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    Clinical Trial Results:
    A Multicenter, Multinational, Phase II Study to Evaluate Perjeta in Combination With Herceptin and Standard Neoadjuvant Anthracycline-Based Chemotherapy in Patients With HER2-Positive, Locally Advanced, Inflammatory, or Early-Stage Breast Cancer

    Summary
    EudraCT number
    		 2014-000156-28
    Trial protocol
    		 DE   GB   ES   IT   PT   FR   PL   DK  
    Global end of trial date
    25 Aug 2020

    Results information
    Results version number
    		 v2(current)
    This version publication date
    03 Sep 2021
    First version publication date
    17 Mar 2017
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    WO29217
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02132949
    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
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, 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 Aug 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Aug 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This is a non-randomized, open-label, multicenter, multinational, phase 2 clinical trial including two parallel cohorts of participants. The primary objective of this study was to evaluate the cardiac safety of neoadjuvant treatment with the following regimens: A) dose-dense doxorubicin and cyclophosphamide (ddAC), followed by paclitaxel with pertuzumab and trastuzumab; B) 5-fluoracil, epirrubicin and cyclophosphamide (FEC), followed by docetaxel with pertuzumab and trastuzumab. Secondary safety objectives of the study included evaluation of the cardiac and overall safety profiles of these 2 treatment regimens during the neoadjuvant, adjuvant, and treatment-free follow-up periods, as well as an assessment of anti-tumor activity in the form of pathological complete response (pCR), clinical response, event-free survival (EFS), invasive disease-free survival (iDFS), and overall survival (OS) of each cohort.
    Protection of trial subjects
    The study was conducted in accordance with the principles of the “Declaration of Helsinki” and Good Clinical Practice (GCP).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Jul 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 91
    Country: Number of subjects enrolled
    Canada: 21
    Country: Number of subjects enrolled
    Denmark: 15
    Country: Number of subjects enrolled
    France: 75
    Country: Number of subjects enrolled
    United Kingdom: 34
    Country: Number of subjects enrolled
    Germany: 29
    Country: Number of subjects enrolled
    Italy: 14
    Country: Number of subjects enrolled
    Mexico: 6
    Country: Number of subjects enrolled
    Norway: 12
    Country: Number of subjects enrolled
    Poland: 10
    Country: Number of subjects enrolled
    Portugal: 31
    Country: Number of subjects enrolled
    Spain: 62
    Worldwide total number of subjects
    400
    EEA total number of subjects
    248
    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)
    352
    From 65 to 84 years
    48
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 401 participants were enrolled, 199 in Cohort A and 202 in Cohort B. One participant in Cohort B who was human epidermal growth factor receptor 2 (HER2) negative and was enrolled by error, was excluded from the study. Hence, 199 participants were included in Cohort A and 201 participants in Cohort B.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab
    Arm description
    		 Subjects received neoadjuvant treatment with dose-dense doxorubicin and cyclophosphamide (ddAC), with administration of doxorubicin 60 milligrams per square meter (mg/m^2) intravenously (IV) once every 2 weeks (q2w) and cyclophosphamide 600mg/m^2 IV q2w for 4 cycles, followed by paclitaxel 80mg/m^2 IV once weekly (qw) for 12 weeks. Pertuzumab (840 milligrams [mg] IV loading dose then 420mg IV q3w) and trastuzumab (8 milligrams per kilogram [mg/kg] IV loading dose then 4mg/kg IV q3w) were administered along with paclitaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, subjects received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, subjects were followed for safety and efficacy for up to 5 years.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Adriamycin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received doxorubicin 60 milligrams per square meter (mg/m^2) as an intravenous (IV) bolus over 3-5 minutes (min) or as an infusion over 15-30min q2w for 4 cycles.

    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
    Participants received cyclophosphamide 600mg/m^2 IV bolus over 3-5min or as an infusion, in accordance with local policy, q2w for 4 cycles.

    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
    Participants received paclitaxel 80mg/m^2 IV infusion weekly once (qw) for 12 weeks.

    Investigational medicinal product name
    Pertuzumab
    Investigational medicinal product code
    Other name
    Perjeta
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received pertuzumab 840mg loading dose IV, then 420mg IV q3w for 17 cycles.

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Herceptin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received trastuzumab 8 milligrams per kilogram (mg/kg) loading dose IV, then 6mg/kg q3w for 17 cycles.

    Arm title
    		 Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
    Arm description
    		 Subjects received neoadjuvant treatment with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC), with administration of 5-fluorouracil 500mg/m^2 intravenously (IV) q3w, epirubicin 100mg/m^2 IV q3w, and cyclophosphamide 600mg/m^2 IV q3w for 4 cycles, followed by docetaxel (with starting dose of 75mg/m^2 in Cycle 5, then 100mg/m^2 for Cycles 6-8) q3w for 4 cycles. Pertuzumab (840 mg IV loading dose then 420mg IV q3w) and trastuzumab (8 mg/kg IV loading dose then 4mg/kg IV q3w) were given along with doectaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, subjects received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, subjects were followed for safety and efficacy for up to 5 years.
    Arm type
    		 Experimental

    Investigational medicinal product name
    5-Fluorouracil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received 5-fluorouracil 500mg/m^2 as an IV bolus or as an infusion, in accordance with local policy, q3w for 4 cycles.

    Investigational medicinal product name
    Epirubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received epirubicin 100mg/m^2 as an IV bolus over 3-5min or as an infusion over 3-5min, in accordance with local policy, q3w for 4 cycles.

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received docetaxel with starting dose of 75mg/m^2 in Cycle 5, then 100mg/m^2 for Cycles 6-8 q3w for 4 cycles.

    Investigational medicinal product name
    Pertuzumab
    Investigational medicinal product code
    Other name
    Perjeta
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received pertuzumab 840mg loading dose IV, then 420mg IV q3w for 17 cycles.

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Herceptin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received trastuzumab 8 milligrams per kilogram (mg/kg) loading dose IV, then 6mg/kg q3w for 17 cycles.

    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
    Participants received cyclophosphamide 600mg/m^2 IV bolus over 3-5min or as an infusion, in accordance with local policy, q2w for 4 cycles.

    Number of subjects in period 1
    		Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
    Started
    199
    201
    Received any Cohort A Treatment (Safety)
    198
    1 [1]
    Received any Cohort B Treatment (Safety)
    0 [2]
    198
    Underwent Surgery
    187
    194
    Completed Neoadjuvant Treatment
    182
    189
    Started Adjuvant Treatment
    181
    190
    Completed Adjuvant Treatment
    163
    176
    Started Treatment-Free Follow-Up
    195
    195
    Completed
    158
    173
    Not completed
    41
    28
         Consent withdrawn by subject
    6
    5
         Physician decision
    3
    1
         Adverse event, non-fatal
    2
    1
         Death
    7
    13
         Withdrew Prior to Treatment
    1
    2
         Lost to follow-up
    14
    4
         Reason Unspecified
    -
    1
         Disease Progression
    3
    -
         Noncompliance
    5
    1
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: One subject who had enrolled in Cohort B received Cohort A treatment, and they were counted as part of the Cohort A safety analysis population.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: None of the subjects who had enrolled in Cohort A received any Cohort B treatment.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab
    Reporting group description
    		 Subjects received neoadjuvant treatment with dose-dense doxorubicin and cyclophosphamide (ddAC), with administration of doxorubicin 60 milligrams per square meter (mg/m^2) intravenously (IV) once every 2 weeks (q2w) and cyclophosphamide 600mg/m^2 IV q2w for 4 cycles, followed by paclitaxel 80mg/m^2 IV once weekly (qw) for 12 weeks. Pertuzumab (840 milligrams [mg] IV loading dose then 420mg IV q3w) and trastuzumab (8 milligrams per kilogram [mg/kg] IV loading dose then 4mg/kg IV q3w) were administered along with paclitaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, subjects received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, subjects were followed for safety and efficacy for up to 5 years.

