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    Clinical Trial Results:
    Prospective, Open-Label, Randomized Study of Combination Therapy of MYOCET® Plus Cyclophosphamide and Trastuzumab Versus Free Doxorubicin Plus Cyclophosphamide Alone, Each Followed by Docetaxel and Trastuzumab, in Neoadjuvant Setting in Treatment-Naïve Patients With HER2-Positive Breast Cancer

    Summary
    EudraCT number
    2008-000709-12
    Trial protocol
    FR   BE   ES   AT   NL   GB   IT  
    Global end of trial date
    17 Sep 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    17 Feb 2017
    First version publication date
    17 Feb 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    C19562/2037/BC/EU
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00712881
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Sponsor short code: C19562/2037
    Sponsors
    Sponsor organisation name
    Teva Branded Pharmaceutical Products R&D, Inc
    Sponsor organisation address
    41 Moores Road, Frazer, Pennsylvania, United States, 19355
    Public contact
    Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., 001 215-591-3000, info.era-clinical@teva.de
    Scientific contact
    Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., 001 215-591-3000, info.era-clinical@teva.de
    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
    17 Oct 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Sep 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to compare the efficacy of up to 8 cycles (24 weeks) of MYOCET plus cyclophosphamide and trastuzumab for 4 cycles followed by docetaxel plus trastuzumab for 4 cycles (MCH→TH) with free doxorubicin plus cyclophosphamide alone for 4 cycles followed by docetaxel plus trastuzumab for 4 cycles (AC→TH), each on day 1 of a 21-day cycle, as assessed by the proportion of patients with pathological complete response (pCR) in breast.
    Protection of trial subjects
    This study was conducted in full accordance with the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Consolidated Guideline (E6) and any applicable national and local laws and regulations (eg, Code of Federal Regulations Title 21, Parts 50, 54, 56, 312, and 314; European Union Directive 2001/20/EC on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use). Written and/or oral information about the study was provided to all patients in a language understandable by the patient. The information included an adequate explanation of the aims, methods, anticipated benefits, potential hazards, and insurance arrangements in force. Written informed consent was obtained from each patient before any study procedures or assessments were done. It was explained to the patients that they were free to refuse entry into the study and free to withdraw from the study at any time without prejudice to future treatment. Each patient’s willingness to participate in the study was documented in writing in an informed consent form that was signed by the patient with the date of that signature indicated. Each investigator kept the original consent forms, and copies were given to the patients.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    02 Jun 2008
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 39
    Country: Number of subjects enrolled
    Austria: 7
    Country: Number of subjects enrolled
    Belgium: 10
    Country: Number of subjects enrolled
    France: 8
    Country: Number of subjects enrolled
    Germany: 49
    Country: Number of subjects enrolled
    Italy: 13
    Worldwide total number of subjects
    126
    EEA total number of subjects
    126
    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)
    112
    From 65 to 84 years
    14
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 137 patients with treatment naïve, HER2+ breast cancer were screened for enrollment and 126 patients met entry criteria. Of the 11 patients who were not enrolled, 8 were excluded on the basis of inclusion/exclusion criteria, 1 patient withdrew consent, 1 had an AE, and 1 patient was excluded for a reason of “other.”

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    MCH - TH
    Arm description
    - MCH: On day 1 of each of 4 consecutive 21-day cycles, each patient was infused with liposomal doxorubicin hydrochloride (60 mg/m^2), cyclophosphamide (600 mg/m^2), and trastuzumab (8 or 6 mg/kg). For the first cycle, the loading dose of trastuzumab was 8 mg/kg; 6 mg/kg was used for the remaining cycles. - TH: After 4 cycles of MCH, the treatment changed to 4 consecutive 21 day cycles of docetaxel (100 mg/m^2) and trastuzumab (6 mg/kg).
    Arm type
    Experimental

    Investigational medicinal product name
    liposomal doxorubicin hydrochloride
    Investigational medicinal product code
    Other name
    Myocet®, CEP-19562
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Liposomal doxorubicin hydrochloride, 60 mg/m^2, was infused in 1 hour on day 1 of each of four 21 day cycles.

    Investigational medicinal product name
    cyclophosphamide
    Investigational medicinal product code
    Other name
    cytophosphane
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cyclophosphamide, 600 mg/m^2, was infused on day 1 of each of four 21 day cycles. Marketed formulations of cyclophosphamide were constituted and used as directed in the summary of product characteristics that accompany the study drugs.

