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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

    Results information
    Results version number
    		 v1
    This version publication date
    17 Mar 2017
    First version publication date
    17 Mar 2017
    Other versions
    		 v2

    Trial information

    		 Close Top of page
    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
    Interim
    Date of interim/final analysis
    03 Mar 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Mar 2016
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    This is a non-randomized, open-label, multicenter, multinational, Phase 2 trial including two parallel groups of participants. Objectives of the study included evaluation of cardiac safety, safety profiles of the two treatment regimens during the neoadjuvant and adjuvant treatment periods, and assessment of anti-tumor activity, clinical response, event-free survival (EFS), invasive disease-free survival (iDFS), and overall survival (OS) for each treatment regimen. Treatment regimens included a) dose-dense doxorubicin and cyclophosphamide (ddAC), followed by paclitaxel with pertuzumab and trastuzumab and b) 5-fluorouracil, epirubicin and cyclophosphamide (FEC), followed by docetaxel with pertuzumab and trastuzumab.
    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
    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: 11
    Country: Number of subjects enrolled
    Portugal: 31
    Country: Number of subjects enrolled
    Spain: 62
    Worldwide total number of subjects
    401
    EEA total number of subjects
    283
    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)
    353
    From 65 to 84 years
    48
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    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. Hence, 199 participants were included in Cohort A and 201 participants in Cohort B.

    Period 1
    Period 1 title
    Neoadjuvant Treatment 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
    		 Participants received doxorubicin and cyclophosphamide every 2 weeks (q2w) for 4 cycles, followed by paclitaxel for 12 weeks, with pertuzumab and trastuzumab given every 3 weeks (q3w) (8 cycles of chemotherapy in total prior to surgery) from the start of paclitaxel.
    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
    		 Participants received 5-fluorouracil, epirubicin, and cyclophosphamide given q3w for 4 cycles, followed by docetaxel q3w for 4 cycles, with pertuzumab and trastuzumab given q3w (8 cycles of chemotherapy in total prior to surgery) from the start of docetaxel.
    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 [1]
    		Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
    Started
    199
    201
    Completed
    182
    189
    Not completed
    17
    12
         Consent withdrawn by subject
    1
    -
         Physician decision
    2
    -
         Early surgery
    4
    3
         Adverse event
    6
    3
         Reason unspecified
    3
    1
         Withdrew prior to receiving study treatment
    -
    3
         Disease Progression
    1
    1
         Lack of efficacy
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: One participant in Cohort B, who was HER2 negative and was enrolled by error, was excluded. Thus, the number of subjects in the baseline period do not match with the worldwide number enrolled in the trial.
    Period 2
    Period 2 title
    Adjuvant Treatment Period
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab
    Arm description
    		 Following surgery, participants received further adjuvant pertuzumab and trastuzumab q3w (13 cycles), such that a total of 17 cycles of pertuzumab and trastuzumab therapy are given during the study.
    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 15-30 min 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 600 mg/m^2 IV bolus over 3-5 min 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 80 mg/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 840 mg loading dose IV, then 420 mg 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 6 mg/kg q3w for 17 cycles.

    Arm title
    		 Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
    Arm description
    		 Following surgery, participants received further adjuvant pertuzumab and trastuzumab q3w (13 cycles), such that a total of 17 cycles of pertuzumab and trastuzumab therapy are given during the study.
    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 500 mg/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 100 mg/m^2 as an IV bolus over 3-5 min or as an infusion over 3-5 min, 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 840 mg loading dose IV, then 420 mg 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 6 mg/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 600 mg/m^2 IV bolus over 3-5 min or as an infusion, in accordance with local policy, q2w for 4 cycles.

    Number of subjects in period 2
    		Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
    Started
    178
    190
    Completed
    29
    23
    Not completed
    149
    167
         Consent withdrawn by subject
    1
    1
         Physician decision
    1
    -
         Disease Relapse
    -
    1
         Ongoing in Adjuvant Treatment
    142
    157
         Protocol Deviation
    1
    -
         Adverse event
    4
    6
         Reason unspecified
    -
    1
         Disease Progression
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab
    Reporting group description
    		 Participants received doxorubicin and cyclophosphamide every 2 weeks (q2w) for 4 cycles, followed by paclitaxel for 12 weeks, with pertuzumab and trastuzumab given every 3 weeks (q3w) (8 cycles of chemotherapy in total prior to surgery) from the start of paclitaxel.

