic evidence of invasive tumor cells in the surgical breast specimen, axillary nodes after neoadjuvant chemotherapy [ Time Frame: At time of surgery ]
    End point type
    Primary
    End point timeframe
    From randomization to disease progression or death
    End point values
    		 Trastuzumab Neratinib Neratinib + Trastuzumab Neratinib + Trastuzumab NR
    Number of subjects analysed
    42
    42
    42
    12
    Units: Percentage of patients
        number (confidence interval 95%)
    38.1 (23.57 to 54.36)
    33.33 (19.57 to 49.55)
    50 (34.19 to 65.81)
    41.67 (15.17 to 72.33)
    Statistical analysis title
    		 Stratified CMH Test
    Comparison groups
    Trastuzumab v Neratinib
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.6266
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [1] - Descriptive.
    Statistical analysis title
    		 Stratified CMH Test
    Comparison groups
    Trastuzumab v Neratinib + Trastuzumab
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.2198
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [2] - Descirptive
    Statistical analysis title
    		 Stratified CMH Test
    Comparison groups
    Neratinib v Neratinib + Trastuzumab
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.2416
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [3] - Descriptive

    Secondary: Pathologic Complete Response in breast

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    End point title
    		 Pathologic Complete Response in breast
    End point description
    Pathologic complete response in breast. As measured by no histologic evidence of invasive tumor cells in the surgical breast specimen.
    End point type
    Secondary
    End point timeframe
    Time Frame: At time of surgery
    End point values
    		 Trastuzumab Neratinib Neratinib + Trastuzumab Neratinib + Trastuzumab NR
    Number of subjects analysed
    42
    42
    42
    12
    Units: Percent of Patients
        number (confidence interval 95%)
    50 (34.19 to 65.81)
    38.1 (23.57 to 54.36)
    52.38 (36.42 to 68)
    50 (21.09 to 78.91)
    No statistical analyses for this end point

    Secondary: Recurrence-free Interval

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    End point title
    		 Recurrence-free Interval
    End point description
    24-month Kaplan-Meier estimate of time to first disease recurrence.
    End point type
    Secondary
    End point timeframe
    From time of randomization to 24 months
    End point values
    		 Trastuzumab Neratinib Neratinib + Trastuzumab Neratinib + Trastuzumab NR
    Number of subjects analysed
    42
    42
    42
    12
    Units: 24-month RFI
        number (confidence interval 95%)
    100 (100 to 100)
    91.7 (76.5 to 97.3)
    93.6 (76.6 to 98.4)
    100 (100 to 100)
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    24 month Kaplan-Meier estimate of overall survival.
    End point type
    Secondary
    End point timeframe
    From randomization to time of death, censored at 24 months.
    End point values
    		 Trastuzumab Neratinib Neratinib + Trastuzumab Neratinib + Trastuzumab NR
    Number of subjects analysed
    42
    42
    42
    12
    Units: Rate
        number (confidence interval 95%)
    100 (100 to 100)
    100 (100 to 100)
    100 (100 to 100)
    100 (100 to 100)
    No statistical analyses for this end point

    Secondary: Clinical Complete Response

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    End point title
    		 Clinical Complete Response
    End point description
    As measured by physical exam; resolution of all target and non-target lesions identified at baseline and no new lesions or other signs of disease progression, for subjects with palpable disease at baseline.
    End point type
    Secondary
    End point timeframe
    At completion of paclitaxel therapy
    End point values
    		 Trastuzumab Neratinib Neratinib + Trastuzumab Neratinib + Trastuzumab NR
    Number of subjects analysed
    38
    35
    38
    10
    Units: Percentage of participants
        number (confidence interval 95%)
    55.26 (38.3 to 71.38)
    60 (42.11 to 76.13)
    57.89 (40.82 to 73.69)
    20 (2.52 to 55.61)
    No statistical analyses for this end point

    Secondary: Clinical Complete Response

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    End point title
    		 Clinical Complete Response
    End point description
    As measured by physical exam; resolution of all target and non-target lesions identified at baseline and no new lesions or other signs of disease progression.
    End point type
    Secondary
    End point timeframe
    At the completion of AC
    End point values
    		 Trastuzumab Neratinib Neratinib + Trastuzumab Neratinib + Trastuzumab NR
    Number of subjects analysed
    38
    35
    38
    10
    Units: Percentage of participants
        number (confidence interval 95%)
    65.79 (48.65 to 80.37)
    71.43 (53.7 to 85.36)
    73.68 (56.9 to 86.6)
    60 (26.24 to 87.84)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First dose through 28 days after last dose
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Trastuzumab
    Reporting group description
    		 Trastuzumab