    Investigational medicinal product name
    trastuzumab
    Investigational medicinal product code
    Other name
    Herceptin ®
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab was infused in 90 minutes (loading dose of 8 mg/kg;), then in 1 hour (dose of 6 mg/kg) every 3 weeks. Marketed formulations of trastuzumab were constituted and used as directed in the summary of product characteristics that accompany the study drugs.

    Investigational medicinal product name
    docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    100 mg/m^2 Marketed formulations of docetaxel were constituted and used as directed in the summary of product characteristics that accompany the study drugs.

    Arm title
    AC - TH
    Arm description
    - AC: On day 1 of each of 4 consecutive 21-day cycles, each patient was infused with free doxorubicin hydrochloride (60 mg/m^2) and cyclophosphamide (600 mg/m^2). - TH: After 4 cycles of AC, the treatment changed to 4 consecutive 21-day cycles of docetaxel (100 mg/m^2) and trastuzumab (8 or 6 mg/kg). For the first cycle, the loading dose of trastuzumab was 8 mg/kg; 6 mg/kg was used for the remaining 3 cycles.
    Arm type
    Active comparator

    Investigational medicinal product name
    free doxorubicin hydrochloride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Free doxorubicin hydrochloride, 60 mg/m^2, was infused in 1 hour on day 1 of each of four 21 day cycles.

    Investigational medicinal product name
    cyclophosphamide
    Investigational medicinal product code
    Other name
    cytophosphane
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cyclophosphamide, 600 mg/m^2, was infused on day 1 of each of four 21 day cycles. Marketed formulations of cyclophosphamide were constituted and used as directed in the summary of product characteristics that accompany the study drugs.

    Investigational medicinal product name
    docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    100 mg/m^2 Marketed formulations of docetaxel were constituted and used as directed in the summary of product characteristics that accompany the study drugs.

    Investigational medicinal product name
    trastuzumab
    Investigational medicinal product code
    Other name
    Herceptin ®
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab was infused in 90 minutes (loading dose of 8 mg/kg;), then in 1 hour (dose of 6 mg/kg) every 3 weeks. Marketed formulations of trastuzumab were constituted and used as directed in the summary of product characteristics that accompany the study drugs.

    Number of subjects in period 1
    MCH - TH AC - TH
    Started
    63
    63
    Safety analysis set
    62
    63
    Completed four cycles
    60
    61
    Completed eight cycles
    55
    56
    Completed
    55
    56
    Not completed
    8
    7
         Protocol deviation
    1
    1
         Adverse event, non-fatal
    4
    5
         Consent withdrawn by subject
    1
    -
         Noncompliance to study procedures
    1
    -
         Disease progression
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    MCH - TH
    Reporting group description
    - MCH: On day 1 of each of 4 consecutive 21-day cycles, each patient was infused with liposomal doxorubicin hydrochloride (60 mg/m^2), cyclophosphamide (600 mg/m^2), and trastuzumab (8 or 6 mg/kg). For the first cycle, the loading dose of trastuzumab was 8 mg/kg; 6 mg/kg was used for the remaining cycles. - TH: After 4 cycles of MCH, the treatment changed to 4 consecutive 21 day cycles of docetaxel (100 mg/m^2) and trastuzumab (6 mg/kg).

    Reporting group title
    AC - TH
    Reporting group description
    - AC: On day 1 of each of 4 consecutive 21-day cycles, each patient was infused with free doxorubicin hydrochloride (60 mg/m^2) and cyclophosphamide (600 mg/m^2). - TH: After 4 cycles of AC, the treatment changed to 4 consecutive 21-day cycles of docetaxel (100 mg/m^2) and trastuzumab (8 or 6 mg/kg). For the first cycle, the loading dose of trastuzumab was 8 mg/kg; 6 mg/kg was used for the remaining 3 cycles.