    Reporting group title
    Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
    Reporting group description
    		 Subjects received neoadjuvant treatment with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC), with administration of 5-fluorouracil 500mg/m^2 intravenously (IV) q3w, epirubicin 100mg/m^2 IV q3w, and cyclophosphamide 600mg/m^2 IV q3w for 4 cycles, followed by docetaxel (with starting dose of 75mg/m^2 in Cycle 5, then 100mg/m^2 for Cycles 6-8) q3w for 4 cycles. Pertuzumab (840 mg IV loading dose then 420mg IV q3w) and trastuzumab (8 mg/kg IV loading dose then 4mg/kg IV q3w) were given along with doectaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, subjects received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, subjects were followed for safety and efficacy for up to 5 years.

    Reporting group values
    		 Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab Total
    Number of subjects
    		 199 201 400
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 49.8 ( 11.7 ) 49.5 ( 11.5 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 199 200 399
        Male
    		 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab
    Reporting group description
    		 Subjects received neoadjuvant treatment with dose-dense doxorubicin and cyclophosphamide (ddAC), with administration of doxorubicin 60 milligrams per square meter (mg/m^2) intravenously (IV) once every 2 weeks (q2w) and cyclophosphamide 600mg/m^2 IV q2w for 4 cycles, followed by paclitaxel 80mg/m^2 IV once weekly (qw) for 12 weeks. Pertuzumab (840 milligrams [mg] IV loading dose then 420mg IV q3w) and trastuzumab (8 milligrams per kilogram [mg/kg] IV loading dose then 4mg/kg IV q3w) were administered along with paclitaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, subjects received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, subjects were followed for safety and efficacy for up to 5 years.

    Reporting group title
    Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
    Reporting group description
    		 Subjects received neoadjuvant treatment with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC), with administration of 5-fluorouracil 500mg/m^2 intravenously (IV) q3w, epirubicin 100mg/m^2 IV q3w, and cyclophosphamide 600mg/m^2 IV q3w for 4 cycles, followed by docetaxel (with starting dose of 75mg/m^2 in Cycle 5, then 100mg/m^2 for Cycles 6-8) q3w for 4 cycles. Pertuzumab (840 mg IV loading dose then 420mg IV q3w) and trastuzumab (8 mg/kg IV loading dose then 4mg/kg IV q3w) were given along with doectaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, subjects received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, subjects were followed for safety and efficacy for up to 5 years.

    Primary: Percentage of Participants With at Least One Event of New York Heart Association (NYHA) Class III or IV Heart Failure During the Neoadjuvant Treatment Period

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    End point title
    		 Percentage of Participants With at Least One Event of New York Heart Association (NYHA) Class III or IV Heart Failure During the Neoadjuvant Treatment Period [1]
    End point description
    Symptomatic left ventricular systolic dysfunction (otherwise referred to as heart failure) is a serious adverse event. The NYHA Functional Classification System for Heart Failure considers the patient's symptoms: Class III: Marked limitation of physical activity; Comfortable at rest, but less than ordinary activity causes fatigue, palpitation, or dyspnea. Class IV: Unable to carry on any physical activity without discomfort; Symptoms of heart failure at rest; If any physical activity is undertaken, discomfort increases. The 95% CIs were calculated with the Clopper-Pearson method. Results included events with onset from first dose of pertuzumab/trastuzumab prior to surgery through the day before the first dose of any study drug after surgery. If participant withdrew without entering adjuvant period, results included all events with onset from first dose of pertuzumab/trastuzumab through 42 days after last dose of any study drug or on the day of target surgery whichever was later.
    End point type
    Primary
    End point timeframe
    From day of first dose of pertuzumab or trastuzumab until the end of the neoadjuvant treatment period (as defined in the description; up to 25 weeks)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No comparisons were planned to be made between the efficacy and safety results of the two treatment cohorts. All analyses were descriptive.
    End point values
    		 Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
    Number of subjects analysed
    199
    198
    Units: Percentage of participants
        number (confidence interval 95%)
    1.5 (0.31 to 4.34)
    0 (0.00 to 1.85)
    No statistical analyses for this end point

    Primary: Percentage of Participants With at Least One Left Ventricular Ejection Fraction (LVEF) Significant Decline, Defined as a Drop in LVEF of at Least 10 Percentage Points From Baseline and to Below 50%, During the Neoadjuvant Treatment Period

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    End point title
    		 Percentage of Participants With at Least One Left Ventricular Ejection Fraction (LVEF) Significant Decline, Defined as a Drop in LVEF of at Least 10 Percentage Points From Baseline and to Below 50%, During the Neoadjuvant Treatment Period [2]
    End point description
    LVEF significant decline was defined as the decline in LVEF of >/= 10%-points from baseline to an LVEF of < 50%. A Confirmed LVEF Significant Decline was defined as at least two consecutive readings of significant declines in LVEF. A Single LVEF Significant Decline was defined as only one reading of a significant decline (no consecutive readings) in LVEF. The category of 'At Least one LVEF Significant Decline Event' was defined as the total of confirmed and single LVEF significant declines. The 95% confidence intervals (CIs) were calculated using the Clopper-Pearson method. Results include events with onset from the first dose of pertuzumab or trastuzumab prior to surgery through the day before the first dose of any study drug after surgery. If participant withdrew without entering adjuvant period, results included all events with onset from first dose of pertuzumab or trastuzumab through 42 days after last dose of any study drug or on the day of target surgery whichever is later.
    End point type
    Primary
    End point timeframe
    From day of first dose of pertuzumab or trastuzumab until the end of the neoadjuvant treatment period (as defined in the description; up to 25 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: No comparisons were planned to be made between the efficacy and safety results of the two treatment cohorts. All analyses were descriptive.
    End point values
    		 Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
    Number of subjects analysed
    199
    198
    Units: Percentage of participants
    number (confidence interval 95%)
        At Least 1 LVEF Significant Decline Event (Total)
    6.5 (3.5 to 10.9)
    2.0 (0.6 to 5.1)
        At Least 1 Confirmed LVEF Significant Decline
    1.0 (0.1 to 3.6)
    0.5 (0.0 to 2.8)
        At Least 1 Single LVEF Significant Decline
    5.5 (2.8 to 9.7)
    1.5 (0.3 to 4.4)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With at Least One Event of New York Heart Association (NYHA) Class III or IV Heart Failure During the Adjuvant Treatment Period