    Reporting group title
    Neratinib
    Reporting group description
    		 Neratinib

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

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

    Serious adverse events
    		 Trastuzumab Neratinib Neratinib + Trastuzumab Neratinib + Trastuzumab NR
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 42 (16.67%)
    7 / 42 (16.67%)
    10 / 42 (23.81%)
    2 / 12 (16.67%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Radiation skin injury
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Embolism
         subjects affected / exposed
    2 / 42 (4.76%)
    1 / 42 (2.38%)
    1 / 42 (2.38%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    1 / 42 (2.38%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Arrhythmia supraventricular
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 42 (2.38%)
    0 / 42 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac valve disease
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 42 (2.38%)
    0 / 42 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 42 (2.38%)
    0 / 42 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 42 (0.00%)
    1 / 42 (2.38%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    1 / 42 (2.38%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 42 (4.76%)
    1 / 42 (2.38%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    1 / 42 (2.38%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    2 / 42 (4.76%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    1 / 42 (2.38%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    1 / 42 (2.38%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 42 (2.38%)
    0 / 42 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 42 (2.38%)
    0 / 42 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 42 (2.38%)
    0 / 42 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 42 (2.38%)
    0 / 42 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 42 (2.38%)
    0 / 42 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 42 (2.38%)
    0 / 42 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 42 (2.38%)
    1 / 42 (2.38%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 42 (0.00%)
    1 / 42 (2.38%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    1 / 42 (2.38%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    1 / 42 (2.38%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Trastuzumab Neratinib Neratinib + Trastuzumab Neratinib + Trastuzumab NR
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    41 / 42 (97.62%)
    42 / 42 (100.00%)
    42 / 42 (100.00%)
    12 / 12 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Vascular disorders
    Embolism
         subjects affected / exposed
    0 / 42 (0.00%)
    4 / 42 (9.52%)
    1 / 42 (2.38%)
    1 / 12 (8.33%)
         occurrences all number
    0
    4
    1
    1
    Hypertension
         subjects affected / exposed
    7 / 42 (16.67%)
    8 / 42 (19.05%)
    2 / 42 (4.76%)
    0 / 12 (0.00%)
         occurrences all number
    9
    9
    2
    0
    Hypotension
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 42 (2.38%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    9 / 42 (21.43%)
    7 / 42 (16.67%)
    10 / 42 (23.81%)
    0 / 12 (0.00%)
         occurrences all number
    15
    24
    18
    0
    Catheter site pain
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 42 (2.38%)
    1 / 42 (2.38%)
    2 / 12 (16.67%)
         occurrences all number
    1
    1
    1
    2
    Chest pain
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    3 / 42 (7.14%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    3
    1
    Chills
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 42 (4.76%)
    1 / 42 (2.38%)
    1 / 12 (8.33%)
         occurrences all number
    0
    2
    1
    2
    Early satiety
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Fatigue
         subjects affected / exposed
    18 / 42 (42.86%)
    22 / 42 (52.38%)
    18 / 42 (42.86%)
    8 / 12 (66.67%)
         occurrences all number
    18
    31
    23
    18
    Mucosal inflammation
         subjects affected / exposed
    7 / 42 (16.67%)
    3 / 42 (7.14%)
    8 / 42 (19.05%)
    1 / 12 (8.33%)
         occurrences all number
    9
    4
    12
    1
    Oedema peripheral
         subjects affected / exposed
    2 / 42 (4.76%)
    5 / 42 (11.90%)
    3 / 42 (7.14%)