    Reporting group values
    MCH - TH AC - TH Total
    Number of subjects
    63 63 126
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    48.8 ± 11.6 51.1 ± 11.3 -
    Gender categorical
    Units: Subjects
        Female
    63 63 126
        Male
    0 0 0
    Race
    Units: Subjects
        White
    61 59 120
        Black
    0 1 1
        Asian
    1 0 1
        Other
    1 3 4
    HER2 asssessment
    Units: Subjects
        Positive
    63 62 125
        Missing
    0 1 1
    Type of invasive carcinoma
    Units: Subjects
        Ductal
    59 60 119
        Lobular
    2 1 3
        Medullary
    0 1 1
        Micropapillary
    1 0 1
        Mixte
    1 0 1
        Mucinous
    0 1 1
    Histological Elston-Ellis modified SBR grade
    SBR = Scarff-Bloom-Richardson
    Units: Subjects
        Missing
    1 0 1
        Grade 1
    1 2 3
        Grade 2
    30 20 50
        Grade 3
    26 35 61
        NA
    5 6 11
    Estrogen receptor
    Units: Subjects
        Positive
    37 37 74
        Negative
    26 26 52
    Progestrone receptor
    Units: Subjects
        Positive
    29 26 55
        Negative
    34 37 71
    Breast cancer stage
    Units: Subjects
        I: tumor <=2.0, lymph nodes clear, no metastasis
    1 1 2
        IIa: tumor <=2.0 cm, regional lymph node
    20 23 43
        IIb: tumor >2.0<5.0cm, regional lymph nodes
    22 17 39
        IIIa: tumor may be >5.0 cm, regional lymph nodes
    14 12 26
        IIIb: tumor extending to chest wall or skin
    4 5 9
        IIIc: tumor with extensive lymph node involvement
    2 4 6
        IV: distant metastasis
    0 1 1
    Eastern Cooperative Oncology Group (ECOG) Performance Status
    ECOG criteria: 0: Fully active. 1: Ambulatory, carry out work of a light or sedentary nature. 2: Ambulatory, capable of all selfcare. 3: Capable of limited selfcare, confined to bed or chair more than 50% of waking hours. 4: Completely disabled, no selfcare, totally confined to bed or chair. 5: Dead.
    Units: Subjects
        0: Fully active
    60 55 115
        1: Ambulatory, carry out light work
    2 7 9
        Not done
    1 1 2
    Weight
    n=62, 63
    Units: kg
        arithmetic mean (standard deviation)
    68.21 ± 13.69 70.07 ± 14.1 -
    Height
    n=62, 60
    Units: cm
        arithmetic mean (standard deviation)
    161.82 ± 7.92 163.18 ± 7.08 -

    End points

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    End points reporting groups
    Reporting group title
    MCH - TH
    Reporting group description
    - MCH: On day 1 of each of 4 consecutive 21-day cycles, each patient was infused with liposomal doxorubicin hydrochloride (60 mg/m^2), cyclophosphamide (600 mg/m^2), and trastuzumab (8 or 6 mg/kg). For the first cycle, the loading dose of trastuzumab was 8 mg/kg; 6 mg/kg was used for the remaining cycles. - TH: After 4 cycles of MCH, the treatment changed to 4 consecutive 21 day cycles of docetaxel (100 mg/m^2) and trastuzumab (6 mg/kg).

    Reporting group title
    AC - TH
    Reporting group description
    - AC: On day 1 of each of 4 consecutive 21-day cycles, each patient was infused with free doxorubicin hydrochloride (60 mg/m^2) and cyclophosphamide (600 mg/m^2). - TH: After 4 cycles of AC, the treatment changed to 4 consecutive 21-day cycles of docetaxel (100 mg/m^2) and trastuzumab (8 or 6 mg/kg). For the first cycle, the loading dose of trastuzumab was 8 mg/kg; 6 mg/kg was used for the remaining 3 cycles.

    Primary: Percentage of Participants Who Achieved a Pathological Complete Response (pCR) in Breast Following 8 Cycles of Chemotherapy

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    End point title
    Percentage of Participants Who Achieved a Pathological Complete Response (pCR) in Breast Following 8 Cycles of Chemotherapy
    End point description
    Pathological examination of resected tumors retrieved during mastectomy or breast conservative surgery following 8 cycles of chemotherapy was done by central review. If a patient had several responses, only the worst case was taken into account. Patients who dropped out early and had no evidence of pCR were considered non-responders.
    End point type
    Primary
    End point timeframe
    up to 28 weeks (24 weeks treatment, up to 4 additional weeks for surgery)
    End point values
    MCH - TH AC - TH
    Number of subjects analysed
    63 [1]
    63 [2]
    Units: percentage of participants
        number (not applicable)
    41.3
    54
    Notes
    [1] - Enrolled patients
    [2] - Enrolled patients
    Statistical analysis title
    Percentage of pCR in Breast
    Comparison groups
    MCH - TH v AC - TH
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.154 [3]
    Method
    t-test, 2-sided
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.3
         upper limit
    0.05
    Notes
    [3] - Significance at 0.05

    Secondary: Percentage of Participants Who Achieved a Pathological Complete Response in Breast and Axillary Lymph Node Following 8 Cycles of Chemotherapy.

