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    Clinical Trial Results:
    A randomised, multicentre, multinational Phase II study to evaluate pertuzumab in combination with trastuzumab given either concomitantly or sequentially with standard anthracycline based chemotherapy or concomitantly with a non-anthracycline based chemotherapy regimen, as neoadjuvant therapy for subjects with locally advanced, inflammatory or early stage HER2-positive breast cancer.

    Summary
    EudraCT number
    		 2009-012019-17
    Trial protocol
    		 IT   DE   GB   PT   GR   SE  
    Global end of trial date
    25 Jan 2016

    Results information
    Results version number
    		 v2(current)
    This version publication date
    09 Feb 2017
    First version publication date
    26 Jun 2015
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    Final results data are added to existing primary analysis data.

    Trial information

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    Trial identification
    Sponsor protocol code
    BO22280
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00976989
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.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
    25 Jan 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Jan 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To make a preliminary assessment of the tolerability of neoadjuvant treatment with one of the following treatment regimens: Sequential chemotherapy, consisting of cycles of a standard therapy for breast cancer consisting of 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) chemotherapy followed by cycles of docetaxel (FEC->T) with trastuzumab and pertuzumab given from the start of the chemotherapy regimen (i.e. concurrently with the anthracycline). (Arm A). OR FEC ->T with trastuzumab and pertuzumab given from the start of the taxane treatment (i.e. sequentially with the anthracycline). (Arm B). OR Trastuzumab, carboplatin, docetaxel (TCH) with pertuzumab, with both antibodies being given from the start of the chemotherapy. (Arm C).
    Protection of trial subjects
    All study subjects were required to read and sign an informed consent form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Nov 2009
    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
    Switzerland: 13
    Country: Number of subjects enrolled
    Bahamas: 1
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 9
    Country: Number of subjects enrolled
    Brazil: 33
    Country: Number of subjects enrolled
    Canada: 16
    Country: Number of subjects enrolled
    Croatia: 1
    Country: Number of subjects enrolled
    Mexico: 4
    Country: Number of subjects enrolled
    New Zealand: 4
    Country: Number of subjects enrolled
    China: 17
    Country: Number of subjects enrolled
    Korea, Republic of: 16
    Country: Number of subjects enrolled
    Serbia: 1
    Country: Number of subjects enrolled
    South Africa: 6
    Country: Number of subjects enrolled
    Portugal: 3
    Country: Number of subjects enrolled
    Romania: 9
    Country: Number of subjects enrolled
    Spain: 26
    Country: Number of subjects enrolled
    Sweden: 4
    Country: Number of subjects enrolled
    United Kingdom: 19
    Country: Number of subjects enrolled
    Germany: 32
    Country: Number of subjects enrolled
    Italy: 11
    Worldwide total number of subjects
    225
    EEA total number of subjects
    105
    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)
    199
    From 65 to 84 years
    26
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study included 3 periods: Neoadjuvant (pre-operative) period and surgery, adjuvant (post-operative) period and post-treatment follow-up period.

    Pre-assignment
    Screening details
    		 A total of 300 subjects with early stage HER2-positive breast cancer were screened, of whom 225 were randomised.

    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
    		 T+P Concomitant Anthracycline-based Chemotherapy
    Arm description
    		 5-Fluorouracil, epirubicin with cyclophosphamide (FEC), trastuzumab and pertuzumab every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Herceptin
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab was given as an IV infusion, at a loading dose of 8 mg/kg. Three weeks (21 days) after the first dose, and every three weeks thereafter, an IV dose of 6 mg/kg was given.

    Investigational medicinal product name
    5-Fluorouracil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5-Fluorouracil was administered in accordance with the local prescribing information; 500 mg/m^2.

    Investigational medicinal product name
    Epirubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Epirubicin was administered in accordance with the local prescribing information; 100 mg/m^2.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cyclophosphamide was administered in accordance with the local prescribing information; 600 mg/m^2.

    Investigational medicinal product name
    Pertuzumab
    Investigational medicinal product code
    Other name
    Perjeta
    Pharmaceutical forms
    Concentrate and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pertuzumab was given as an IV infusion at a loading dose of 840 mg. Three weeks (21 days) after the first dose, and every three weeks thereafter, an IV dose of 420 mg pertuzumab was given.

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Docetaxel was administered in accordance with the local prescribing information; 75 mg/m^2 for the first dose; 100 mg/m^2 if no dose limiting toxicity occurs.

    Arm title
    		 T+P Sequential Anthracycline-based Chemotherapy
    Arm description
    		 FEC every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 21 as adjuvant therapy post-surgery.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Herceptin
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab was given as an IV infusion, at a loading dose of 8 mg/kg. Three weeks (21 days) after the first dose, and every three weeks thereafter, an IV dose of 6 mg/kg was given.

    Investigational medicinal product name
    Pertuzumab
    Investigational medicinal product code
    Other name
    Perjeta
    Pharmaceutical forms
    Concentrate and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pertuzumab was given as an IV infusion at a loading dose of 840 mg. Three weeks (21 days) after the first dose, and every three weeks thereafter, an IV dose of 420 mg pertuzumab was given.

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Docetaxel was administered in accordance with the local prescribing information; 75 mg/m^2 for the first dose; 100 mg/m^2 if no dose limiting toxicity occurs.