    2 / 12 (16.67%)
         occurrences all number
    2
    9
    6
    2
    Pain
         subjects affected / exposed
    4 / 42 (9.52%)
    9 / 42 (21.43%)
    5 / 42 (11.90%)
    2 / 12 (16.67%)
         occurrences all number
    5
    13
    6
    2
    Pyrexia
         subjects affected / exposed
    1 / 42 (2.38%)
    6 / 42 (14.29%)
    6 / 42 (14.29%)
    3 / 12 (25.00%)
         occurrences all number
    2
    6
    7
    4
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    2 / 42 (4.76%)
    5 / 42 (11.90%)
    6 / 42 (14.29%)
    1 / 12 (8.33%)
         occurrences all number
    4
    6
    7
    3
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    3 / 42 (7.14%)
    4 / 42 (9.52%)
    2 / 42 (4.76%)
    0 / 12 (0.00%)
         occurrences all number
    3
    4
    2
    0
    Pelvic pain
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Cough
         subjects affected / exposed
    8 / 42 (19.05%)
    4 / 42 (9.52%)
    6 / 42 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    9
    5
    6
    0
    Dyspnoea
         subjects affected / exposed
    6 / 42 (14.29%)
    4 / 42 (9.52%)
    2 / 42 (4.76%)
    0 / 12 (0.00%)
         occurrences all number
    8
    4
    2
    0
    Epistaxis
         subjects affected / exposed
    8 / 42 (19.05%)
    8 / 42 (19.05%)
    7 / 42 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    8
    8
    8
    1
    Oropharyngeal pain
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 42 (2.38%)
    3 / 42 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    3
    0
    Rhinorrhoea
         subjects affected / exposed
    3 / 42 (7.14%)
    2 / 42 (4.76%)
    1 / 42 (2.38%)
    0 / 12 (0.00%)
         occurrences all number
    3
    2
    1
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    4 / 42 (9.52%)
    5 / 42 (11.90%)
    4 / 42 (9.52%)
    0 / 12 (0.00%)
         occurrences all number
    4
    5
    4
    0
    Insomnia
         subjects affected / exposed
    8 / 42 (19.05%)
    6 / 42 (14.29%)
    3 / 42 (7.14%)
    3 / 12 (25.00%)
         occurrences all number
    9
    6
    3
    3
    Mood altered
         subjects affected / exposed
    3 / 42 (7.14%)
    4 / 42 (9.52%)
    1 / 42 (2.38%)
    0 / 12 (0.00%)
         occurrences all number
    3
    5
    1
    0
    Investigations
    Alanine aminotransferase
         subjects affected / exposed
    2 / 42 (4.76%)
    2 / 42 (4.76%)
    3 / 42 (7.14%)
    1 / 12 (8.33%)
         occurrences all number
    2
    2
    7
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    7 / 42 (16.67%)
    16 / 42 (38.10%)
    17 / 42 (40.48%)
    7 / 12 (58.33%)
         occurrences all number
    13
    23
    26
    12
    Aspartate aminotransferase increased
         subjects affected / exposed
    6 / 42 (14.29%)
    13 / 42 (30.95%)
    14 / 42 (33.33%)
    8 / 12 (66.67%)
         occurrences all number
    14
    16
    16
    12
    Blood alkaline phosphatase
         subjects affected / exposed
    1 / 42 (2.38%)
    2 / 42 (4.76%)
    0 / 42 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    1
    2
    0
    2
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 42 (4.76%)
    3 / 42 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    4
    0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Blood creatinine increased
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 42 (2.38%)
    4 / 42 (9.52%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    5
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 42 (2.38%)
    4 / 42 (9.52%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    8
    0
    Haemoglobin
         subjects affected / exposed
    2 / 42 (4.76%)
    5 / 42 (11.90%)
    2 / 42 (4.76%)
    2 / 12 (16.67%)
         occurrences all number
    3
    9
    3
    5
    Neutrophil count
         subjects affected / exposed
    5 / 42 (11.90%)
    6 / 42 (14.29%)
    1 / 42 (2.38%)
    0 / 12 (0.00%)
         occurrences all number
    5
    6
    2
    0
    Weight decreased
         subjects affected / exposed
    2 / 42 (4.76%)
    6 / 42 (14.29%)
    4 / 42 (9.52%)
    3 / 12 (25.00%)
         occurrences all number
    2
    6
    4
    3
    White blood cell count
         subjects affected / exposed
    5 / 42 (11.90%)
    4 / 42 (9.52%)
    1 / 42 (2.38%)
    1 / 12 (8.33%)
         occurrences all number
    5
    5
    2
    3