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    End point title
    Percentage of Participants Who Achieved a Pathological Complete Response in Breast and Axillary Lymph Node Following 8 Cycles of Chemotherapy.
    End point description
    Pathological examination of resected tumors and axillary lymph node retrieved during mastectomy or breast conservative surgery following 8 cycles of chemotherapy was done by central review. If a patient had several responses, only the worst case was taken into account. Patients who dropped out early and had no evidence of pCR were considered non-responders.
    End point type
    Secondary
    End point timeframe
    up to 28 weeks (24 weeks treatment, up to 4 additional weeks for surgery)
    End point values
    MCH - TH AC - TH
    Number of subjects analysed
    63 [4]
    63 [5]
    Units: percentage of participants
        number (not applicable)
    38.1
    47.6
    Notes
    [4] - Enrolled patients
    [5] - Enrolled patients
    Statistical analysis title
    Percentage of pCR in Breast + Axillary Lymph Node
    Comparison groups
    MCH - TH v AC - TH
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.28 [6]
    Method
    t-test, 2-sided
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.27
         upper limit
    0.08
    Notes
    [6] - Significance at 0.05

    Secondary: Percentage of Participants Who Achieved an Objective Response As Defined by the World Health Organization

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    End point title
    Percentage of Participants Who Achieved an Objective Response As Defined by the World Health Organization
    End point description
    An objective response using WHO criteria includes a complete response or partial response combined. For target lesions, a complete response was defined as the disappearance of all target lesions; a partial response was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter.
    End point type
    Secondary
    End point timeframe
    up to 28 weeks (24 weeks treatment, up to 4 additional weeks for surgery)
    End point values
    MCH - TH AC - TH
    Number of subjects analysed
    63 [7]
    63 [8]
    Units: percentage of participants
        number (not applicable)
    77.8
    84.1
    Notes
    [7] - Enrolled patients
    [8] - Enrolled patients
    Statistical analysis title
    Objective Response Using WHO
    Comparison groups
    MCH - TH v AC - TH
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.364 [9]
    Method
    t-test, 2-sided
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2
         upper limit
    0.07
    Notes
    [9] - Significance at 0.05

    Secondary: Percentage of Participants Undergoing Breast Conservative Surgery

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    End point title
    Percentage of Participants Undergoing Breast Conservative Surgery
    End point description
    End point type
    Secondary
    End point timeframe
    Weeks 25-28
    End point values
    MCH - TH AC - TH
    Number of subjects analysed
    63 [10]
    63 [11]
    Units: percentage of participants
        number (not applicable)
    58.9
    53.4
    Notes
    [10] - Enrolled patients
    [11] - Enrolled patients
    Statistical analysis title
    Percentage Undergoing Breast Conservation Surgery
    Comparison groups
    MCH - TH v AC - TH
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.556 [12]
    Method
    t-test, 2-sided
    Confidence interval
    Notes
    [12] - Significance at 0.05

    Secondary: Percentage of Participants With Progression-Free Survival (PFS) within 5 Years of Randomization

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    End point title
    Percentage of Participants With Progression-Free Survival (PFS) within 5 Years of Randomization
    End point description
    Progression free survival (PFS) was defined as the time from the randomization date to the date of disease progression or death, whichever was observed first. The disease progression was detected based on at least one of the following methods: physical exam, computed tomography scan, X-ray, ultrasound, magnetic resonance imaging (MRI) and/or pathological examinations. If a patient did not develop an event (disease progression or death), the patient was censored at the last known tumor assessment date (or last follow-up visit without progression documented). This outcome reports the percentage of patients without a PFS event (ie, patients experiencing either disease progression or death) 5 years after randomization.
    End point type
    Secondary
    End point timeframe
    Up to 5 years after randomization
    End point values
    MCH - TH AC - TH
    Number of subjects analysed
    63 [13]
    63 [14]
    Units: percentage of participants
        number (not applicable)
    11.1
    12.7
    Notes
    [13] - Enrolled patients
    [14] - Enrolled patients
    Statistical analysis title
    PFS
    Comparison groups
    MCH - TH v AC - TH
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.783 [15]
    Method
    t-test, 2-sided
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.13
         upper limit
    0.1
    Notes
    [15] - Significance at 0.05

    Secondary: Participants with an Occurrence of New York Heart Association (NYHA) Functional Class 3 or 4 Congestive Heart Failure (CHF) During the Study

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    End point title
    Participants with an Occurrence of New York Heart Association (NYHA) Functional Class 3 or 4 Congestive Heart Failure (CHF) During the Study
    End point description
    The New York Heart Association grades heart failure into 4 classes, I - IV. Of interest to this outcome are patients with a functional class III or IV during the study. Class III: Marked limitation of 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.
    End point type
    Secondary
    End point timeframe
    Screening (approximately Day -21), Baseline (Day -6 to 1), Before each 21-day cycle (8 cycles total), within 1 week before surgery (weeks 25-28), post-surgical follow-up (4 weeks of surgery, approximately week 32)
    End point values
    MCH - TH AC - TH
    Number of subjects analysed
    62 [16]
    63 [17]
    Units: participants
        Class III
    0
    0
        Class IV
    0
    0
    Notes
    [16] - Safety analysis set
    [17] - Safety analysis set
    No statistical analyses for this end point