    Investigational medicinal product name
    5-Fluorouracil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5-Fluorouracil was administered in accordance with the local prescribing information; 500 mg/m^2.

    Investigational medicinal product name
    Epirubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Epirubicin was administered in accordance with the local prescribing information; 100 mg/m^2.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cyclophosphamide was administered in accordance with the local prescribing information: 600 mg/m^2.

    Arm title
    		 T+P Concomitant Non-Anthracycline Chemotherapy
    Arm description
    		 Trastuzumab, carboplatin, docetaxel (TCH) and pertuzumab every three weeks, for six cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Herceptin
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab was given as an IV infusion, at a loading dose of 8 mg/kg. Three weeks (21 days) after the first dose, and every three weeks thereafter, an IV dose of 6 mg/kg was given.

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Docetaxel was administered in accordance with the local prescribing information; 75 mg/m^2 for the first dose; 100 mg/m^2 if no dose limiting toxicity occurs.

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin was administered in accordance with the local prescribing information; at target area under the plasma concentration-time curve (AUC) 6.

    Investigational medicinal product name
    Pertuzumab
    Investigational medicinal product code
    Other name
    Perjeta
    Pharmaceutical forms
    Concentrate and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pertuzumab was given as an IV infusion at a loading dose of 840 mg. Three weeks (21 days) after the first dose, and every three weeks thereafter, an IV dose of 420 mg pertuzumab was given.

    Number of subjects in period 1
    		T+P Concomitant Anthracycline-based Chemotherapy T+P Sequential Anthracycline-based Chemotherapy T+P Concomitant Non-Anthracycline Chemotherapy
    Started
    73
    75
    77
    Completed
    60
    63
    60
    Not completed
    13
    12
    17
         Refused Treatment
    4
    3
    5
         Death
    5
    7
    10
         Recurrence of Disease
    -
    1
    -
         Unspecified
    1
    -
    1
         Failure to Return
    2
    1
    -
         Violation of Selection Criteria at Entry
    1
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    T+P Concomitant Anthracycline-based Chemotherapy
    Reporting group description
    		 5-Fluorouracil, epirubicin with cyclophosphamide (FEC), trastuzumab and pertuzumab every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.

    Reporting group title
    T+P Sequential Anthracycline-based Chemotherapy
    Reporting group description
    		 FEC every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 21 as adjuvant therapy post-surgery.

    Reporting group title
    T+P Concomitant Non-Anthracycline Chemotherapy
    Reporting group description
    		 Trastuzumab, carboplatin, docetaxel (TCH) and pertuzumab every three weeks, for six cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.

    Reporting group values
    		 T+P Concomitant Anthracycline-based Chemotherapy T+P Sequential Anthracycline-based Chemotherapy T+P Concomitant Non-Anthracycline Chemotherapy Total
    Number of subjects
    		 73 75 77 225
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 49.6 ( 11.41 ) 50.5 ( 10.7 ) 50.6 ( 10.58 ) -
    Gender categorical
    Units: Subjects
        Female
    		 73 75 77 225
        Male
    		 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    T+P Concomitant Anthracycline-based Chemotherapy
    Reporting group description
    		 5-Fluorouracil, epirubicin with cyclophosphamide (FEC), trastuzumab and pertuzumab every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.

    Reporting group title
    T+P Sequential Anthracycline-based Chemotherapy
    Reporting group description
    		 FEC every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 21 as adjuvant therapy post-surgery.

    Reporting group title
    T+P Concomitant Non-Anthracycline Chemotherapy
    Reporting group description
    		 Trastuzumab, carboplatin, docetaxel (TCH) and pertuzumab every three weeks, for six cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.

    Primary: Percentage of Subjects With Symptomatic Cardiac Events as Assessed by the Investigator

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    End point title
    		 Percentage of Subjects With Symptomatic Cardiac Events as Assessed by the Investigator [1]
    End point description
    Left ventricular systolic dysfunction (LVSD) as assessed by the Investigator, including Grade 3, 4 or 5 symptomatic LVSD with symptomatic cardiac events. Safety population included all subjects who were randomised and received study drug.
    End point type
    Primary
    End point timeframe
    From baseline up to approximately 3.5 years
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned for this endpoint.
    End point values
    		 T+P Concomitant Anthracycline-based Chemotherapy T+P Sequential Anthracycline-based Chemotherapy T+P Concomitant Non-Anthracycline Chemotherapy
    Number of subjects analysed
    72
    75
    76
    Units: percentage of subjects
        number (not applicable)
    0
    2.7
    1.3
    No statistical analyses for this end point

    Primary: Percentage of Subjects With Left Ventricular Ejection Fraction (LVEF) Decline During Pre-operative (Neoadjuvant) Period

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    End point title
    		 Percentage of Subjects With Left Ventricular Ejection Fraction (LVEF) Decline During Pre-operative (Neoadjuvant) Period [2]
    End point description
    Percentage of subjects with LVEF measures decline of ≥ 10% from baseline and to a value of <50% during the pre-operative (neoadjuvant) period. Safety population included all subjects who were randomised and received study drug.
    End point type
    Primary
    End point timeframe
    From baseline up to approximately 18 weeks
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned for this endpoint.
    End point values
    		 T+P Concomitant Anthracycline-based Chemotherapy T+P Sequential Anthracycline-based Chemotherapy T+P Concomitant Non-Anthracycline Chemotherapy
    Number of subjects analysed
    72
    75
    76
    Units: percentage of subjects
        number (not applicable)
    5.6
    5.3
    3.9
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Complete Pathological Response (pCR)