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    End point title
    		 Percentage of Participants With at Least One Event of New York Heart Association (NYHA) Class III or IV Heart Failure During the Adjuvant Treatment Period
    End point description
    Symptomatic left ventricular systolic dysfunction (otherwise referred to as heart failure) is a serious adverse event. The NYHA Functional Classification System for Heart Failure considers the patient's symptoms: Class III: Marked limitation of physical activity; Comfortable at rest, but less than ordinary activity causes fatigue, palpitation, or dyspnea. Class IV: Unable to carry on any physical activity without discomfort; Symptoms of heart failure at rest; If any physical activity is undertaken, discomfort increases. The 95% CIs were calculated with the Clopper-Pearson method. Results included events with onset from the first dose of any study drug after surgery through 42 days after the last dose of any study drug.
    End point type
    Secondary
    End point timeframe
    From the first dose of any study drug after surgery through 42 days after the last dose of any study drug (during the adjuvant treatment period; up to approximately 39 weeks)
    End point values
    		 Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
    Number of subjects analysed
    181 [3]
    190 [4]
    Units: Percentage of participants
        number (confidence interval 95%)
    0 (0.00 to 2.02)
    0.5 (0.01 to 2.90)
    Notes
    [3] - Includes subjects that started adjuvant treatment.
    [4] - Includes subjects that started adjuvant treatment.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With at Least One Left Ventricular Ejection Fraction (LVEF) Significant Decline, Defined as a Drop in LVEF of at Least 10 Percentage Points From Baseline and to Below 50%, During the Adjuvant Treatment Period

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    End point title
    		 Percentage of Participants With at Least One Left Ventricular Ejection Fraction (LVEF) Significant Decline, Defined as a Drop in LVEF of at Least 10 Percentage Points From Baseline and to Below 50%, During the Adjuvant Treatment Period
    End point description
    LVEF significant decline was defined as the decline in LVEF of >/= 10%-points from baseline to an LVEF of < 50%. A Confirmed LVEF Significant Decline was defined as at least two consecutive readings of significant declines in LVEF. A Single LVEF Significant Decline was defined as only one reading of a significant decline (no consecutive readings) in LVEF. The category of 'At Least one LVEF Significant Decline Event' was defined as the total of confirmed and single LVEF significant declines. The 95% confidence intervals were calculated using the Clopper-Pearson method. Results included events with onset from the first dose of any study drug after surgery through 42 days after the last dose of any study drug.
    End point type
    Secondary
    End point timeframe
    From the first dose of any study drug after surgery through 42 days after the last dose of any study drug (during the adjuvant treatment period; up to approximately 39 weeks)
    End point values
    		 Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
    Number of subjects analysed
    181 [5]
    190 [6]
    Units: Percentage of participants
    number (confidence interval 95%)
        At Least 1 LVEF Significant Decline Event (Total)
    7.7 (4.3 to 12.6)
    10.5 (6.5 to 15.8)
        At Least 1 Confirmed LVEF Significant Decline
    2.8 (0.9 to 6.3)
    3.2 (1.2 to 6.7)
        At Least 1 Single LVEF Significant Decline
    5.0 (2.3 to 9.2)
    7.4 (4.1 to 12.1)
    Notes
    [5] - Includes subjects that started adjuvant treatment.
    [6] - Includes subjects that started adjuvant treatment.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With at Least One Event of New York Heart Association (NYHA) Class III or IV Heart Failure During the Treatment-Free Follow-Up Period

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    End point title
    		 Percentage of Participants With at Least One Event of New York Heart Association (NYHA) Class III or IV Heart Failure During the Treatment-Free Follow-Up Period
    End point description
    Symptomatic left ventricular systolic dysfunction (otherwise referred to as heart failure) is a serious adverse event. The NYHA Functional Classification System for Heart Failure considers the patient's symptoms: Class III: Marked limitation of physical activity; Comfortable at rest, but less than ordinary activity causes fatigue, palpitation, or dyspnea. Class IV: Unable to carry on any physical activity without discomfort; Symptoms of heart failure at rest; If any physical activity is undertaken, discomfort increases. The 95% CIs were calculated with the Clopper-Pearson method.
    End point type
    Secondary
    End point timeframe
    From 42 days after the last dose of study treatment until the end of treatment-free follow-up (up to 5 years)
    End point values
    		 Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
    Number of subjects analysed
    199
    198
    Units: Percentage of participants
        number (confidence interval 95%)
    0 (0.00 to 1.84)
    0.5 (0.01 to 2.78)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With at Least One Left Ventricular Ejection Fraction (LVEF) Significant Decline, Defined as a Drop in LVEF of at Least 10 Percentage Points From Baseline and to Below 50%, During the Treatment-Free Follow-Up Period

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    End point title
    		 Percentage of Participants With at Least One Left Ventricular Ejection Fraction (LVEF) Significant Decline, Defined as a Drop in LVEF of at Least 10 Percentage Points From Baseline and to Below 50%, During the Treatment-Free Follow-Up Period
    End point description
    LVEF significant decline was defined as the decline in LVEF of >/= 10%-points from baseline to an LVEF of < 50%. A Confirmed LVEF Significant Decline was defined as at least two consecutive readings of significant declines in LVEF. A Single LVEF Significant Decline was defined as only one reading of a significant decline (no consecutive readings) in LVEF. The category of 'At Least one LVEF Significant Decline Event' was defined as the total of confirmed and single LVEF significant declines. The 95% confidence intervals were calculated using the Clopper-Pearson method.
    End point type
    Secondary
    End point timeframe
    From 42 days after the last dose of study treatment until the end of treatment-free follow-up (up to 5 years)
    End point values
    		 Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
    Number of subjects analysed
    199
    198
    Units: Percentage of participants
    number (confidence interval 95%)
        At Least 1 LVEF Significant Decline Event (Total)
    6.0 (3.2 to 10.3)
    3.5 (1.4 to 7.1)
        At Least 1 Confirmed LVEF Significant Decline
    3.0 (1.1 to 6.4)
    1.0 (0.1 to 3.6)
        At Least 1 Single LVEF Significant Decline
    3.0 (1.1 to 6.4)
    2.5 (0.8 to 5.8)
    No statistical analyses for this end point

    Secondary: Overview of the Number of Participants With at Least One Adverse Event During the Neoadjuvant Treatment Period

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    End point title
    		 Overview of the Number of Participants With at Least One Adverse Event During the Neoadjuvant Treatment Period
    End point description
    An adverse event (AE) is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. The terms “severe” and “serious” are not synonymous with respect to an AE. Severity refers to the intensity of an AE (rated according to NCI-CTCAE v4.0 criteria or, if not listed, the following scale: Grade 3 is severe, Grade 4 is life-threatening, and Grade 5 is death related to AE), whereas a serious AE (SAE) is a significant medical event (per standard criteria). Severity and seriousness needed to be independently assessed for each AE that was recorded. Selected AEs for reporting included heart failure (NYHA Class II/III/IV) and asymptomatic declines in LVEF (reported as an AE with the term of ejection fraction decreased). In the results table, multiple occurrences of the same AE in one individual were counted only once. Any AE includes all serious and non-serious AEs.
    End point type
    Secondary
    End point timeframe
    From first dose of any study drug prior to surgery through the day before the first dose of study drug after surgery (up to 25 weeks)
    End point values
    		 Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
    Number of subjects analysed
    199
    198
    Units: Participants
        Any Adverse Event (AE)
    198
    198
        NCI-CTCAE Grade 3-5 AE
    99
    108
        Serious AE
    45
    52
        Deaths
    0
    0
        Ejection Fraction Decreased (Any Grade)
    14
    7
        Heart Failure (Any Grade)
    4
    0
    No statistical analyses for this end point