    Reporting group title
    Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
    Reporting group description
    		 Participants received 5-fluorouracil, epirubicin, and cyclophosphamide given q3w for 4 cycles, followed by docetaxel q3w for 4 cycles, with pertuzumab and trastuzumab given q3w (8 cycles of chemotherapy in total prior to surgery) from the start of docetaxel.

    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
    		 Participants received doxorubicin and cyclophosphamide every 2 weeks (q2w) for 4 cycles, followed by paclitaxel for 12 weeks, with pertuzumab and trastuzumab given every 3 weeks (q3w) (8 cycles of chemotherapy in total prior to surgery) from the start of paclitaxel.

    Reporting group title
    Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
    Reporting group description
    		 Participants received 5-fluorouracil, epirubicin, and cyclophosphamide given q3w for 4 cycles, followed by docetaxel q3w for 4 cycles, with pertuzumab and trastuzumab given q3w (8 cycles of chemotherapy in total prior to surgery) from the start of docetaxel.
    Reporting group title
    Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab
    Reporting group description
    		 Following surgery, participants received further adjuvant pertuzumab and trastuzumab q3w (13 cycles), such that a total of 17 cycles of pertuzumab and trastuzumab therapy are given during the study.

    Reporting group title
    Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
    Reporting group description
    		 Following surgery, participants received further adjuvant pertuzumab and trastuzumab q3w (13 cycles), such that a total of 17 cycles of pertuzumab and trastuzumab therapy are given during the study.

    Primary: Percentage of Participants with New York Heart Association (NYHA) Class III and IV Heart Failure during the Neoadjuvant Treatment Period

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    End point title
    		 Percentage of Participants with New York Heart Association (NYHA) Class III and IV Heart Failure during the Neoadjuvant Treatment Period [1]
    End point description
    Symptomatic left ventricular systolic dysfunction (LVSD) is defined as heart failure. NYHA classifies participants' heart failure condition based on the participant's symptoms. Class III: marked limitation of the physical activity. Comfortable at rest. 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. 95 percent (%) confidence intervals (CIs) are calculated with the use of the Clopper-Pearson method. Safety analysis population included all participants who received any amount of study drug.
    End point type
    Primary
    End point timeframe
    Baseline to 24 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 statistical analysis was planned for this end point.
    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 to 1.85)
    No statistical analyses for this end point

    Primary: Percentage of Participants with Drop in Left Ventricular Ejection Fraction (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 Drop in Left Ventricular Ejection Fraction (LVEF) of at least 10 Percentage Points from Baseline and to Below 50% During the Neoadjuvant Treatment Period [2]
    End point description
    A confirmed event was defined as at least two consecutive readings of declines in LVEF. 95% CIs are calculated with the use of the Clopper-Pearson method. Safety analysis population was considered for analysis of this end point.
    End point type
    Primary
    End point timeframe
    Baseline to 24 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 statistical analysis was planned for this end point.
    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%)
    6.5 (3.5 to 10.9)
    2 (0.6 to 5.1)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with NYHA Class III and IV Heart Failure during the Adjuvant Treatment Period at Primary Completion Date (03 March 2016)

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    End point title
    		 Percentage of Participants with NYHA Class III and IV Heart Failure during the Adjuvant Treatment Period at Primary Completion Date (03 March 2016)
    End point description
    LVSD is defined as heart failure. NYHA classifies participants' heart failure condition based on the participant's symptoms. Class III: marked limitation of the physical activity. Comfortable at rest. 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. 95% CIs will be calculated with the use of the Clopper-Pearson method. Safety analysis population who have started adjuvant treatment and were analyzable at the clinical cut-off date (03 March 2016).
    End point type
    Secondary
    End point timeframe
    Cycle 9 to Cycle 21 (cycle length=3 weeks; up to approximately 8 months) up to clinical cut-off date, 03 March 2016 (Month 20)
    End point values
    		 Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
    Number of subjects analysed
    178
    190
    Units: percentage of participants
        number (confidence interval 95%)
    0 (0 to 2.05)
    0.5 (0.01 to 2.9)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Drop in LVEF of at least 10 Points from Baseline and to Below 50% During the Adjuvant Treatment Period at Primary Completion Date (03 March 2016)