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    1 / 42 (2.38%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    2
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    4 / 42 (9.52%)
    5 / 42 (11.90%)
    6 / 42 (14.29%)
    4 / 12 (33.33%)
         occurrences all number
    4
    5
    7
    5
    Dysgeusia
         subjects affected / exposed
    3 / 42 (7.14%)
    8 / 42 (19.05%)
    7 / 42 (16.67%)
    3 / 12 (25.00%)
         occurrences all number
    3
    8
    8
    3
    Dyskinesia
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    1
    Headache
         subjects affected / exposed
    10 / 42 (23.81%)
    7 / 42 (16.67%)
    7 / 42 (16.67%)
    4 / 12 (33.33%)
         occurrences all number
    10
    7
    7
    5
    Hypoaesthesia
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 42 (2.38%)
    4 / 42 (9.52%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    4
    1
    Neuropathy peripheral
         subjects affected / exposed
    6 / 42 (14.29%)
    5 / 42 (11.90%)
    3 / 42 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    6
    8
    3
    0
    Neurotoxicity
         subjects affected / exposed
    2 / 42 (4.76%)
    1 / 42 (2.38%)
    3 / 42 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    2
    1
    3
    0
    Paraesthesia
         subjects affected / exposed
    4 / 42 (9.52%)
    4 / 42 (9.52%)
    5 / 42 (11.90%)
    1 / 12 (8.33%)
         occurrences all number
    5
    4
    7
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    8 / 42 (19.05%)
    8 / 42 (19.05%)
    4 / 42 (9.52%)
    3 / 12 (25.00%)
         occurrences all number
    9
    9
    7
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    9 / 42 (21.43%)
    5 / 42 (11.90%)
    8 / 42 (19.05%)
    2 / 12 (16.67%)
         occurrences all number
    19
    6
    12
    3
    Leukopenia
         subjects affected / exposed
    5 / 42 (11.90%)
    6 / 42 (14.29%)
    2 / 42 (4.76%)
    0 / 12 (0.00%)
         occurrences all number
    6
    12
    3
    0
    Neutropenia
         subjects affected / exposed
    13 / 42 (30.95%)
    9 / 42 (21.43%)
    8 / 42 (19.05%)
    3 / 12 (25.00%)
         occurrences all number
    21
    10
    12
    6
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 42 (0.00%)
    1 / 42 (2.38%)
    1 / 12 (8.33%)
         occurrences all number
    2
    0
    1
    1
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    0 / 42 (0.00%)
    3 / 42 (7.14%)
    3 / 42 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    0
    3
    3
    0
    Photopsia
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Vision blurred
         subjects affected / exposed
    3 / 42 (7.14%)
    6 / 42 (14.29%)
    1 / 42 (2.38%)
    1 / 12 (8.33%)
         occurrences all number
    3
    7
    1
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 42 (0.00%)
    3 / 42 (7.14%)
    2 / 42 (4.76%)
    2 / 12 (16.67%)
         occurrences all number
    0
    3
    3
    3
    Abdominal pain
         subjects affected / exposed
    3 / 42 (7.14%)
    3 / 42 (7.14%)
    4 / 42 (9.52%)
    3 / 12 (25.00%)
         occurrences all number
    3
    3
    6
    5
    Abdominal pain upper
         subjects affected / exposed
    3 / 42 (7.14%)
    0 / 42 (0.00%)
    3 / 42 (7.14%)
    2 / 12 (16.67%)
         occurrences all number
    3
    0
    3
    2
    Constipation
         subjects affected / exposed
    6 / 42 (14.29%)
    12 / 42 (28.57%)
    11 / 42 (26.19%)
    7 / 12 (58.33%)
         occurrences all number
    7
    14
    14
    8
    Diarrhoea
         subjects affected / exposed
    16 / 42 (38.10%)
    42 / 42 (100.00%)
    41 / 42 (97.62%)
    12 / 12 (100.00%)
         occurrences all number
    18
    136
    157
    53
    Dry mouth
         subjects affected / exposed
    0 / 42 (0.00%)
    3 / 42 (7.14%)
    3 / 42 (7.14%)
    1 / 12 (8.33%)
         occurrences all number
    0
    4
    3
    1
    Dyspepsia
         subjects affected / exposed
    9 / 42 (21.43%)
    13 / 42 (30.95%)
    6 / 42 (14.29%)
    2 / 12 (16.67%)
         occurrences all number
    11
    15
    6
    3
    Dysphagia
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 42 (4.76%)
    2 / 42 (4.76%)
    1 / 12 (8.33%)
         occurrences all number
    0
    3
    2
    1
    Flatulence
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 42 (2.38%)