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    End point title
    		 Percentage of Subjects With Complete Pathological Response (pCR)
    End point description
    pCR is defined as the absence of invasive neoplastic cells at microscopic examination of the tumour remnants after surgery following primary systemic therapy. pCR is evaluated after 6 cycles of treatment and surgery or following withdrawal from the study whichever occurs sooner. Intent to treat (ITT) population included all subjects who were randomised to treatment.
    End point type
    Secondary
    End point timeframe
    At surgery, after 18 weeks (6 cycles) of treatment
    End point values
    		 T+P Concomitant Anthracycline-based Chemotherapy T+P Sequential Anthracycline-based Chemotherapy T+P Concomitant Non-Anthracycline Chemotherapy
    Number of subjects analysed
    73
    75
    77
    Units: percentage of subjects
        number (confidence interval 95%)
    61.6 (49.5 to 72.8)
    57.3 (45.4 to 68.7)
    66.2 (54.6 to 76.6)
    No statistical analyses for this end point

    Secondary: Clinical Response Rate

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    End point title
    		 Clinical Response Rate
    End point description
    Tumour response is defined as complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD) and is identified as per local practice. Clinical response rate is defined as the percentage of subjects who achieve a response of CR or PR at any time pre-surgery. Per Response Evaluation Criteria in Solid Tumours Criteria (RECIST v1.0) for target lesions and assessed by mammogram or magnetic resonance imaging (MRI) and clinical breast examination (CBE): CR is disappearance of all target lesions; PR is >=30% decrease in the sum of the longest diameter of target lesions.
    End point type
    Secondary
    End point timeframe
    During each 3-week cycle of 6 total cycles: up to 18 weeks
    End point values
    		 T+P Concomitant Anthracycline-based Chemotherapy T+P Sequential Anthracycline-based Chemotherapy T+P Concomitant Non-Anthracycline Chemotherapy
    Number of subjects analysed
    73
    75
    77
    Units: percentage of subjects
        number (not applicable)
    91.8
    94.7
    89.6
    No statistical analyses for this end point

    Secondary: Time to Clinical Response

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    End point title
    		 Time to Clinical Response
    End point description
    Time to clinical response rate is defined as the time from the date of first dose received to the first date of assessment of clinical response. Clinical response is defined as a response of CR or PR at any time pre-surgery. Per RECIST v1.0 for target lesions and assessed by mammogram or MRI and CBE, CR is disappearance of all target lesions; PR is >=30% decrease in the sum of the longest diameter of target lesions. ITT population included all subjects who were randomised to treatment.
    End point type
    Secondary
    End point timeframe
    Up to 18 weeks
    End point values
    		 T+P Concomitant Anthracycline-based Chemotherapy T+P Sequential Anthracycline-based Chemotherapy T+P Concomitant Non-Anthracycline Chemotherapy
    Number of subjects analysed
    73
    75
    77
    Units: weeks
        median (confidence interval 95%)
    3.6 (3 to 6)
    6.3 (6 to 7)
    4.9 (4 to 6)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Achieving Breast Conserving Surgery

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    End point title
    		 Percentage of Subjects Achieving Breast Conserving Surgery
    End point description
    This is the percentage of subjects who achieved breast conserving surgery out of the intent-to-treat population without inflammatory breast cancer, as these subjects received mastectomy irrespective of their response to neoadjuvant (pre-operative) treatment. Number of subjects analysed represents the subjects with T2-3 tumours for whom mastectomy was planned.
    End point type
    Secondary
    End point timeframe
    At approximately 18 weeks
    End point values
    		 T+P Concomitant Anthracycline-based Chemotherapy T+P Sequential Anthracycline-based Chemotherapy T+P Concomitant Non-Anthracycline Chemotherapy
    Number of subjects analysed
    46
    36
    37
    Units: percentage of subjects
        number (not applicable)
    21.7
    16.7
    27
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Without an Overall Survival (OS) Event

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    End point title
    		 Percentage of Subjects Without an Overall Survival (OS) Event
    End point description
    Overall survival (OS) was defined as the time from randomisation to the date of death from any cause. Subjects who were alive or lost to follow-up were censored at the last known alive date. Subjects with no post-baseline information were censored. ITT population included all subjects who were randomised to treatment.
    End point type
    Secondary
    End point timeframe
    From baseline to end of study up to 5 years
    End point values
    		 T+P Concomitant Anthracycline-based Chemotherapy T+P Sequential Anthracycline-based Chemotherapy T+P Concomitant Non-Anthracycline Chemotherapy
    Number of subjects analysed
    73
    75
    77
    Units: percentage of subjects
        number (not applicable)
    93.2
    90.7
    87
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Without a Disease-Free Survival (DFS) Event