    Secondary: Participants with a Reduction from Baseline in Left Ventricular Ejection Fraction (LVEF) At Any Time During the Study

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    End point title
    Participants with a Reduction from Baseline in Left Ventricular Ejection Fraction (LVEF) At Any Time During the Study
    End point description
    Left ventricular ejection fraction (LVEF) “events” were defined in the SAP as either a decrease from baseline of more than 15% or a decrease from baseline of ≤15% (but more than 10%) with an absolute value of ≤50%. Data are offered at Week 4, and cumulatively over the course of the study and follow-up.
    End point type
    Secondary
    End point timeframe
    Baseline (Day -6 to Day 1), after each 4 cycles (Weeks 12 and 24), within 3 weeks before surgery (Weeks 26-28), 4 weeks after surgery (Week 32), annually during the 5-year follow-up
    End point values
    MCH - TH AC - TH
    Number of subjects analysed
    62 [18]
    63 [19]
    Units: participants
        Week 4
    1
    1
        Throughout the study and follow-up
    6
    7
    Notes
    [18] - Safety analysis set
    [19] - Safety analysis set
    No statistical analyses for this end point

    Secondary: Participants with Treatment-emergent Adverse Events

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    End point title
    Participants with Treatment-emergent Adverse Events
    End point description
    An adverse event was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of 1-5; reported are the most severe ratings of 3 (severe AE), 4 (life threatening or disabling AE) and 5 (death due to an AE). Relationship of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes.
    End point type
    Secondary
    End point timeframe
    Day 1 to Week 32
    End point values
    MCH - TH AC - TH
    Number of subjects analysed
    62 [20]
    63 [21]
    Units: participants
        >= 1 adverse event
    62
    63
        >=1 severe AE (grades 3-5)
    51
    50
        >=1 treatment-related AE
    62
    44
        AEs resulting in death
    0
    0
        Deaths due to any cause
    0
    4
        Serious AE
    18
    21
        Withdrawn from the study due to an AE
    4
    5
    Notes
    [20] - Safety analysis set
    [21] - Safety analysis set
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 to Week 32
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    11.1
    Reporting groups
    Reporting group title
    MCH - TH
    Reporting group description
    - MCH: On day 1 of each of 4 consecutive 21-day cycles, each patient was infused with liposomal doxorubicin hydrochloride (60 mg/m^2), cyclophosphamide (600 mg/m^2), and trastuzumab (8 or 6 mg/kg). For the first cycle, the loading dose of trastuzumab was 8 mg/kg; 6 mg/kg was used for the remaining cycles. - TH: After 4 cycles of MCH, the treatment changed to 4 consecutive 21 day cycles of docetaxel (100 mg/m^2) and trastuzumab (6 mg/kg).

    Reporting group title
    AC - TH
    Reporting group description
    - AC: On day 1 of each of 4 consecutive 21-day cycles, each patient was infused with free doxorubicin hydrochloride (60 mg/m^2) and cyclophosphamide (600 mg/m^2). - TH: After 4 cycles of AC, the treatment changed to 4 consecutive 21-day cycles of docetaxel (100 mg/m^2) and trastuzumab (8 or 6 mg/kg). For the first cycle, the loading dose of trastuzumab was 8 mg/kg; 6 mg/kg was used for the remaining 3 cycles.