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    End point title
    		 Percentage of Participants with Drop in LVEF of at least 10 Points from Baseline and to Below 50% During the Adjuvant Treatment Period at Primary Completion Date (03 March 2016)
    End point description
    A confirmed event was defined as at least two consecutive readings of declines in LVEF. 95% CIs will be calculated with the use of the Clopper-Pearson method. Safety analysis population who have started adjuvant treatment and were analyzable at the clinical cut-off date (03 March 2016).
    End point type
    Secondary
    End point timeframe
    Cycle 9 to Cycle 21 (cycle length=3 weeks; up to approximately 8 months) up to clinical cut-off date, 03 March 2016 (Month 20)
    End point values
    		 Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
    Number of subjects analysed
    178
    190
    Units: percentage of participants
        number (confidence interval 95%)
    5.1 (2.3 to 9.4)
    6.8 (3.7 to 11.4)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with NYHA Class III and IV Heart Failure at the End of Study

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    End point title
    		 Percentage of Participants with NYHA Class III and IV Heart Failure at the End of Study
    End point description
    LVSD is defined as heart failure. NYHA classifies participants' heart failure condition based on the participant's symptoms. Class III: marked limitation of the physical activity. Comfortable at rest. 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. 95% CIs will be calculated with the use of the Clopper-Pearson method.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 6.5 years
    End point values
    		 Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
    Number of subjects analysed
    0 [3]
    0 [4]
    Units: percentage of participants
        number (not applicable)
    Notes
    [3] - Because the study is ongoing, results of this end point are anticipated by December 2020.
    [4] - Because the study is ongoing, results of this end point are anticipated by December 2020.
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Drop in LVEF of at least 10 Points from Baseline and to Below 50% at the End of Study

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    End point title
    		 Percentage of Participants with Drop in LVEF of at least 10 Points from Baseline and to Below 50% at the End of Study
    End point description
    A confirmed event was defined as at least two consecutive readings of declines in LVEF. 95% CIs will be calculated with the use of the Clopper-Pearson method.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 6.5 years
    End point values
    		 Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
    Number of subjects analysed
    0 [5]
    0 [6]
    Units: percentage of participants
        number (not applicable)
    Notes
    [5] - Because the study is ongoing, results of this end point are anticipated by December 2020.
    [6] - Because the study is ongoing, results of this end point are anticipated by December 2020.
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Anti-Therapeutic Antibodies (ATAs) to Pertuzumab

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    End point title
    		 Percentage of Participants with Anti-Therapeutic Antibodies (ATAs) to Pertuzumab
    End point description
    ITT population included all participants who were enrolled correctly irrespective of whether they received study drug or not. Here, "number of subjects analyzed" include those who were evaluable for the end point.
    End point type
    Secondary
    End point timeframe
    Screening 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 6.5 years)
    End point values
    		 Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
    Number of subjects analysed
    186
    197
    Units: percentage of participants
        number (not applicable)
    0
    0.5
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Total Pathological Complete Response (tpCR) Evaluated at the Time of Surgery Based on Local Pathologist's Assessment After Surgery

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    End point title
    		 Percentage of Participants with Total Pathological Complete Response (tpCR) Evaluated at the Time of Surgery Based on Local Pathologist's Assessment After Surgery
    End point description
    tpCR is defined as the absence of any residual invasive cancer in the breast and the absence of any metastatic cells in the regional lymph nodes. ITT population
    End point type
    Secondary
    End point timeframe
    24 weeks after neoadjuvant therapy (Post 8 cycles of neo­adjuvant therapy [cycle length=2­3 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
    Clinical response was classified as either complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD). CR: disappearance of all target lesions; PR: at least a 30% decrease in the sum of the longest diameter compared to Baseline. SD: neither sufficient shrinkage to qualify for PR nor sufficient (20%) increase to qualify for disease progression, in addition to no new target lesions. 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. 95% CIs are calculated with the use of the Clopper-Pearson method. ITT population.
    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%)
        Complete response
    39.7 (32.85 to 46.86)
    23.9 (18.16 to 30.39)
        Partial response
    27.6 (21.55 to 34.41)
    36.3 (29.67 to 43.38)
        Stable disease
    7 (3.9 to 11.52)
    10 (6.18 to 14.95)
        Progressive disease
    0.5 (0.01 to 2.77)
    1 (0.12 to 3.55)
    No statistical analyses for this end point

    Secondary: Event-Free Survival Determined by the Investigator According to RECIST v1.1