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    End point title
    		 Percentage of Subjects Without a Disease-Free Survival (DFS) Event
    End point description
    The DFS was defined as the time from the first date of no disease (i.e., date of surgery) to the first documentation of progressive disease (PD) or death. PD was assessed using RECIST v1.0 and mammogram or MRI and CBE. It was defined as at least a 20% increase in the sum of diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions. Any evidence of contralateral disease in situ was not considered as PD. Subjects who were withdrawn from the study without documented PD were censored at the date of the last assessment when the subject was known to be disease-free. ITT population included all subjects who were randomised to treatment. Number of subjects analysed is total number of subjects evaluable during each period.
    End point type
    Secondary
    End point timeframe
    From baseline to end of study up to 5 years
    End point values
    		 T+P Concomitant Anthracycline-based Chemotherapy T+P Sequential Anthracycline-based Chemotherapy T+P Concomitant Non-Anthracycline Chemotherapy
    Number of subjects analysed
    69
    67
    72
    Units: percentage of subjects
        number (not applicable)
    85.5
    88.1
    84.7
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Without a Progression-Free Survival (PFS) Event

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    End point title
    		 Percentage of Subjects Without a Progression-Free Survival (PFS) Event
    End point description
    Progression-free survival was defined as the time from the date of randomisation to the first documentation of PD or death from any cause, whichever occurred first. PD was assessed using RECIST v1.0 and mammogram or MRI and CBE. It was defined as at least a 20% increase in the sum of diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions. Subjects who were withdrawn from the study without documented PD were censored at the date of the last assessment when the subject was known to be free from PD. Subjects without post-baseline assessments but known to be alive were censored at the time of randomisation plus one day. ITT population included all subjects who were randomised to treatment.
    End point type
    Secondary
    End point timeframe
    From baseline to end of study up to 5 years
    End point values
    		 T+P Concomitant Anthracycline-based Chemotherapy T+P Sequential Anthracycline-based Chemotherapy T+P Concomitant Non-Anthracycline Chemotherapy
    Number of subjects analysed
    73
    75
    77
    Units: percentage of subjects
        number (not applicable)
    86.3
    85.3
    81.8
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Cardiac Symptoms Associated With Symptomatic Left Ventricular Systolic Dysfunction (LVSD)

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    End point title
    		 Percentage of Subjects With Cardiac Symptoms Associated With Symptomatic Left Ventricular Systolic Dysfunction (LVSD)
    End point description
    Percentage of subjects with signs or symptoms of cardiac events. Safety analysis population included all randomised subjects who received treatment. Number of subjects analysed is total number of subjects evaluable during each period.
    End point type
    Secondary
    End point timeframe
    From Baseline to end of Neoadjuvant Period (up to 18 weeks), Adjuvant Period (up to 1.5 years), Follow-up Period (up to 3.5 years)
    End point values
    		 T+P Concomitant Anthracycline-based Chemotherapy T+P Sequential Anthracycline-based Chemotherapy T+P Concomitant Non-Anthracycline Chemotherapy
    Number of subjects analysed
    72
    75
    76
    Units: percentage of subjects
    number (not applicable)
        Neoadjuvant Period (n=72, 75, 76)
    1.4
    2.7
    0
        Adjuvant Period (n= 68, 65, 67)
    0
    0
    1.5
        Follow-up Period (n=70, 75, 74)
    0
    1.3
    0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Asymptomatic Left Ventricular Ejection Fraction (LVEF) Events

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    End point title
    		 Percentage of Subjects With Asymptomatic Left Ventricular Ejection Fraction (LVEF) Events
    End point description
    Percentage of subjects with LVEF events without signs or symptoms of cardiac events. Safety analysis population included all randomised subjects who received treatment. Number of subjects analysed is total number of subjects evaluable during each period.
    End point type
    Secondary
    End point timeframe
    From baseline to end of Neoadjuvant Period (up to 18 weeks), Adjuvant Period (up to 1.5 years), Follow-up Period (up to 3.5 years)
    End point values
    		 T+P Concomitant Anthracycline-based Chemotherapy T+P Sequential Anthracycline-based Chemotherapy T+P Concomitant Non-Anthracycline Chemotherapy
    Number of subjects analysed
    72
    75
    76
    Units: percentage of subjects
    number (not applicable)
        Neoadjuvant Period (n=72, 75, 76)
    5.6
    4
    2.6
        Adjuvant Period (n= 66, 64, 63)
    3
    0
    4.8
        Follow-up Period (n=21, 18, 23)
    0
    11.1
    4.3
    No statistical analyses for this end point

    Secondary: Maximum Decrease in Left Ventricular Ejection Fraction (LVEF) Measures

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    End point title
    		 Maximum Decrease in Left Ventricular Ejection Fraction (LVEF) Measures
    End point description
    Maximum decrease in LVEF measures is the change from baseline at worst treatment value. LVEF is measured as percentage. Safety analysis population included all randomised subjects who received treatment. Number of subjects analysed is total number of subjects evaluable.
    End point type
    Secondary
    End point timeframe
    From baseline up to approximately 3.5 years
    End point values
    		 T+P Concomitant Anthracycline-based Chemotherapy T+P Sequential Anthracycline-based Chemotherapy T+P Concomitant Non-Anthracycline Chemotherapy
    Number of subjects analysed
    71
    72
    73
    Units: percentage (ejection fraction)
        arithmetic mean (standard deviation)
    -6.6 ( 5.15 )
    -8.4 ( 5.66 )
    -7 ( 6.48 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 5 years
    Adverse event reporting additional description
    Safety population included all subjects who were randomised and received study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    T+P Concomitant Anthracycline-based Chemotherapy
    Reporting group description
    		 5-Fluorouracil, epirubicin with cyclophosphamide (FEC), trastuzumab and pertuzumab every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.