    Secondary: Overview of the Number of Participants With at Least One Adverse Event During the Adjuvant Treatment Period

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    End point title
    		 Overview of the Number of Participants With at Least One Adverse Event During the Adjuvant Treatment Period
    End point description
    An adverse event (AE) is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. The terms “severe” and “serious” are not synonymous with respect to an AE. Severity refers to the intensity of an AE (rated according to NCI-CTCAE v4.0 criteria or, if not listed, the following scale: Grade 3 is severe, Grade 4 is life-threatening, and Grade 5 is death related to AE), whereas a serious AE (SAE) is a significant medical event (per standard criteria). Severity and seriousness needed to be independently assessed for each AE that was recorded. Selected AEs for reporting included heart failure (NYHA Class II/III/IV) and asymptomatic declines in LVEF (reported as an AE with the term of ejection fraction decreased). In the results table, multiple occurrences of the same AE in one individual were counted only once. Any AE includes all serious and non-serious AEs.
    End point type
    Secondary
    End point timeframe
    From the first dose of any study drug after surgery through 42 days after the last dose of any study drug (during the adjuvant treatment period; up to approximately 39 weeks)
    End point values
    		 Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
    Number of subjects analysed
    181 [7]
    190 [8]
    Units: Participants
        Any Adverse Event (AE)
    171
    171
        NCI-CTCAE Grade 3-5 AE
    23
    40
        Serious AE
    15
    17
        Deaths
    0
    0
        Ejection Fraction Decreased (Any Grade)
    15
    20
        Heart Failure (Any Grade)
    0
    2
    Notes
    [7] - Includes subjects that started adjuvant treatment.
    [8] - Includes subjects that started adjuvant treatment.
    No statistical analyses for this end point

    Secondary: Overview of the Number of Participants With at Least One Adverse Event During the Treatment-Free Follow-Up Period

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    End point title
    		 Overview of the Number of Participants With at Least One Adverse Event During the Treatment-Free Follow-Up Period
    End point description
    An adverse event (AE) is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of an AE (rated according to NCI-CTCAE v4.0 criteria or, if not listed, the following scale: Grade 3 is severe, Grade 4 is life-threatening, and Grade 5 is death related to AE), and a serious AE (SAE) is a significant medical event (per standard criteria). Severity and seriousness were independently assessed for each AE. Selected AEs for reporting included heart failure (NYHA Class II/III/IV) and asymptomatic declines in LVEF (reported as ejection fraction decreased). During TFFU, only heart failure, pregnancies, and non-breast-related second primary malignancies, irrespective of causal relationship with study treatment, and drug-related SAEs were reported. Multiple occurrences of the same AE in 1 subject were counted only once.
    End point type
    Secondary
    End point timeframe
    From 42 days after the last dose of study treatment until the end of treatment-free follow-up (TFFU; up to 5 years)
    End point values
    		 Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
    Number of subjects analysed
    199
    198
    Units: Participants
        Any Adverse Event (AE)
    3
    7
        NCI-CTCAE Grade 3-5 AE
    2
    5
        Serious AE
    3
    7
        Deaths
    7
    13
        Ejection Fraction Decreased (Any Grade)
    1
    1
        Heart Failure (Any Grade)
    0
    1
    No statistical analyses for this end point

    Secondary: Percentage of Participants Positive for Anti-Therapeutic Antibodies (ATAs) to Pertuzumab at Baseline and Anytime Post-Baseline

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    End point title
    		 Percentage of Participants Positive for Anti-Therapeutic Antibodies (ATAs) to Pertuzumab at Baseline and Anytime Post-Baseline
    End point description
    ATAs to pertuzumab in serum samples were detected using a validated bridging enzyme-linked immunosorbent assay (ELISA) method. This analysis only included participants with an ATA assay result from a baseline sample and/or at least one post-baseline sample.
    End point type
    Secondary
    End point timeframe
    Screening (baseline) then prior to pertuzumab infusion (Hour 0) in Cycles 5, 14, 18 thereafter anytime between Cycle 8 Day 21 and surgery, up to treatment completion visit (cycle length=2-3 weeks; up to approximately 1 year, 3 months)
    End point values
    		 Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
    Number of subjects analysed
    199
    201
    Units: Percentage of participants
    number (not applicable)
        At Baseline (n = 190, 191)
    1.6
    2.1
        Anytime Post-Baseline (n = 195, 197)
    4.6
    3.6
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Total Pathologic Complete Response (tpCR), Evaluated After Surgery

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    End point title
    		 Percentage of Participants With Total Pathologic Complete Response (tpCR), Evaluated After Surgery
    End point description
    Total pathologic complete response (tpCR) was the pCR based on tumor and nodal staging (i.e., histological confirmation of pCR in breast and nodes at surgery) and was defined as the absence of any residual invasive cancer in the breast and the absence of any metastatic cells in the regional lymph nodes (i.e., ypT0/is ypN0 tpCR). Participants who did not undergo surgery or did not have a valid pCR assessment were considered non-responders in the analysis. The 95% CIs were calculated using the Clopper-Pearson method. ITT population: included all participants who were enrolled regardless of whether they received any study treatment, grouped according to the arm to which a participant was enrolled.
    End point type
    Secondary
    End point timeframe
    After completion of neoadjuvant treatment and surgery (up to 25 weeks)
    End point values
    		 Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
    Number of subjects analysed
    199
    201
    Units: Percentage of participants
        number (confidence interval 95%)
    61.8 (54.67 to 68.59)
    60.7 (53.58 to 67.49)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Clinical Response as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 During the Neoadjuvant Treatment Period

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    End point title
    		 Percentage of Participants With Clinical Response as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 During the Neoadjuvant Treatment Period
    End point description
    The clinical response rate was defined as the percentage of participants in the ITT population who achieved a complete response (CR) or partial response (PR) prior to surgery, according to RECIST v1.1. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of the longest diameter compared to Baseline. Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient (20%) increase to qualify for disease progression, in addition to no new target lesions. Progressive Disease (PD): at least a 20% increase in the sum of the longest diameter, taking as reference the smallest sum of the longest diameter observed at previous tumor assessment, or the appearance of any new lesions. Participants were classified as missing or unevaluable if no assessments were measured prior to surgery on the ipsilateral breast. The 95% CIs were calculated using the Clopper-Pearson method; they were only calculated for responses (not for missing or unevaluable data).
    End point type
    Secondary
    End point timeframe
    Baseline until disease progression or death due to any cause up to 24 weeks (assessed on Day 1 of Cycles 1-8 [cycle length=2-3 weeks])
    End point values
    		 Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
    Number of subjects analysed
    199
    201
    Units: percentage of participants
    number (confidence interval 95%)
        Clinical Response Rate (CR+PR)
    67.3 (60.35 to 73.80)
    60.2 (53.07 to 67.02)
        Complete Response (CR)
    39.7 (32.85 to 46.86)
    23.9 (18.16 to 30.39)
        Partial Response (PR)
    27.6 (21.55 to 34.41)
    36.3 (29.67 to 43.38)
        Stable Disease (SD)
    7.0 (3.90 to 11.52)
    10.0 (6.18 to 14.95)
        Progressive Disease (PD)
    0.5 (0.01 to 2.77)
    1.0 (0.12 to 3.55)
        Missing or Unevaluable
    25.1 (-999999 to 999999)
    28.9 (-999999 to 999999)
    No statistical analyses for this end point