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    End point title
    		 Event-Free Survival Determined by the Investigator According to RECIST v1.1
    End point description
    EFS is defined as the time from enrollment to the first occurrence of progressive disease, relapse, or death from any cause. 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.
    End point type
    Secondary
    End point timeframe
    Baseline until disease progression or death due to any cause up to approximately 6.5 years (assessed on Day 1 of Cycles 1-8 [cycle length=2-3 weeks] and every 3 months thereafter until study completion or early termination)
    End point values
    		 Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
    Number of subjects analysed
    0 [7]
    0 [8]
    Units: months
        median (full range (min-max))
    ( to )
    ( to )
    Notes
    [7] - Because the study is ongoing, results of this end point are anticipated by December 2020.
    [8] - Because the study is ongoing, results of this end point are anticipated by December 2020.
    No statistical analyses for this end point

    Secondary: Invasive Disease Free Survival (iDFS) Determined by the Investigator According to RECIST v1.1

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    End point title
    		 Invasive Disease Free Survival (iDFS) Determined by the Investigator According to RECIST v1.1
    End point description
    iDFS is defined as the time from the first date of no disease (the date of surgery) to the first documentation of progressive invasive disease, relapse, or death. 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.
    End point type
    Secondary
    End point timeframe
    Baseline until disease progression or death due to any cause up to approximately 6.5 years (assessed on Day 1 of Cycles 1-8 [cycle length=2-3 weeks] and every 3 months thereafter until study completion or early termination)
    End point values
    		 Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
    Number of subjects analysed
    0 [9]
    0 [10]
    Units: months
        median (full range (min-max))
    ( to )
    ( to )
    Notes
    [9] - Because the study is ongoing, results of this end point are anticipated by December 2020.
    [10] - Because the study is ongoing, results of this end point are anticipated by December 2020.
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    OS was defined as the time from enrollment to death from any cause.
    End point type
    Secondary
    End point timeframe
    Baseline up to death (approximately 6.5 years)
    End point values
    		 Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
    Number of subjects analysed
    0 [11]
    0 [12]
    Units: months
        median (full range (min-max))
    ( to )
    ( to )
    Notes
    [11] - Because the study is ongoing, results of this end point are anticipated by December 2020.
    [12] - Because the study is ongoing, results of this end point are anticipated by December 2020.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to 24 weeks
    Adverse event reporting additional description
    Safety analysis population. Reported adverse events data covers the safety information until the neoadjuvant period.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0.
    Reporting groups
    Reporting group title
    Cohort B: FEC+Docetaxel+Pertuzumab+Trastuzumab
    Reporting group description
    		 Participants received 5-fluorouracil, epirubicin, and cyclophosphamide given q3w for 4 cycles, followed by docetaxel q3w for 4 cycles, with pertuzumab and trastuzumab given q3w (8 cycles of chemotherapy in total prior to surgery) from the start of docetaxel. Following surgery, participants received/will receive further adjuvant pertuzumab and trastuzumab q3w (13 cycles), such that a total of 17 cycles of pertuzumab and trastuzumab therapy are given during the study.

    Reporting group title
    Cohort A: ddAC+Paclitaxel+Pertuzumab+Trastuzumab
    Reporting group description
    		 Participants received doxorubicin and cyclophosphamide every 2 weeks (q2w) for 4 cycles, followed by paclitaxel for 12 weeks, with pertuzumab and trastuzumab given every 3 weeks (q3w) (8 cycles of chemotherapy in total prior to surgery) from the start of paclitaxel. Following surgery, participants received/will receive further adjuvant pertuzumab and trastuzumab q3w (13 cycles), such that a total of 17 cycles of pertuzumab and trastuzumab therapy are given during the study.