    Reporting group title
    T+P Sequential Anthracycline-based Chemotherapy
    Reporting group description
    		 FEC every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 21 as adjuvant therapy post-surgery.

    Reporting group title
    T+P Concomitant Non-Anthracycline Chemotherapy
    Reporting group description
    		 Trastuzumab, carboplatin, docetaxel (TCH) and pertuzumab every three weeks, for six cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.

    Serious adverse events
    		 T+P Concomitant Anthracycline-based Chemotherapy T+P Sequential Anthracycline-based Chemotherapy T+P Concomitant Non-Anthracycline Chemotherapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    23 / 72 (31.94%)
    18 / 75 (24.00%)
    31 / 76 (40.79%)
         number of deaths (all causes)
    1
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastatic neoplasm
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Mucosal inflammation
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 75 (0.00%)
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 75 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 75 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 75 (0.00%)
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaphylactic reaction
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 75 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Breast mass
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 75 (1.33%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast necrosis
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 75 (1.33%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 75 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 75 (1.33%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Panic attack
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 75 (1.33%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Post procedural haematoma
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 75 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seroma
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 75 (1.33%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 72 (1.39%)
    3 / 75 (4.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiovascular disorder
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 75 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Conduction disorder
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 75 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 75 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 75 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile Neutropenia
         subjects affected / exposed
    10 / 72 (13.89%)
    4 / 75 (5.33%)
    11 / 76 (14.47%)
         occurrences causally related to treatment / all
    10 / 10
    4 / 4
    13 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 72 (2.78%)
    3 / 75 (4.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    2 / 72 (2.78%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 75 (0.00%)
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 72 (1.39%)
    3 / 75 (4.00%)
    4 / 76 (5.26%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 75 (2.67%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 75 (1.33%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 75 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    2 / 72 (2.78%)
    0 / 75 (0.00%)
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 75 (2.67%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 75 (1.33%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 75 (1.33%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 75 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 75 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 75 (1.33%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 75 (1.33%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 75 (1.33%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 75 (1.33%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung Abscess
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 75 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pseudomembranous colitis
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 75 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 75 (1.33%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 75 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 75 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 75 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 75 (1.33%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 T+P Concomitant Anthracycline-based Chemotherapy T+P Sequential Anthracycline-based Chemotherapy T+P Concomitant Non-Anthracycline Chemotherapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    72 / 72 (100.00%)
    73 / 75 (97.33%)
    76 / 76 (100.00%)
    Vascular disorders
    Hot Flush
         subjects affected / exposed
    11 / 72 (15.28%)
    9 / 75 (12.00%)
    10 / 76 (13.16%)
         occurrences all number
    12
    12
    12
    Hypertension
         subjects affected / exposed
    5 / 72 (6.94%)
    2 / 75 (2.67%)
    5 / 76 (6.58%)
         occurrences all number
    5
    2
    5
    Lymphoedema
         subjects affected / exposed
    2 / 72 (2.78%)
    5 / 75 (6.67%)
    4 / 76 (5.26%)
         occurrences all number
    2
    5
    4
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    30 / 72 (41.67%)