    Secondary: Kaplan-Meier Estimate of the Percentage of Participants Event-Free for Event-Free Survival at 1 to 5 Years, Determined by the Investigator According to RECIST v1.1

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    End point title
    		 Kaplan-Meier Estimate of the Percentage of Participants Event-Free for Event-Free Survival at 1 to 5 Years, Determined by the Investigator According to RECIST v1.1
    End point description
    The Kaplan-Meier method was used to estimate the percentage of participants who were event-free at landmark timepoints. Event-free survival (EFS) was defined as the time from enrollment to the first occurrence of progressive disease (PD), relapse, or death from any cause, with tumor evaluations performed by the investigator according to RECIST v1.1. Ipsilateral or contralateral in situ disease and second primary non-breast cancers (including in situ carcinomas and non-melanoma skin cancers) were not counted as progressive disease or relapse. Participants who withdrew from the study without documented progression or relapse and for whom there existed evidence that evaluations had been made, were censored at the date of the last assessment at which the participant was known to be free from progressive disease or relapse. Participants with no tumor evaluations after baseline were censored at the date of enrollment plus 1 day.
    End point type
    Secondary
    End point timeframe
    At 1, 2, 3, 4, and 5 years
    End point values
    		 Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
    Number of subjects analysed
    199 [9]
    201 [10]
    Units: Estimate of percentage of participants
    number (confidence interval 95%)
        1 Year (n = 191, 190)
    98.47 (96.75 to 100.00)
    97.48 (95.29 to 99.66)
        2 Years (n = 176, 180)
    95.80 (92.94 to 98.65)
    92.86 (89.25 to 96.46)
        3 Years (n = 163, 174)
    93.58 (90.06 to 97.10)
    90.78 (86.72 to 94.84)
        4 Years (n = 154, 172)
    92.39 (88.55 to 96.23)
    89.73 (85.47 to 94.00)
        5 Years (n = 96, 141)
    90.84 (86.48 to 95.20)
    89.20 (84.84 to 93.57)
    Notes
    [9] - ITT Population. 'n' represents the number remaining at risk at each timepoint.
    [10] - ITT Population. 'n' represents the number remaining at risk at each timepoint.
    No statistical analyses for this end point

    Secondary: Kaplan-Meier Estimate of the Percentage of Participants Event-Free for Invasive Disease-Free Survival (iDFS) at 1 to 4 Years, Determined by the Investigator According to RECIST v1.1

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    End point title
    		 Kaplan-Meier Estimate of the Percentage of Participants Event-Free for Invasive Disease-Free Survival (iDFS) at 1 to 4 Years, Determined by the Investigator According to RECIST v1.1
    End point description
    The Kaplan-Meier method was used to estimate the percentage of subjects event-free at landmark timepoints. Invasive disease-free survival (iDFS) was defined as the time from the first date of no disease (date of surgery) to the first documentation of progressive invasive disease, relapse, or death, with tumor evaluations made by the investigator according to RECISTv1.1. Ipsilateral or contralateral in situ disease and second primary non-breast cancers were not counted as events. Subjects who withdrew from study without documented progression or relapse and for whom evidence existed that evaluations had been made, were censored at the date of the last assessment they were known to be alive and disease-free. Subjects with no postbaseline information and those who did not undergo surgery were excluded from analysis.
    End point type
    Secondary
    End point timeframe
    At 1, 2, 3, and 4 years
    End point values
    		 Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
    Number of subjects analysed
    187 [11]
    194 [12]
    Units: Estimate of percentage of participants
    number (confidence interval 95%)
        1 Year (n = 180, 184)
    98.91 (97.41 to 100.00)
    96.34 (93.68 to 99.00)
        2 Years (n = 167, 178)
    95.57 (92.57 to 98.57)
    94.25 (90.94 to 97.55)
        3 Years (n = 158, 171)
    94.42 (91.06 to 97.78)
    91.06 (87.00 to 95.11)
        4 Years (n = 131, 168)
    92.60 (88.72 to 96.48)
    91.06 (87.00 to 95.11)
    Notes
    [11] - ITT Population. 'n' represents the number remaining at risk at each timepoint.
    [12] - ITT Population. 'n' represents the number remaining at risk at each timepoint.
    No statistical analyses for this end point

    Secondary: Kaplan-Meier Estimate of the Percentage of Participants Event-Free for Overall Survival (OS) at 1 to 5 Years

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    End point title
    		 Kaplan-Meier Estimate of the Percentage of Participants Event-Free for Overall Survival (OS) at 1 to 5 Years
    End point description
    The Kaplan-Meier method was used to estimate the percentage of participants who were event-free at landmark timepoints. Overall survival (OS) was defined as the time from enrollment to death from any cause. Participants who were alive or lost to follow-up were censored at their last known date in the study. Participants with no post-baseline assessments were censored at the date of enrollment plus 1 day.
    End point type
    Secondary
    End point timeframe
    At 1, 2, 3, 4, and 5 years
    End point values
    		 Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
    Number of subjects analysed
    199 [13]
    201 [14]
    Units: Estimate of percentage of participants
    number (confidence interval 95%)
        1 Year (n = 193, 194)
    99.48 (98.48 to 100.00)
    100.00 (100.00 to 100.00)
        2 Years (n = 183, 190)
    98.96 (97.52 to 100.00)
    97.94 (95.94 to 99.94)
        3 Years (n = 176, 185)
    97.86 (95.78 to 99.94)
    96.38 (93.74 to 99.01)
        4 Years (n = 171, 180)
    97.86 (95.78 to 99.94)
    94.81 (91.68 to 97.94)
        5 Years (n = 158, 177)
    96.10 (93.26 to 98.94)
    93.75 (90.33 to 97.17)
    Notes
    [13] - ITT Population. 'n' represents the number remaining at risk at each timepoint.
    [14] - ITT Population. 'n' represents the number remaining at risk at each timepoint.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of any study drug until the end of treatment-free follow-up (up to 6 years, 1 month)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
    Reporting group description
    		 Subjects received neoadjuvant treatment with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC), with administration of 5-fluorouracil 500mg/m^2 intravenously (IV) q3w, epirubicin 100mg/m^2 IV q3w, and cyclophosphamide 600mg/m^2 IV q3w for 4 cycles, followed by docetaxel (with starting dose of 75mg/m^2 in Cycle 5, then 100mg/m^2 for Cycles 6-8) q3w for 4 cycles. Pertuzumab (840 mg IV loading dose then 420mg IV q3w) and trastuzumab (8 mg/kg IV loading dose then 4mg/kg IV q3w) were given along with doectaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, subjects received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, subjects were followed for safety and efficacy for up to 5 years.

    Reporting group title
    Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab
    Reporting group description
    		 Subjects received neoadjuvant treatment with dose-dense doxorubicin and cyclophosphamide (ddAC), with administration of doxorubicin 60 milligrams per square meter (mg/m^2) intravenously (IV) once every 2 weeks (q2w) and cyclophosphamide 600mg/m^2 IV q2w for 4 cycles, followed by paclitaxel 80mg/m^2 IV once weekly (qw) for 12 weeks. Pertuzumab (840 milligrams [mg] IV loading dose then 420mg IV q3w) and trastuzumab (8 milligrams per kilogram [mg/kg] IV loading dose then 4mg/kg IV q3w) were administered along with paclitaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, subjects received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, subjects were followed for safety and efficacy for up to 5 years.