    Serious adverse events
    MCH - TH AC - TH
    Total subjects affected by serious adverse events
         subjects affected / exposed
    18 / 62 (29.03%)
    21 / 63 (33.33%)
         number of deaths (all causes)
    0
    4
         number of deaths resulting from adverse events
    Vascular disorders
    Capillary leak syndrome
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aneurysm
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Whiplash injury
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cyanosis
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 63 (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 / 62 (1.61%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    9 / 62 (14.52%)
    7 / 63 (11.11%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Acute polyneuropathy
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 63 (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
    Pyrexia
         subjects affected / exposed
    1 / 62 (1.61%)
    2 / 63 (3.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 62 (0.00%)
    2 / 63 (3.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Erythema multiforme
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Wound infection
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter related infection
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 63 (1.59%)
         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
    1 / 62 (1.61%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    MCH - TH AC - TH
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    62 / 62 (100.00%)
    63 / 63 (100.00%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    10 / 62 (16.13%)
    12 / 63 (19.05%)
         occurrences all number
    12
    20
    Hypertension
         subjects affected / exposed
    3 / 62 (4.84%)
    4 / 63 (6.35%)
         occurrences all number
    5
    4
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    28 / 62 (45.16%)
    36 / 63 (57.14%)
         occurrences all number
    115
    116
    Mucosal inflammation
         subjects affected / exposed
    32 / 62 (51.61%)
    25 / 63 (39.68%)
         occurrences all number
    62
    55
    Fatigue
         subjects affected / exposed
    19 / 62 (30.65%)
    15 / 63 (23.81%)
         occurrences all number
    62
    54
    Pyrexia
         subjects affected / exposed
    17 / 62 (27.42%)
    11 / 63 (17.46%)
         occurrences all number
    21
    21
    Oedema peripheral
         subjects affected / exposed
    9 / 62 (14.52%)
    11 / 63 (17.46%)
         occurrences all number
    10
    15
    Oedema
         subjects affected / exposed
    10 / 62 (16.13%)
    7 / 63 (11.11%)
         occurrences all number
    13
    9
    Infusion related reaction
         subjects affected / exposed
    3 / 62 (4.84%)
    4 / 63 (6.35%)
         occurrences all number
    5
    4
    Pain
         subjects affected / exposed
    1 / 62 (1.61%)
    4 / 63 (6.35%)
         occurrences all number
    2
    5
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    7 / 62 (11.29%)
    7 / 63 (11.11%)
         occurrences all number
    10
    8
    Anxiety
         subjects affected / exposed
    3 / 62 (4.84%)
    5 / 63 (7.94%)
         occurrences all number
    3
    5
    Depression
         subjects affected / exposed
    4 / 62 (6.45%)
    3 / 63 (4.76%)
         occurrences all number
    4
    4
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    10 / 62 (16.13%)
    4 / 63 (6.35%)
         occurrences all number
    17
    6
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    10 / 62 (16.13%)
    4 / 63 (6.35%)
         occurrences all number
    18
    4
    Aspartate aminotransferase increased
         subjects affected / exposed
    6 / 62 (9.68%)
    5 / 63 (7.94%)
         occurrences all number
    8
    6
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    4 / 62 (6.45%)
    1 / 63 (1.59%)
         occurrences all number
    4
    1
    Weight increased
         subjects affected / exposed
    0 / 62 (0.00%)
    4 / 63 (6.35%)
         occurrences all number
    0
    5
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    41 / 62 (66.13%)
    46 / 63 (73.02%)
         occurrences all number
    145
    143
    Leukopenia
         subjects affected / exposed
    24 / 62 (38.71%)
    34 / 63 (53.97%)
         occurrences all number
    77
    111
    Anaemia
         subjects affected / exposed
    13 / 62 (20.97%)
    21 / 63 (33.33%)
         occurrences all number
    27
    60
    Thrombocytopenia
         subjects affected / exposed
    5 / 62 (8.06%)
    5 / 63 (7.94%)
         occurrences all number
    5
    8
    Lymphopenia
         subjects affected / exposed
    3 / 62 (4.84%)
    6 / 63 (9.52%)
         occurrences all number
    15
    17
    Febrile neutropenia
         subjects affected / exposed
    2 / 62 (3.23%)
    4 / 63 (6.35%)
         occurrences all number
    2
    4
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    7 / 62 (11.29%)
    6 / 63 (9.52%)
         occurrences all number
    8
    6
    Dyspnoea
         subjects affected / exposed
    5 / 62 (8.06%)
    8 / 63 (12.70%)
         occurrences all number
    9
    12
    Oropharyngeal pain
         subjects affected / exposed
    7 / 62 (11.29%)
    4 / 63 (6.35%)
         occurrences all number
    7
    4
    Cough
         subjects affected / exposed
    6 / 62 (9.68%)
    4 / 63 (6.35%)
         occurrences all number
    6
    4
    Nasal mucosal disorder
         subjects affected / exposed
    7 / 62 (11.29%)
    2 / 63 (3.17%)
         occurrences all number
    8
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    13 / 62 (20.97%)