    1 / 42 (2.38%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    1
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 42 (2.38%)
    1 / 42 (2.38%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    1
    1
    Haemorrhoids
         subjects affected / exposed
    1 / 42 (2.38%)
    2 / 42 (4.76%)
    4 / 42 (9.52%)
    0 / 12 (0.00%)
         occurrences all number
    1
    2
    4
    0
    Nausea
         subjects affected / exposed
    12 / 42 (28.57%)
    25 / 42 (59.52%)
    20 / 42 (47.62%)
    8 / 12 (66.67%)
         occurrences all number
    13
    39
    30
    10
    Oesophagitis
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Oral pain
         subjects affected / exposed
    2 / 42 (4.76%)
    1 / 42 (2.38%)
    1 / 42 (2.38%)
    1 / 12 (8.33%)
         occurrences all number
    3
    1
    3
    2
    Rectal haemorrhage
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Stomatitis
         subjects affected / exposed
    2 / 42 (4.76%)
    6 / 42 (14.29%)
    7 / 42 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    3
    10
    7
    1
    Vomiting
         subjects affected / exposed
    7 / 42 (16.67%)
    16 / 42 (38.10%)
    13 / 42 (30.95%)
    6 / 12 (50.00%)
         occurrences all number
    7
    23
    19
    8
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 42 (2.38%)
    0 / 42 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    1
    2
    0
    4
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    4 / 42 (9.52%)
    4 / 42 (9.52%)
    1 / 42 (2.38%)
    0 / 12 (0.00%)
         occurrences all number
    11
    8
    1
    0
    Alopecia
         subjects affected / exposed
    20 / 42 (47.62%)
    22 / 42 (52.38%)
    15 / 42 (35.71%)
    6 / 12 (50.00%)
         occurrences all number
    28
    30
    16
    9
    Dermatitis acneiform
         subjects affected / exposed
    0 / 42 (0.00%)
    3 / 42 (7.14%)
    2 / 42 (4.76%)
    1 / 12 (8.33%)
         occurrences all number
    0
    4
    2
    2
    Dry skin
         subjects affected / exposed
    0 / 42 (0.00%)
    4 / 42 (9.52%)
    2 / 42 (4.76%)
    3 / 12 (25.00%)
         occurrences all number
    0
    4
    2
    4
    Erythema
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 42 (4.76%)
    2 / 42 (4.76%)
    1 / 12 (8.33%)
         occurrences all number
    0
    2
    2
    1
    Nail disorder
         subjects affected / exposed
    3 / 42 (7.14%)
    1 / 42 (2.38%)
    3 / 42 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    3
    1
    3
    0
    Pruritus
         subjects affected / exposed
    5 / 42 (11.90%)
    4 / 42 (9.52%)
    2 / 42 (4.76%)
    1 / 12 (8.33%)
         occurrences all number
    6
    5
    2
    2
    Rash
         subjects affected / exposed
    9 / 42 (21.43%)
    9 / 42 (21.43%)
    6 / 42 (14.29%)
    5 / 12 (41.67%)
         occurrences all number
    9
    14
    13
    5
    Rash generalised
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Skin disorder
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 42 (2.38%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    0
    2
    Skin hyperpigmentation
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    1 / 42 (2.38%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    2 / 42 (4.76%)
    4 / 42 (9.52%)
    1 / 42 (2.38%)
    0 / 12 (0.00%)
         occurrences all number
    2
    4
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    6 / 42 (14.29%)
    2 / 42 (4.76%)
    3 / 42 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    7
    2
    3
    0
    Back pain
         subjects affected / exposed
    0 / 42 (0.00%)
    3 / 42 (7.14%)
    4 / 42 (9.52%)
    0 / 12 (0.00%)
         occurrences all number
    0
    4
    4
    0
    Bone pain
         subjects affected / exposed
    3 / 42 (7.14%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    3
    0
    0
    1
    Flank pain
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Muscle tightness
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Muscular weakness
         subjects affected / exposed
    1 / 42 (2.38%)
    3 / 42 (7.14%)
    1 / 42 (2.38%)
    0 / 12 (0.00%)
         occurrences all number
    1
    4
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 42 (2.38%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    3
    1
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    5 / 42 (11.90%)
    0 / 42 (0.00%)