    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
    52 / 198 (26.26%)
    45 / 199 (22.61%)
         number of deaths (all causes)
    1
    1
         number of deaths resulting from adverse events
    Surgical and medical procedures
    Mastectomy
         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
    General disorders and administration site conditions
    General physical health deterioration
         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
    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%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         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
    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
    0 / 198 (0.00%)
    3 / 199 (1.51%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         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
    Cardiac disorders
    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
    Cardiac failure
         subjects affected / exposed
    0 / 198 (0.00%)
    2 / 199 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         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
    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
    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
    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%)
    12 / 199 (6.03%)
         occurrences causally related to treatment / all
    28 / 28
    12 / 12
         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%)
    2 / 199 (1.01%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         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
    Gastrointestinal disorders
    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
    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
    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
    Infections and infestations
    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
    2 / 198 (1.01%)
    4 / 199 (2.01%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile infection
         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
    Gastrointestinal 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
    Lower 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
    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
    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
    Urinary tract infection
         subjects affected / exposed
    0 / 198 (0.00%)
    2 / 199 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 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
    Hot flush
         subjects affected / exposed
    26 / 198 (13.13%)
    38 / 199 (19.10%)
         occurrences all number
    27
    39
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    82 / 198 (41.41%)
    37 / 199 (18.59%)
         occurrences all number
    104
    56
    Chills
         subjects affected / exposed
    2 / 198 (1.01%)
    13 / 199 (6.53%)
         occurrences all number
    2
    15
    Fatigue
         subjects affected / exposed
    76 / 198 (38.38%)
    116 / 199 (58.29%)
         occurrences all number
    98
    125
    Influenza like illness
         subjects affected / exposed
    15 / 198 (7.58%)
    2 / 199 (1.01%)
         occurrences all number
    16
    2
    Mucosal inflammation
         subjects affected / exposed
    74 / 198 (37.37%)
    43 / 199 (21.61%)
         occurrences all number
    99
    50
    Oedema peripheral
         subjects affected / exposed
    24 / 198 (12.12%)
    18 / 199 (9.05%)
         occurrences all number
    27
    21
    Pain
         subjects affected / exposed
    4 / 198 (2.02%)
    14 / 199 (7.04%)
         occurrences all number
    4
    14
    Pyrexia
         subjects affected / exposed
    31 / 198 (15.66%)
    29 / 199 (14.57%)
         occurrences all number
    40
    32
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    12 / 198 (6.06%)
    13 / 199 (6.53%)
         occurrences all number
    12
    14
    Vulvovaginal dryness
         subjects affected / exposed
    4 / 198 (2.02%)
    12 / 199 (6.03%)
         occurrences all number
    4
    12
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    17 / 198 (8.59%)
    40 / 199 (20.10%)
         occurrences all number
    19
    44
    Dyspnoea
         subjects affected / exposed
    29 / 198 (14.65%)
    28 / 199 (14.07%)
         occurrences all number
    30
    29
    Epistaxis
         subjects affected / exposed
    37 / 198 (18.69%)
    50 / 199 (25.13%)
         occurrences all number
    38
    52
    Nasal congestion
         subjects affected / exposed
    2 / 198 (1.01%)
    15 / 199 (7.54%)
         occurrences all number
    2
    15
    Oropharyngeal pain
         subjects affected / exposed
    15 / 198 (7.58%)
    20 / 199 (10.05%)
         occurrences all number
    16
    22
    Upper-airway cough syndrome
         subjects affected / exposed
    0 / 198 (0.00%)
    11 / 199 (5.53%)
         occurrences all number
    0
    12
    Rhinorrhoea
         subjects affected / exposed
    19 / 198 (9.60%)