    15 / 63 (23.81%)
         occurrences all number
    20
    20
    Dysgeusia
         subjects affected / exposed
    14 / 62 (22.58%)
    13 / 63 (20.63%)
         occurrences all number
    24
    15
    Paraesthesia
         subjects affected / exposed
    9 / 62 (14.52%)
    15 / 63 (23.81%)
         occurrences all number
    14
    31
    Peripheral sensory neuropathy
         subjects affected / exposed
    8 / 62 (12.90%)
    2 / 63 (3.17%)
         occurrences all number
    14
    3
    Neuropathy peripheral
         subjects affected / exposed
    1 / 62 (1.61%)
    7 / 63 (11.11%)
         occurrences all number
    1
    9
    Dizziness
         subjects affected / exposed
    4 / 62 (6.45%)
    3 / 63 (4.76%)
         occurrences all number
    4
    3
    Disturbance in attention
         subjects affected / exposed
    4 / 62 (6.45%)
    3 / 63 (4.76%)
         occurrences all number
    5
    4
    Neurotoxicity
         subjects affected / exposed
    1 / 62 (1.61%)
    4 / 63 (6.35%)
         occurrences all number
    1
    6
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    11 / 62 (17.74%)
    10 / 63 (15.87%)
         occurrences all number
    12
    13
    Lacrimation increased
         subjects affected / exposed
    6 / 62 (9.68%)
    8 / 63 (12.70%)
         occurrences all number
    7
    9
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    5 / 62 (8.06%)
    5 / 63 (7.94%)
         occurrences all number
    8
    6
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    44 / 62 (70.97%)
    39 / 63 (61.90%)
         occurrences all number
    95
    95
    Stomatitis
         subjects affected / exposed
    21 / 62 (33.87%)
    21 / 63 (33.33%)
         occurrences all number
    47
    45
    Diarrhoea
         subjects affected / exposed
    27 / 62 (43.55%)
    25 / 63 (39.68%)
         occurrences all number
    57
    44
    Vomiting
         subjects affected / exposed
    17 / 62 (27.42%)
    21 / 63 (33.33%)
         occurrences all number
    29
    38
    Constipation
         subjects affected / exposed
    19 / 62 (30.65%)
    16 / 63 (25.40%)
         occurrences all number
    35
    28
    Abdominal pain upper
         subjects affected / exposed
    12 / 62 (19.35%)
    12 / 63 (19.05%)
         occurrences all number
    19
    16
    Dyspepsia
         subjects affected / exposed
    8 / 62 (12.90%)
    9 / 63 (14.29%)
         occurrences all number
    9
    10
    Abdominal pain
         subjects affected / exposed
    5 / 62 (8.06%)
    4 / 63 (6.35%)
         occurrences all number
    8
    5
    Dry mouth
         subjects affected / exposed
    1 / 62 (1.61%)
    4 / 63 (6.35%)
         occurrences all number
    1
    5
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    37 / 62 (59.68%)
    41 / 63 (65.08%)
         occurrences all number
    55
    52
    Nail disorder
         subjects affected / exposed
    13 / 62 (20.97%)
    11 / 63 (17.46%)
         occurrences all number
    19
    13
    Dry skin
         subjects affected / exposed
    15 / 62 (24.19%)
    7 / 63 (11.11%)
         occurrences all number
    17
    8
    Rash
         subjects affected / exposed
    11 / 62 (17.74%)
    8 / 63 (12.70%)
         occurrences all number
    16
    14
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    9 / 62 (14.52%)
    7 / 63 (11.11%)
         occurrences all number
    13
    12
    Skin toxicity
         subjects affected / exposed
    10 / 62 (16.13%)
    4 / 63 (6.35%)
         occurrences all number
    11
    8
    Nail toxicity
         subjects affected / exposed
    8 / 62 (12.90%)
    6 / 63 (9.52%)
         occurrences all number
    1
    7
    Pruritus
         subjects affected / exposed
    5 / 62 (8.06%)
    4 / 63 (6.35%)
         occurrences all number
    6
    4
    Erythema
         subjects affected / exposed
    6 / 62 (9.68%)
    1 / 63 (1.59%)
         occurrences all number
    8
    1
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    17 / 62 (27.42%)
    17 / 63 (26.98%)
         occurrences all number
    26
    23
    Bone pain
         subjects affected / exposed
    18 / 62 (29.03%)
    15 / 63 (23.81%)
         occurrences all number
    28
    33
    Musculoskeletal pain
         subjects affected / exposed
    13 / 62 (20.97%)
    13 / 63 (20.63%)
         occurrences all number
    35
    36
    Arthralgia
         subjects affected / exposed
    10 / 62 (16.13%)
    10 / 63 (15.87%)
         occurrences all number
    16
    15
    Back pain
         subjects affected / exposed
    6 / 62 (9.68%)
    2 / 63 (3.17%)
         occurrences all number
    6
    3
    Pain in extremity
         subjects affected / exposed
    4 / 62 (6.45%)
    2 / 63 (3.17%)
         occurrences all number
    6
    2
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    12 / 62 (19.35%)
    12 / 63 (19.05%)
         occurrences all number
    16
    23
    Infections and infestations
    Vulvovaginal mycotic infection
         subjects affected / exposed
    4 / 62 (6.45%)
    0 / 63 (0.00%)
         occurrences all number
    7
    0
    Nasopharyngitis
         subjects affected / exposed
    4 / 62 (6.45%)
    16 / 63 (25.40%)
         occurrences all number
    6
    21
    Respiratory tract infection
         subjects affected / exposed
    4 / 62 (6.45%)
    4 / 63 (6.35%)
         occurrences all number
    4
    5
    Bronchitis
         subjects affected / exposed
    3 / 62 (4.84%)
    4 / 63 (6.35%)
         occurrences all number
    4
    7
    Urinary tract infection
         subjects affected / exposed
    4 / 62 (6.45%)
    1 / 63 (1.59%)
         occurrences all number
    4
    2