    28 / 75 (37.33%)
    33 / 76 (43.42%)
         occurrences all number
    51
    46
    46
    Mucosal inflammation
         subjects affected / exposed
    17 / 72 (23.61%)
    15 / 75 (20.00%)
    12 / 76 (15.79%)
         occurrences all number
    31
    21
    21
    Pyrexia
         subjects affected / exposed
    11 / 72 (15.28%)
    9 / 75 (12.00%)
    15 / 76 (19.74%)
         occurrences all number
    11
    13
    20
    Asthenia
         subjects affected / exposed
    9 / 72 (12.50%)
    14 / 75 (18.67%)
    10 / 76 (13.16%)
         occurrences all number
    13
    24
    28
    Oedema peripheral
         subjects affected / exposed
    10 / 72 (13.89%)
    5 / 75 (6.67%)
    9 / 76 (11.84%)
         occurrences all number
    13
    5
    11
    Pain
         subjects affected / exposed
    3 / 72 (4.17%)
    7 / 75 (9.33%)
    4 / 76 (5.26%)
         occurrences all number
    3
    7
    5
    Chills
         subjects affected / exposed
    4 / 72 (5.56%)
    1 / 75 (1.33%)
    7 / 76 (9.21%)
         occurrences all number
    4
    1
    9
    Chest pain
         subjects affected / exposed
    2 / 72 (2.78%)
    4 / 75 (5.33%)
    5 / 76 (6.58%)
         occurrences all number
    2
    4
    5
    Influenza like illness
         subjects affected / exposed
    2 / 72 (2.78%)
    5 / 75 (6.67%)
    2 / 76 (2.63%)
         occurrences all number
    2
    6
    3
    Oedema
         subjects affected / exposed
    1 / 72 (1.39%)
    3 / 75 (4.00%)
    5 / 76 (6.58%)
         occurrences all number
    1
    3
    6
    Axillary pain
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 75 (0.00%)
    5 / 76 (6.58%)
         occurrences all number
    0
    0
    5
    Malaise
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 75 (2.67%)
    5 / 76 (6.58%)
         occurrences all number
    0
    4
    15
    Chest discomfort
         subjects affected / exposed
    4 / 72 (5.56%)
    3 / 75 (4.00%)
    3 / 76 (3.95%)
         occurrences all number
    5
    4
    4
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    6 / 72 (8.33%)
    2 / 75 (2.67%)
    7 / 76 (9.21%)
         occurrences all number
    9
    3
    11
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    2 / 72 (2.78%)
    3 / 75 (4.00%)
    6 / 76 (7.89%)
         occurrences all number
    2
    4
    7
    Vulvovaginal dryness
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 75 (1.33%)
    4 / 76 (5.26%)
         occurrences all number
    0
    1
    4
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    13 / 72 (18.06%)
    8 / 75 (10.67%)
    10 / 76 (13.16%)
         occurrences all number
    15
    9
    11
    Epistaxis
         subjects affected / exposed
    8 / 72 (11.11%)
    10 / 75 (13.33%)
    11 / 76 (14.47%)
         occurrences all number
    12
    12
    16
    Cough
         subjects affected / exposed
    10 / 72 (13.89%)
    8 / 75 (10.67%)
    10 / 76 (13.16%)
         occurrences all number
    14
    9
    12
    Oropharyngeal pain
         subjects affected / exposed
    7 / 72 (9.72%)
    6 / 75 (8.00%)
    9 / 76 (11.84%)
         occurrences all number
    7
    9
    15
    Rhinorrhoea
         subjects affected / exposed
    3 / 72 (4.17%)
    5 / 75 (6.67%)
    7 / 76 (9.21%)
         occurrences all number
    5
    5
    7
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    12 / 72 (16.67%)
    13 / 75 (17.33%)
    17 / 76 (22.37%)
         occurrences all number
    14
    13
    22
    Depression
         subjects affected / exposed
    3 / 72 (4.17%)
    3 / 75 (4.00%)
    4 / 76 (5.26%)
         occurrences all number
    3
    3
    4
    Anxiety
         subjects affected / exposed
    1 / 72 (1.39%)
    4 / 75 (5.33%)
    4 / 76 (5.26%)
         occurrences all number
    1
    5
    4
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    6 / 72 (8.33%)
    4 / 75 (5.33%)
    7 / 76 (9.21%)
         occurrences all number
    7
    8
    8
    Alanine aminotransferase increased
         subjects affected / exposed
    5 / 72 (6.94%)
    3 / 75 (4.00%)
    8 / 76 (10.53%)
         occurrences all number
    5
    5
    10
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 72 (5.56%)
    3 / 75 (4.00%)
    5 / 76 (6.58%)
         occurrences all number
    4
    4
    5
    Weight decreased
         subjects affected / exposed
    3 / 72 (4.17%)
    4 / 75 (5.33%)
    5 / 76 (6.58%)
         occurrences all number
    3
    5
    5
    Injury, poisoning and procedural complications
    Radiation skin injury
         subjects affected / exposed
    11 / 72 (15.28%)
    14 / 75 (18.67%)
    7 / 76 (9.21%)
         occurrences all number
    14
    16
    7
    Seroma
         subjects affected / exposed
    4 / 72 (5.56%)
    4 / 75 (5.33%)
    1 / 76 (1.32%)
         occurrences all number
    5
    4
    2
    Cardiac disorders
    Left ventricular dysfunction
         subjects affected / exposed
    7 / 72 (9.72%)
    8 / 75 (10.67%)
    7 / 76 (9.21%)
         occurrences all number
    12
    12
    10
    Palpitations
         subjects affected / exposed
    3 / 72 (4.17%)
    1 / 75 (1.33%)
    4 / 76 (5.26%)
         occurrences all number
    3
    1
    5
    Nervous system disorders
    Headache
         subjects affected / exposed
    20 / 72 (27.78%)
    15 / 75 (20.00%)
    16 / 76 (21.05%)
         occurrences all number