    Serious adverse events
    		 Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    66 / 198 (33.33%)
    56 / 199 (28.14%)
         number of deaths (all causes)
    13
    7
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    ADENOCARCINOMA OF COLON
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BASAL CELL CARCINOMA
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COLON CANCER
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LUNG NEOPLASM MALIGNANT
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NON-HODGKIN'S LYMPHOMA
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PLASMA CELL MYELOMA
         subjects affected / exposed
    2 / 198 (1.01%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RENAL CANCER
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vascular disorders
    HAEMATOMA
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    ABORTION INDUCED
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    GENERAL PHYSICAL HEALTH DETERIORATION
         subjects affected / exposed
    0 / 198 (0.00%)
    2 / 199 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MUCOSAL INFLAMMATION
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PYREXIA
         subjects affected / exposed
    4 / 198 (2.02%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    4 / 5
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SYSTEMIC INFLAMMATORY RESPONSE SYNDROME
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    ANAPHYLACTIC REACTION
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERSENSITIVITY
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    BREAST HAEMATOMA
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    DYSPNOEA
         subjects affected / exposed
    1 / 198 (0.51%)
    2 / 199 (1.01%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PAINFUL RESPIRATION
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONITIS
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    0 / 198 (0.00%)
    2 / 199 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    DEPRESSION
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    EJECTION FRACTION DECREASED
         subjects affected / exposed
    5 / 198 (2.53%)
    5 / 199 (2.51%)
         occurrences causally related to treatment / all
    5 / 5
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEUTROPHIL COUNT DECREASED
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TRANSAMINASES INCREASED
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    WHITE BLOOD CELL COUNT DECREASED
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    INFUSION RELATED REACTION
         subjects affected / exposed
    2 / 198 (1.01%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    POST PROCEDURAL HAEMATOMA
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEROMA
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    WOUND DECOMPOSITION
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    ACUTE MYOCARDIAL INFARCTION
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATRIAL FLUTTER
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATRIAL THROMBOSIS
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIAC FAILURE
         subjects affected / exposed
    4 / 198 (2.02%)
    3 / 199 (1.51%)
         occurrences causally related to treatment / all
    4 / 4
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIAC FAILURE CONGESTIVE
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIOGENIC SHOCK
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MYOCARDIAL ISCHAEMIA
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    CEREBELLAR SYNDROME
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEADACHE
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PRESYNCOPE
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SYNCOPE
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TRANSIENT ISCHAEMIC ATTACK
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    AGRANULOCYTOSIS
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ANAEMIA
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BONE MARROW FAILURE
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEBRILE NEUTROPENIA
         subjects affected / exposed
    27 / 198 (13.64%)
    11 / 199 (5.53%)
         occurrences causally related to treatment / all
    28 / 28
    11 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LEUKOPENIA
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEUTROPENIA
         subjects affected / exposed
    2 / 198 (1.01%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PANCYTOPENIA
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    COLITIS
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    11 / 198 (5.56%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    9 / 12
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMORRHOIDAL HAEMORRHAGE
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEUTROPENIC COLITIS
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ODYNOPHAGIA
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PANCREATITIS
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PANCREATITIS ACUTE
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PROCTALGIA
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VOMITING
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    CHOLECYSTITIS
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHOLELITHIASIS
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    ERYTHEMA MULTIFORME
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SKIN NECROSIS
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    0 / 198 (0.00%)
    2 / 199 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    MYALGIA
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    BREAST CELLULITIS
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CELLULITIS
         subjects affected / exposed
    0 / 198 (0.00%)
    2 / 199 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEVICE RELATED INFECTION
         subjects affected / exposed
    0 / 198 (0.00%)
    3 / 199 (1.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ERYSIPELAS
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROENTERITIS
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROENTERITIS VIRAL
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROINTESTINAL INFECTION
         subjects affected / exposed
    0 / 198 (0.00%)
    2 / 199 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LOWER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 198 (0.00%)
    2 / 199 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MASTITIS
         subjects affected / exposed
    0 / 198 (0.00%)
    2 / 199 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEUTROPENIC SEPSIS
         subjects affected / exposed
    7 / 198 (3.54%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    7 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERITONITIS
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    1 / 198 (0.51%)
    2 / 199 (1.01%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    POST PROCEDURAL INFECTION
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PSEUDOMONAL BACTERAEMIA
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PYELONEPHRITIS
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    0 / 198 (0.00%)
    3 / 199 (1.51%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VASCULAR DEVICE INFECTION
         subjects affected / exposed
    3 / 198 (1.52%)
    2 / 199 (1.01%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    WOUND INFECTION
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DEHYDRATION
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    198 / 198 (100.00%)
    197 / 199 (98.99%)
    Vascular disorders
    HYPERTENSION
         subjects affected / exposed
    12 / 198 (6.06%)
    14 / 199 (7.04%)
         occurrences all number
    14
    14
    HOT FLUSH
         subjects affected / exposed