    12 / 199 (6.03%)
         occurrences all number
    19
    12
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    9 / 198 (4.55%)
    17 / 199 (8.54%)
         occurrences all number
    9
    18
    Depression
         subjects affected / exposed
    4 / 198 (2.02%)
    12 / 199 (6.03%)
         occurrences all number
    4
    12
    Insomnia
         subjects affected / exposed
    25 / 198 (12.63%)
    37 / 199 (18.59%)
         occurrences all number
    27
    40
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    10 / 198 (5.05%)
    14 / 199 (7.04%)
         occurrences all number
    11
    15
    Aspartate aminotransferase increased
         subjects affected / exposed
    8 / 198 (4.04%)
    14 / 199 (7.04%)
         occurrences all number
    9
    16
    Ejection fraction decreased
         subjects affected / exposed
    7 / 198 (3.54%)
    11 / 199 (5.53%)
         occurrences all number
    7
    13
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 198 (0.00%)
    10 / 199 (5.03%)
         occurrences all number
    0
    10
    Neutrophil count decreased
         subjects affected / exposed
    17 / 198 (8.59%)
    17 / 199 (8.54%)
         occurrences all number
    20
    20
    Weight decreased
         subjects affected / exposed
    8 / 198 (4.04%)
    13 / 199 (6.53%)
         occurrences all number
    8
    13
    White blood cell count decreased
         subjects affected / exposed
    5 / 198 (2.53%)
    21 / 199 (10.55%)
         occurrences all number
    5
    24
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    23 / 198 (11.62%)
    31 / 199 (15.58%)
         occurrences all number
    27
    33
    Procedural pain
         subjects affected / exposed
    8 / 198 (4.04%)
    15 / 199 (7.54%)
         occurrences all number
    8
    15
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    15 / 198 (7.58%)
    23 / 199 (11.56%)
         occurrences all number
    17
    28
    Dysgeusia
         subjects affected / exposed
    38 / 198 (19.19%)
    39 / 199 (19.60%)
         occurrences all number
    44
    42
    Headache
         subjects affected / exposed
    28 / 198 (14.14%)
    60 / 199 (30.15%)
         occurrences all number
    32
    70
    Hypoaesthesia
         subjects affected / exposed
    7 / 198 (3.54%)
    11 / 199 (5.53%)
         occurrences all number
    7
    11
    Neuropathy peripheral
         subjects affected / exposed
    26 / 198 (13.13%)
    46 / 199 (23.12%)
         occurrences all number
    28
    47
    Paraesthesia
         subjects affected / exposed
    18 / 198 (9.09%)
    29 / 199 (14.57%)
         occurrences all number
    20
    33
    Peripheral sensory neuropathy
         subjects affected / exposed
    15 / 198 (7.58%)
    38 / 199 (19.10%)
         occurrences all number
    17
    41
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    60 / 198 (30.30%)
    54 / 199 (27.14%)
         occurrences all number
    67
    62
    Neutropenia
         subjects affected / exposed
    31 / 198 (15.66%)
    42 / 199 (21.11%)
         occurrences all number
    40
    52
    Eye disorders
    Dry eye
         subjects affected / exposed
    10 / 198 (5.05%)
    12 / 199 (6.03%)
         occurrences all number
    10
    12
    Lacrimation increased
         subjects affected / exposed
    36 / 198 (18.18%)
    18 / 199 (9.05%)
         occurrences all number
    36
    18
    Vision blurred
         subjects affected / exposed
    1 / 198 (0.51%)
    13 / 199 (6.53%)
         occurrences all number
    1
    14
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    20 / 198 (10.10%)
    10 / 199 (5.03%)
         occurrences all number
    21
    10
    Abdominal pain upper
         subjects affected / exposed
    26 / 198 (13.13%)
    12 / 199 (6.03%)
         occurrences all number
    28
    12
    Constipation
         subjects affected / exposed
    76 / 198 (38.38%)
    69 / 199 (34.67%)
         occurrences all number
    86
    78
    Diarrhoea
         subjects affected / exposed
    130 / 198 (65.66%)
    132 / 199 (66.33%)
         occurrences all number
    176
    179
    Dry mouth
         subjects affected / exposed
    14 / 198 (7.07%)
    9 / 199 (4.52%)
         occurrences all number
    14
    9
    Dyspepsia
         subjects affected / exposed
    32 / 198 (16.16%)
    38 / 199 (19.10%)
         occurrences all number
    36
    41
    Gastrooesophageal reflux disease
         subjects affected / exposed
    4 / 198 (2.02%)
    23 / 199 (11.56%)
         occurrences all number
    4
    23
    Haemorrhoids
         subjects affected / exposed
    17 / 198 (8.59%)
    16 / 199 (8.04%)
         occurrences all number
    19
    16
    Mouth ulceration
         subjects affected / exposed
    12 / 198 (6.06%)
    5 / 199 (2.51%)
         occurrences all number
    13
    5
    Nausea
         subjects affected / exposed
    137 / 198 (69.19%)
    141 / 199 (70.85%)
         occurrences all number
    182
    166
    Stomatitis
         subjects affected / exposed