    30
    23
    20
    Dysgeusia
         subjects affected / exposed
    8 / 72 (11.11%)
    10 / 75 (13.33%)
    16 / 76 (21.05%)
         occurrences all number
    10
    11
    22
    Dizziness
         subjects affected / exposed
    7 / 72 (9.72%)
    9 / 75 (12.00%)
    15 / 76 (19.74%)
         occurrences all number
    12
    11
    21
    Neuropathy peripheral
         subjects affected / exposed
    5 / 72 (6.94%)
    4 / 75 (5.33%)
    8 / 76 (10.53%)
         occurrences all number
    5
    4
    10
    Peripheral sensory neuropathy
         subjects affected / exposed
    4 / 72 (5.56%)
    8 / 75 (10.67%)
    5 / 76 (6.58%)
         occurrences all number
    12
    14
    10
    Polyneuropathy
         subjects affected / exposed
    4 / 72 (5.56%)
    1 / 75 (1.33%)
    4 / 76 (5.26%)
         occurrences all number
    4
    1
    4
    Paraesthesia
         subjects affected / exposed
    3 / 72 (4.17%)
    4 / 75 (5.33%)
    9 / 76 (11.84%)
         occurrences all number
    3
    7
    11
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    36 / 72 (50.00%)
    33 / 75 (44.00%)
    37 / 76 (48.68%)
         occurrences all number
    102
    86
    107
    Anaemia
         subjects affected / exposed
    14 / 72 (19.44%)
    8 / 75 (10.67%)
    29 / 76 (38.16%)
         occurrences all number
    17
    11
    48
    Leukopenia
         subjects affected / exposed
    16 / 72 (22.22%)
    12 / 75 (16.00%)
    13 / 76 (17.11%)
         occurrences all number
    61
    37
    36
    Thrombocytopenia
         subjects affected / exposed
    5 / 72 (6.94%)
    1 / 75 (1.33%)
    23 / 76 (30.26%)
         occurrences all number
    8
    1
    40
    Febrile neutropenia
         subjects affected / exposed
    4 / 72 (5.56%)
    3 / 75 (4.00%)
    2 / 76 (2.63%)
         occurrences all number
    4
    3
    2
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    9 / 72 (12.50%)
    4 / 75 (5.33%)
    6 / 76 (7.89%)
         occurrences all number
    11
    5
    6
    Eyelid oedema
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 75 (1.33%)
    4 / 76 (5.26%)
         occurrences all number
    1
    1
    4
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    46 / 72 (63.89%)
    44 / 75 (58.67%)
    55 / 76 (72.37%)
         occurrences all number
    91
    68
    129
    Nausea
         subjects affected / exposed
    38 / 72 (52.78%)
    41 / 75 (54.67%)
    34 / 76 (44.74%)
         occurrences all number
    84
    71
    71
    Vomiting
         subjects affected / exposed
    29 / 72 (40.28%)
    27 / 75 (36.00%)
    30 / 76 (39.47%)
         occurrences all number
    44
    36
    60
    Dyspepsia
         subjects affected / exposed
    19 / 72 (26.39%)
    9 / 75 (12.00%)
    17 / 76 (22.37%)
         occurrences all number
    21
    9
    21
    Constipation
         subjects affected / exposed
    14 / 72 (19.44%)
    18 / 75 (24.00%)
    13 / 76 (17.11%)
         occurrences all number
    21
    25
    19
    Abdominal pain upper
         subjects affected / exposed
    7 / 72 (9.72%)
    6 / 75 (8.00%)
    5 / 76 (6.58%)
         occurrences all number
    8
    9
    8
    Abdominal pain
         subjects affected / exposed
    3 / 72 (4.17%)
    7 / 75 (9.33%)
    6 / 76 (7.89%)
         occurrences all number
    3
    8
    9
    Dry mouth
         subjects affected / exposed
    4 / 72 (5.56%)
    2 / 75 (2.67%)
    8 / 76 (10.53%)
         occurrences all number
    4
    2
    9
    Haemorrhoids
         subjects affected / exposed
    5 / 72 (6.94%)
    1 / 75 (1.33%)
    4 / 76 (5.26%)
         occurrences all number
    5
    1
    4
    Abdominal distension
         subjects affected / exposed
    2 / 72 (2.78%)
    2 / 75 (2.67%)
    4 / 76 (5.26%)
         occurrences all number
    2
    2
    4
    Oral pain
         subjects affected / exposed
    1 / 72 (1.39%)
    4 / 75 (5.33%)
    2 / 76 (2.63%)
         occurrences all number
    1
    5
    2
    Stomatitis
         subjects affected / exposed
    10 / 72 (13.89%)
    13 / 75 (17.33%)
    9 / 76 (11.84%)
         occurrences all number
    12
    19
    10
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    35 / 72 (48.61%)
    39 / 75 (52.00%)
    42 / 76 (55.26%)
         occurrences all number
    35
    39
    45
    Rash
         subjects affected / exposed
    17 / 72 (23.61%)
    8 / 75 (10.67%)
    20 / 76 (26.32%)
         occurrences all number
    18
    13
    20
    Nail disorder
         subjects affected / exposed
    9 / 72 (12.50%)
    8 / 75 (10.67%)
    10 / 76 (13.16%)
         occurrences all number
    9
    9
    13
    Erythema
         subjects affected / exposed
    10 / 72 (13.89%)
    5 / 75 (6.67%)
    11 / 76 (14.47%)
         occurrences all number
    10
    6
    15
    Dry skin
         subjects affected / exposed
    5 / 72 (6.94%)
    7 / 75 (9.33%)
    8 / 76 (10.53%)
         occurrences all number
    6
    7
    11
    Palmar -plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    5 / 72 (6.94%)
    9 / 75 (12.00%)
    6 / 76 (7.89%)
         occurrences all number
    7
    9
    6
    Pruritus
         subjects affected / exposed
    3 / 72 (4.17%)
    7 / 75 (9.33%)
    4 / 76 (5.26%)
         occurrences all number
    4
    10
    5
    Skin reaction
         subjects affected / exposed
    2 / 72 (2.78%)
    5 / 75 (6.67%)