    48 / 198 (24.24%)
    69 / 199 (34.67%)
         occurrences all number
    55
    77
    LYMPHOEDEMA
         subjects affected / exposed
    16 / 198 (8.08%)
    14 / 199 (7.04%)
         occurrences all number
    17
    15
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    85 / 198 (42.93%)
    41 / 199 (20.60%)
         occurrences all number
    130
    72
    CHILLS
         subjects affected / exposed
    4 / 198 (2.02%)
    12 / 199 (6.03%)
         occurrences all number
    4
    14
    FATIGUE
         subjects affected / exposed
    81 / 198 (40.91%)
    125 / 199 (62.81%)
         occurrences all number
    119
    151
    INFLUENZA LIKE ILLNESS
         subjects affected / exposed
    21 / 198 (10.61%)
    7 / 199 (3.52%)
         occurrences all number
    24
    8
    MUCOSAL INFLAMMATION
         subjects affected / exposed
    77 / 198 (38.89%)
    46 / 199 (23.12%)
         occurrences all number
    106
    55
    OEDEMA PERIPHERAL
         subjects affected / exposed
    28 / 198 (14.14%)
    22 / 199 (11.06%)
         occurrences all number
    35
    25
    OEDEMA
         subjects affected / exposed
    10 / 198 (5.05%)
    5 / 199 (2.51%)
         occurrences all number
    10
    5
    PAIN
         subjects affected / exposed
    6 / 198 (3.03%)
    16 / 199 (8.04%)
         occurrences all number
    6
    18
    PYREXIA
         subjects affected / exposed
    39 / 198 (19.70%)
    39 / 199 (19.60%)
         occurrences all number
    53
    45
    Reproductive system and breast disorders
    BREAST PAIN
         subjects affected / exposed
    20 / 198 (10.10%)
    27 / 199 (13.57%)
         occurrences all number
    21
    28
    AMENORRHOEA
         subjects affected / exposed
    10 / 198 (5.05%)
    9 / 199 (4.52%)
         occurrences all number
    10
    10
    VULVOVAGINAL DRYNESS
         subjects affected / exposed
    14 / 198 (7.07%)
    22 / 199 (11.06%)
         occurrences all number
    14
    22
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    27 / 198 (13.64%)
    50 / 199 (25.13%)
         occurrences all number
    30
    64
    DYSPNOEA
         subjects affected / exposed
    37 / 198 (18.69%)
    29 / 199 (14.57%)
         occurrences all number
    38
    33
    NASAL CONGESTION
         subjects affected / exposed
    4 / 198 (2.02%)
    21 / 199 (10.55%)
         occurrences all number
    4
    23
    EPISTAXIS
         subjects affected / exposed
    41 / 198 (20.71%)
    54 / 199 (27.14%)
         occurrences all number
    45
    61
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    21 / 198 (10.61%)
    26 / 199 (13.07%)
         occurrences all number
    23
    31
    UPPER-AIRWAY COUGH SYNDROME
         subjects affected / exposed
    0 / 198 (0.00%)
    12 / 199 (6.03%)
         occurrences all number
    0
    13
    RHINORRHOEA
         subjects affected / exposed
    22 / 198 (11.11%)
    21 / 199 (10.55%)
         occurrences all number
    22
    23
    Psychiatric disorders
    ANXIETY
         subjects affected / exposed
    18 / 198 (9.09%)
    23 / 199 (11.56%)
         occurrences all number
    20
    24
    DEPRESSION
         subjects affected / exposed
    11 / 198 (5.56%)
    23 / 199 (11.56%)
         occurrences all number
    11
    23
    INSOMNIA
         subjects affected / exposed
    35 / 198 (17.68%)
    45 / 199 (22.61%)
         occurrences all number
    38
    52
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    13 / 198 (6.57%)
    15 / 199 (7.54%)
         occurrences all number
    15
    19
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    11 / 198 (5.56%)
    14 / 199 (7.04%)
         occurrences all number
    12
    18
    EJECTION FRACTION DECREASED
         subjects affected / exposed
    22 / 198 (11.11%)
    22 / 199 (11.06%)
         occurrences all number
    27
    27
    LYMPHOCYTE COUNT DECREASED
         subjects affected / exposed
    0 / 198 (0.00%)
    12 / 199 (6.03%)
         occurrences all number
    0
    15
    NEUTROPHIL COUNT DECREASED
         subjects affected / exposed
    19 / 198 (9.60%)
    18 / 199 (9.05%)
         occurrences all number
    26
    22
    WEIGHT DECREASED
         subjects affected / exposed
    13 / 198 (6.57%)
    19 / 199 (9.55%)
         occurrences all number
    13
    19
    WHITE BLOOD CELL COUNT DECREASED
         subjects affected / exposed
    6 / 198 (3.03%)
    22 / 199 (11.06%)
         occurrences all number
    6
    29
    Injury, poisoning and procedural complications
    INFUSION RELATED REACTION
         subjects affected / exposed
    35 / 198 (17.68%)
    38 / 199 (19.10%)
         occurrences all number
    50
    42
    PROCEDURAL PAIN
         subjects affected / exposed
    12 / 198 (6.06%)
    17 / 199 (8.54%)
         occurrences all number
    14
    18
    RADIATION SKIN INJURY
         subjects affected / exposed
    58 / 198 (29.29%)
    36 / 199 (18.09%)
         occurrences all number
    59
    36
    Cardiac disorders
    PALPITATIONS
         subjects affected / exposed
    11 / 198 (5.56%)
    10 / 199 (5.03%)
         occurrences all number
    12
    12
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    20 / 198 (10.10%)
    33 / 199 (16.58%)
         occurrences all number
    22
    37
    DYSGEUSIA
         subjects affected / exposed
    35 / 198 (17.68%)
    37 / 199 (18.59%)
         occurrences all number
    44
    41
    HEADACHE
         subjects affected / exposed
    41 / 198 (20.71%)
    70 / 199 (35.18%)
         occurrences all number
    48
    85
    HYPOAESTHESIA
         subjects affected / exposed
    10 / 198 (5.05%)
    10 / 199 (5.03%)
         occurrences all number
    10
    10
    NEUROPATHY PERIPHERAL
         subjects affected / exposed
    34 / 198 (17.17%)
    56 / 199 (28.14%)
         occurrences all number
    37
    60
    PARAESTHESIA
         subjects affected / exposed
    27 / 198 (13.64%)
    35 / 199 (17.59%)
         occurrences all number
    31
    44
    PERIPHERAL SENSORY NEUROPATHY
         subjects affected / exposed
    21 / 198 (10.61%)
    40 / 199 (20.10%)
         occurrences all number
    23
    44
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    64 / 198 (32.32%)
    56 / 199 (28.14%)
         occurrences all number
    78
    65
    FEBRILE NEUTROPENIA
         subjects affected / exposed
    10 / 198 (5.05%)
    3 / 199 (1.51%)
         occurrences all number
    10
    3
    LYMPHOPENIA
         subjects affected / exposed
    11 / 198 (5.56%)
    5 / 199 (2.51%)
         occurrences all number
    16
    5
    NEUTROPENIA
         subjects affected / exposed
    31 / 198 (15.66%)
    43 / 199 (21.61%)
         occurrences all number
    43
    54
    Ear and labyrinth disorders
    VERTIGO
         subjects affected / exposed
    10 / 198 (5.05%)
    4 / 199 (2.01%)
         occurrences all number
    11
    4
    Eye disorders
    LACRIMATION INCREASED
         subjects affected / exposed
    37 / 198 (18.69%)
    20 / 199 (10.05%)
         occurrences all number
    37
    20
    DRY EYE
         subjects affected / exposed
    13 / 198 (6.57%)
    13 / 199 (6.53%)
         occurrences all number
    13
    13
    VISION BLURRED
         subjects affected / exposed
    2 / 198 (1.01%)
    13 / 199 (6.53%)
         occurrences all number
    2
    16
    Gastrointestinal disorders
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    31 / 198 (15.66%)
    15 / 199 (7.54%)
         occurrences all number
    33
    17
    ABDOMINAL PAIN
         subjects affected / exposed
    27 / 198 (13.64%)
    12 / 199 (6.03%)
         occurrences all number
    38
    12
    CONSTIPATION
         subjects affected / exposed
    78 / 198 (39.39%)
    73 / 199 (36.68%)
         occurrences all number
    90
    87
    DIARRHOEA
         subjects affected / exposed