    54 / 198 (27.27%)
    49 / 199 (24.62%)
         occurrences all number
    67
    54
    Vomiting
         subjects affected / exposed
    69 / 198 (34.85%)
    45 / 199 (22.61%)
         occurrences all number
    96
    50
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform
         subjects affected / exposed
    6 / 198 (3.03%)
    11 / 199 (5.53%)
         occurrences all number
    6
    14
    Alopecia
         subjects affected / exposed
    116 / 198 (58.59%)
    124 / 199 (62.31%)
         occurrences all number
    117
    124
    Dry skin
         subjects affected / exposed
    19 / 198 (9.60%)
    27 / 199 (13.57%)
         occurrences all number
    20
    27
    Erythema
         subjects affected / exposed
    11 / 198 (5.56%)
    3 / 199 (1.51%)
         occurrences all number
    14
    3
    Nail discolouration
         subjects affected / exposed
    3 / 198 (1.52%)
    29 / 199 (14.57%)
         occurrences all number
    3
    29
    Nail disorder
         subjects affected / exposed
    19 / 198 (9.60%)
    14 / 199 (7.04%)
         occurrences all number
    19
    14
    Onycholysis
         subjects affected / exposed
    9 / 198 (4.55%)
    11 / 199 (5.53%)
         occurrences all number
    9
    12
    Onychomadesis
         subjects affected / exposed
    1 / 198 (0.51%)
    18 / 199 (9.05%)
         occurrences all number
    1
    18
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    20 / 198 (10.10%)
    11 / 199 (5.53%)
         occurrences all number
    20
    11
    Pruritus
         subjects affected / exposed
    16 / 198 (8.08%)
    15 / 199 (7.54%)
         occurrences all number
    18
    16
    Rash
         subjects affected / exposed
    21 / 198 (10.61%)
    28 / 199 (14.07%)
         occurrences all number
    22
    31
    Rash maculo-papular
         subjects affected / exposed
    1 / 198 (0.51%)
    16 / 199 (8.04%)
         occurrences all number
    1
    16
    Skin hyperpigmentation
         subjects affected / exposed
    3 / 198 (1.52%)
    10 / 199 (5.03%)
         occurrences all number
    3
    10
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    2 / 198 (1.01%)
    13 / 199 (6.53%)
         occurrences all number
    2
    14
    Pollakiuria
         subjects affected / exposed
    2 / 198 (1.01%)
    12 / 199 (6.03%)
         occurrences all number
    2
    13
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    42 / 198 (21.21%)
    39 / 199 (19.60%)
         occurrences all number
    48
    44
    Back pain
         subjects affected / exposed
    17 / 198 (8.59%)
    20 / 199 (10.05%)
         occurrences all number
    18
    23
    Bone pain
         subjects affected / exposed
    9 / 198 (4.55%)
    23 / 199 (11.56%)
         occurrences all number
    13
    26
    Muscle spasms
         subjects affected / exposed
    2 / 198 (1.01%)
    15 / 199 (7.54%)
         occurrences all number
    2
    15
    Musculoskeletal pain
         subjects affected / exposed
    10 / 198 (5.05%)
    9 / 199 (4.52%)
         occurrences all number
    10
    9
    Myalgia
         subjects affected / exposed
    66 / 198 (33.33%)
    40 / 199 (20.10%)
         occurrences all number
    80
    43
    Pain in extremity
         subjects affected / exposed
    15 / 198 (7.58%)
    20 / 199 (10.05%)
         occurrences all number
    17
    20
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    16 / 198 (8.08%)
    8 / 199 (4.02%)
         occurrences all number
    16
    8
    Nasopharyngitis
         subjects affected / exposed
    17 / 198 (8.59%)
    14 / 199 (7.04%)
         occurrences all number
    18
    16
    Oral candidiasis
         subjects affected / exposed
    11 / 198 (5.56%)
    1 / 199 (0.50%)
         occurrences all number
    11
    1
    Rhinitis
         subjects affected / exposed
    14 / 198 (7.07%)
    6 / 199 (3.02%)
         occurrences all number
    14
    6
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 198 (2.02%)
    14 / 199 (7.04%)
         occurrences all number
    4
    15
    Urinary tract infection
         subjects affected / exposed
    4 / 198 (2.02%)
    19 / 199 (9.55%)
         occurrences all number
    4
    22
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    45 / 198 (22.73%)
    39 / 199 (19.60%)
         occurrences all number
    48
    41
    Dehydration
         subjects affected / exposed
    1 / 198 (0.51%)
    10 / 199 (5.03%)
         occurrences all number
    1
    14
    Hypokalaemia
         subjects affected / exposed
    5 / 198 (2.53%)
    14 / 199 (7.04%)
         occurrences all number
    6
    15

    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.
    The study is still ongoing and the results are based on the primary analysis (clinical cutoff date of 03 March 2016). Full data from the adjuvant and treatment-free follow-up periods are anticipated by December 2020.
    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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