    3 / 76 (3.95%)
         occurrences all number
    2
    5
    3
    Dermatitis
         subjects affected / exposed
    1 / 72 (1.39%)
    5 / 75 (6.67%)
    0 / 76 (0.00%)
         occurrences all number
    1
    5
    0
    Hyperhidrosis
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 75 (0.00%)
    5 / 76 (6.58%)
         occurrences all number
    1
    0
    6
    Night sweats
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 75 (0.00%)
    5 / 76 (6.58%)
         occurrences all number
    1
    0
    6
    Skin hyperpigmentation
         subjects affected / exposed
    2 / 72 (2.78%)
    4 / 75 (5.33%)
    0 / 76 (0.00%)
         occurrences all number
    2
    5
    0
    Skin exfoliation
         subjects affected / exposed
    0 / 72 (0.00%)
    4 / 75 (5.33%)
    0 / 76 (0.00%)
         occurrences all number
    0
    4
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    2 / 72 (2.78%)
    0 / 75 (0.00%)
    7 / 76 (9.21%)
         occurrences all number
    2
    0
    8
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    18 / 72 (25.00%)
    18 / 75 (24.00%)
    11 / 76 (14.47%)
         occurrences all number
    22
    24
    12
    Myalgia
         subjects affected / exposed
    14 / 72 (19.44%)
    16 / 75 (21.33%)
    8 / 76 (10.53%)
         occurrences all number
    21
    22
    14
    Back pain
         subjects affected / exposed
    11 / 72 (15.28%)
    9 / 75 (12.00%)
    7 / 76 (9.21%)
         occurrences all number
    15
    10
    7
    Musculoskeletal pain
         subjects affected / exposed
    11 / 72 (15.28%)
    8 / 75 (10.67%)
    5 / 76 (6.58%)
         occurrences all number
    13
    11
    5
    Pain in extremity
         subjects affected / exposed
    7 / 72 (9.72%)
    7 / 75 (9.33%)
    7 / 76 (9.21%)
         occurrences all number
    7
    8
    7
    Muscle spasms
         subjects affected / exposed
    4 / 72 (5.56%)
    4 / 75 (5.33%)
    6 / 76 (7.89%)
         occurrences all number
    5
    4
    7
    Musculoskeletal chest pain
         subjects affected / exposed
    5 / 72 (6.94%)
    3 / 75 (4.00%)
    5 / 76 (6.58%)
         occurrences all number
    6
    3
    7
    Bone pain
         subjects affected / exposed
    4 / 72 (5.56%)
    4 / 75 (5.33%)
    2 / 76 (2.63%)
         occurrences all number
    4
    4
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    6 / 72 (8.33%)
    9 / 75 (12.00%)
    9 / 76 (11.84%)
         occurrences all number
    7
    13
    9
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 72 (9.72%)
    10 / 75 (13.33%)
    3 / 76 (3.95%)
         occurrences all number
    10
    13
    5
    Urinary tract infection
         subjects affected / exposed
    5 / 72 (6.94%)
    7 / 75 (9.33%)
    7 / 76 (9.21%)
         occurrences all number
    5
    7
    11
    Rhinitis
         subjects affected / exposed
    6 / 72 (8.33%)
    1 / 75 (1.33%)
    4 / 76 (5.26%)
         occurrences all number
    8
    1
    5
    Cystitis
         subjects affected / exposed
    0 / 72 (0.00%)
    4 / 75 (5.33%)
    6 / 76 (7.89%)
         occurrences all number
    0
    4
    7
    Conjunctivitis
         subjects affected / exposed
    3 / 72 (4.17%)
    2 / 75 (2.67%)
    4 / 76 (5.26%)
         occurrences all number
    3
    2
    4
    Influenza
         subjects affected / exposed
    5 / 72 (6.94%)
    4 / 75 (5.33%)
    2 / 76 (2.63%)
         occurrences all number
    5
    4
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    15 / 72 (20.83%)
    8 / 75 (10.67%)
    16 / 76 (21.05%)
         occurrences all number
    18
    11
    27

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 May 2010
    The protocol has been amended to accommodate following changes: 1. The protocol requirement for a mammogram between study day -14 and start of treatment was a significant issue for many centres. Many subjects would have had a mammogram before study day -14 and concerns were raised over repeat exposure to radiation within a short timeframe which would not be in the subject's interest and could be potentially harmful. An extension of the window for the mammogram to be performed in screening period has been made to remove need for a second ‘study’ mammogram if subject has recently received a mammogram as part of standard practice. In addition, centres will be able to use magnetic resonance imaging in place of mammography according to local practice. 2. To provide information on the ‘Emergency Medical Call Centre Help Desk’ for medical emergencies outside regular business hours. 3. To clarify schedule of electrocardiogram assessments in treatment period of study, information on suspected unexpected serious adverse reaction reporting, need for clinical breast exam and mammogram at end of Cycle 6 and prior to surgery, clarification of complete blood count assessment schedule by treatment arm in neoadjuvant period of study. 4. Clarification that Steering Committee will also look at key safety outputs from the neoadjuvant portion of the study. 5. To clarify that investigators may adjust dose of study medications based upon small changes in body weight or body surface area. 6. Clarification of modifications of dosing of non-investigational medicinal products.

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

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