    3 / 42 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    5
    0
    3
    0
    Myalgia
         subjects affected / exposed
    4 / 42 (9.52%)
    3 / 42 (7.14%)
    2 / 42 (4.76%)
    1 / 12 (8.33%)
         occurrences all number
    4
    4
    4
    1
    Pain in jaw
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Infections and infestations
    Folliculitis
         subjects affected / exposed
    3 / 42 (7.14%)
    1 / 42 (2.38%)
    0 / 42 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    11
    1
    0
    0
    Infection
         subjects affected / exposed
    5 / 42 (11.90%)
    2 / 42 (4.76%)
    2 / 42 (4.76%)
    0 / 12 (0.00%)
         occurrences all number
    5
    2
    5
    0
    Influenza
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 42 (0.00%)
    3 / 42 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    3
    0
    Localised infection
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    1 / 42 (2.38%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    1
    Nasopharyngitis
         subjects affected / exposed
    3 / 42 (7.14%)
    2 / 42 (4.76%)
    2 / 42 (4.76%)
    1 / 12 (8.33%)
         occurrences all number
    3
    2
    3
    1
    Rhinitis
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Urinary tract infection
         subjects affected / exposed
    4 / 42 (9.52%)
    3 / 42 (7.14%)
    0 / 42 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    4
    3
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 42 (4.76%)
    11 / 42 (26.19%)
    11 / 42 (26.19%)
    2 / 12 (16.67%)
         occurrences all number
    2
    14
    12
    4
    Dehydration
         subjects affected / exposed
    2 / 42 (4.76%)
    3 / 42 (7.14%)
    1 / 42 (2.38%)
    1 / 12 (8.33%)
         occurrences all number
    2
    4
    1
    1
    Hyperglycaemia
         subjects affected / exposed
    4 / 42 (9.52%)
    8 / 42 (19.05%)
    3 / 42 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    4
    8
    5
    0
    Hypocalcaemia
         subjects affected / exposed
    1 / 42 (2.38%)
    5 / 42 (11.90%)
    4 / 42 (9.52%)
    0 / 12 (0.00%)
         occurrences all number
    1
    5
    4
    0
    Hypokalaemia
         subjects affected / exposed
    1 / 42 (2.38%)
    7 / 42 (16.67%)
    6 / 42 (14.29%)
    6 / 12 (50.00%)
         occurrences all number
    1
    12
    6
    11
    Hypomagnesaemia
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 42 (2.38%)
    3 / 42 (7.14%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    5
    0
    Hyponatraemia
         subjects affected / exposed
    1 / 42 (2.38%)
    6 / 42 (14.29%)
    4 / 42 (9.52%)
    1 / 12 (8.33%)
         occurrences all number
    1
    6
    4
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Jun 2011
    Amendment #1: Eligibility criteria regarding disease staging, documentation required from sites upon death of study subjects, and Appendix E were updated.
    20 Aug 2012
    Amendment #2: Pharmaceutical sponsorship changed from Wyeth Pharmaceuticals Inc., a Pfizer Company, to Puma Biotechnology, Inc. Third arm added, including neratinib, trastuzumab, and paclitaxel.
    14 Nov 2012
    Amendment #3: Informed consent updated.
    04 Jan 2013
    Amendment #4: Informed consent updated.
    24 Jun 2013
    Amendment #5: Protocol Chair updated.
    12 Jul 2013
    Amendment #6: Breast biopsy changed from required to optional in study procedures.
    15 Nov 2013
    Amendment #7 (EU Only): Study was expanded to European Union (EU), and Puma Biotechnology, Inc. added as Sponsor for EU region.
    20 Nov 2013
    Amendment #8 (US and Canada only): Arm 1 (paclitaxel plus trastuzumab) and Arm 2 (paclitaxel plus neratinib) closed to accrual in the United States (US). US patients previously randomized to Arm 1 or Arm 2 should continue to receive study treatment and follow-up as per protocol. Subsequent US patients were entered on Arm 3-NR (non-randomized) until completion of US accrual.
    11 Feb 2014
    Amendment #7.1 (France Only): Several inclusion/exclusion criteria were revised in order to be consistent with SmPc of trastuzumab and paclitaxel for patients undergoing treatment with these agents.
    22 May 2014
    Amendment 9: Accrual closed in the U.S.

    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/24077916
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