    141 / 198 (71.21%)
    143 / 199 (71.86%)
         occurrences all number
    238
    207
    DYSPEPSIA
         subjects affected / exposed
    35 / 198 (17.68%)
    40 / 199 (20.10%)
         occurrences all number
    42
    46
    DRY MOUTH
         subjects affected / exposed
    17 / 198 (8.59%)
    13 / 199 (6.53%)
         occurrences all number
    18
    13
    HAEMORRHOIDS
         subjects affected / exposed
    22 / 198 (11.11%)
    19 / 199 (9.55%)
         occurrences all number
    26
    20
    GASTROOESOPHAGEAL REFLUX DISEASE
         subjects affected / exposed
    6 / 198 (3.03%)
    27 / 199 (13.57%)
         occurrences all number
    6
    27
    NAUSEA
         subjects affected / exposed
    142 / 198 (71.72%)
    144 / 199 (72.36%)
         occurrences all number
    196
    181
    MOUTH ULCERATION
         subjects affected / exposed
    15 / 198 (7.58%)
    5 / 199 (2.51%)
         occurrences all number
    16
    5
    ODYNOPHAGIA
         subjects affected / exposed
    10 / 198 (5.05%)
    7 / 199 (3.52%)
         occurrences all number
    13
    7
    STOMATITIS
         subjects affected / exposed
    56 / 198 (28.28%)
    49 / 199 (24.62%)
         occurrences all number
    73
    53
    VOMITING
         subjects affected / exposed
    71 / 198 (35.86%)
    46 / 199 (23.12%)
         occurrences all number
    107
    57
    Skin and subcutaneous tissue disorders
    ALOPECIA
         subjects affected / exposed
    117 / 198 (59.09%)
    127 / 199 (63.82%)
         occurrences all number
    119
    127
    DERMATITIS
         subjects affected / exposed
    12 / 198 (6.06%)
    9 / 199 (4.52%)
         occurrences all number
    12
    11
    DERMATITIS ACNEIFORM
         subjects affected / exposed
    9 / 198 (4.55%)
    15 / 199 (7.54%)
         occurrences all number
    10
    18
    DRY SKIN
         subjects affected / exposed
    28 / 198 (14.14%)
    31 / 199 (15.58%)
         occurrences all number
    29
    32
    ERYTHEMA
         subjects affected / exposed
    32 / 198 (16.16%)
    19 / 199 (9.55%)
         occurrences all number
    36
    20
    NAIL DISCOLOURATION
         subjects affected / exposed
    4 / 198 (2.02%)
    31 / 199 (15.58%)
         occurrences all number
    4
    31
    NAIL DISORDER
         subjects affected / exposed
    21 / 198 (10.61%)
    13 / 199 (6.53%)
         occurrences all number
    22
    13
    ONYCHOCLASIS
         subjects affected / exposed
    10 / 198 (5.05%)
    3 / 199 (1.51%)
         occurrences all number
    10
    3
    NAIL TOXICITY
         subjects affected / exposed
    6 / 198 (3.03%)
    10 / 199 (5.03%)
         occurrences all number
    6
    12
    ONYCHOLYSIS
         subjects affected / exposed
    15 / 198 (7.58%)
    14 / 199 (7.04%)
         occurrences all number
    15
    16
    ONYCHOMADESIS
         subjects affected / exposed
    5 / 198 (2.53%)
    19 / 199 (9.55%)
         occurrences all number
    5
    20
    PALMAR-PLANTAR ERYTHRODYSAESTHESIA SYNDROME
         subjects affected / exposed
    23 / 198 (11.62%)
    11 / 199 (5.53%)
         occurrences all number
    26
    11
    PRURITUS
         subjects affected / exposed
    44 / 198 (22.22%)
    36 / 199 (18.09%)
         occurrences all number
    49
    42
    RASH
         subjects affected / exposed
    40 / 198 (20.20%)
    46 / 199 (23.12%)
         occurrences all number
    47
    52
    RASH MACULO-PAPULAR
         subjects affected / exposed
    3 / 198 (1.52%)
    19 / 199 (9.55%)
         occurrences all number
    3
    19
    SKIN HYPERPIGMENTATION
         subjects affected / exposed
    7 / 198 (3.54%)
    11 / 199 (5.53%)
         occurrences all number
    8
    11
    Renal and urinary disorders
    POLLAKIURIA
         subjects affected / exposed
    2 / 198 (1.01%)
    13 / 199 (6.53%)
         occurrences all number
    2
    14
    DYSURIA
         subjects affected / exposed
    5 / 198 (2.53%)
    15 / 199 (7.54%)
         occurrences all number
    5
    16
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    67 / 198 (33.84%)
    73 / 199 (36.68%)
         occurrences all number
    81
    96
    BACK PAIN
         subjects affected / exposed
    22 / 198 (11.11%)
    30 / 199 (15.08%)
         occurrences all number
    25
    36
    BONE PAIN
         subjects affected / exposed
    13 / 198 (6.57%)
    24 / 199 (12.06%)
         occurrences all number
    18
    27
    MUSCLE SPASMS
         subjects affected / exposed
    16 / 198 (8.08%)
    32 / 199 (16.08%)
         occurrences all number
    16
    37
    MUSCULOSKELETAL CHEST PAIN
         subjects affected / exposed
    6 / 198 (3.03%)
    13 / 199 (6.53%)
         occurrences all number
    6
    13
    MUSCULOSKELETAL PAIN
         subjects affected / exposed
    27 / 198 (13.64%)
    17 / 199 (8.54%)
         occurrences all number
    28
    18
    MYALGIA
         subjects affected / exposed
    76 / 198 (38.38%)
    49 / 199 (24.62%)
         occurrences all number
    95
    57
    PAIN IN EXTREMITY
         subjects affected / exposed
    30 / 198 (15.15%)
    27 / 199 (13.57%)
         occurrences all number
    36
    29
    Infections and infestations
    CONJUNCTIVITIS
         subjects affected / exposed
    16 / 198 (8.08%)
    10 / 199 (5.03%)
         occurrences all number
    18
    10
    INFLUENZA
         subjects affected / exposed
    14 / 198 (7.07%)
    8 / 199 (4.02%)
         occurrences all number
    16
    9
    NASOPHARYNGITIS
         subjects affected / exposed
    33 / 198 (16.67%)
    21 / 199 (10.55%)
         occurrences all number
    40
    30
    ORAL CANDIDIASIS
         subjects affected / exposed
    10 / 198 (5.05%)
    1 / 199 (0.50%)
         occurrences all number
    10
    1
    PHARYNGITIS
         subjects affected / exposed
    13 / 198 (6.57%)
    8 / 199 (4.02%)
         occurrences all number
    14
    8
    SINUSITIS
         subjects affected / exposed
    9 / 198 (4.55%)
    11 / 199 (5.53%)
         occurrences all number
    9
    12
    RHINITIS
         subjects affected / exposed
    18 / 198 (9.09%)
    7 / 199 (3.52%)
         occurrences all number
    19
    8
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    6 / 198 (3.03%)
    25 / 199 (12.56%)
         occurrences all number
    7
    28
    URINARY TRACT INFECTION
         subjects affected / exposed
    10 / 198 (5.05%)
    32 / 199 (16.08%)
         occurrences all number
    11
    36
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    49 / 198 (24.75%)
    40 / 199 (20.10%)
         occurrences all number
    59
    42
    DEHYDRATION
         subjects affected / exposed
    1 / 198 (0.51%)
    10 / 199 (5.03%)
         occurrences all number
    1
    14
    HYPOKALAEMIA
         subjects affected / exposed
    6 / 198 (3.03%)
    16 / 199 (8.04%)
         occurrences all number
    10
    18

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Feb 2014
    It was amended to extend the duration of reporting pregnancy and the time of prohibition of breast feeding to 7 months after receipt of the final dose of study drug.
    17 Jun 2014
    The protocol was updated to specify that anti-HER2 treatment should not start if the LVEF is <50% after anthracycline treatment for participants in both Cohorts A and B. The echocardiogram (ECHO)/multiple gated acquisition scan (MUGA) assessment at Cycle 3 or 4 has been removed to be more in line with clinical practice.
    26 May 2016
    A minor modification of the exclusion criterion regarding history of malignancy has been made for alignment with current clinical practice. Clarification that participants with prior breast malignancies within 5 years of study entry should be excluded was made.

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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