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 May 2008
    Amendment 1 was issued before any patients were enrolled into the study. • An Independent Safety Data Monitoring Committee was set-up to review the patients safety events including: - suspected unexpected serious adverse reactions, - All grade 3, 4 or 5 non-hematologic AEs (grading according to NCI CTCAE version 3.0), - Febrile neutropenia, - Thrombocytopenia with hemorrhage, - Events of interest, such as symptomatic cardiac function failure (NYHA Class 3 or 4) or asymptomatic decrease in LVEF. • The Steering Committee reviewed and implemented the recommendation issued by the Independent Safety Data Monitoring Committee.
    07 Jul 2008
    Amendment 2 was issued before any patients were enrolled into the study. • In the primary objective, the primary efficacy variable was clarified to indicate the proportion of patients who achieve pCR in breast. • The secondary objectives were updated and 2 additional secondary objectives were to be evaluated: - The proportion of patients who achieve pCR in breast and axillary lymph node. - The proportion of patients with conservative surgery. • SISH and CISH tests, in addition to the FISH test, were allowed to check the amplification of the HER2 gene. These 2 tests were the reference tests in some European centers. • Additional information concerning diagnosis biopsy and SLN procedure have been included as follows: - Introduction of a tumor clip at the time of the diagnosis biopsy is highly recommended. - Pre-treatment SLN is not a standard procedure but is acceptable for clinical stage T2, N0 patients. • The following statement was deleted concerning anti estrogen or anti aromatase hormonal treatment: - Patients with ER positive tumors will be allowed to receive anti estrogen or anti aromatase hormonal treatment at the discretion of the investigator. • The timing of the postsurgical visit was clarified from Postsurgical follow-up to end of cycle 8/Postsurgical visit. • The number and timing of mammography/MRI procedures to be performed was changed to avoid unnecessary repetition of these procedures. • Clarification concerning the breast surgery and axillary dissection as follows: The patient will then undergo surgery: mastectomy or breast conservative surgery that must remove all residual tumor providing clear margins (>2 mm). Axillary dissection is mandatory in the absence of pre-treatment negative SLN. • The timing for platelet and absolute neutrophil counts was modified to avoid unnecessary repetition of procedures; the number of blood tests was reduced from a weekly schedule at each cycle to a weekly schedule for selected cycles.
    15 Sep 2010
    Amendment 3 was issued after 122 patients were enrolled. • The planned study end date and the duration of the study were changed to the last patient last visit by third quarter 2012 including the 2-year follow-up period, with a duration of 48 months. The expected study end date and duration were updated according to currently available information on patients’ inclusion and accrual rates and a clarification was added indicating that the end of the study was after the 2-year follow-up period. • A sentence was added in order to clarify that all patients who received treatment should still be monitored after they stopped receiving study treatment for up to 2 years from randomization. • In Appendix D of the protocol (NYHA Functional Classification of Cardiac Disease), the presentation of the NYHA classification was modified in order to clarify that patients with no cardiac disease should not be classified according the Functional Capacity Class and to avoid any confusion between the Functional Capacity Class and the Objective Assessment. • In Appendix F (WHO criteria of tumor response) of the protocol, the table for the determination of overall response was simplified.
    23 Feb 2011
    Amendment 4 (dated 23 February 2011) to the protocol was issued after 125 patients were enrolled. Administrative changes in study personnel (sponsor’s medical expert and contact person for medical issues) were made to the protocol.
    29 Feb 2012
    Amendment 5 (dated 29 February 2012) to the protocol was issued after 125 patients were enrolled. • The duration of follow-up for PFS and cardiac insufficiency was changed from 2 to 5 years so that data on PFS and cardiac insufficiency were collected for 3 more years. • The duration of the study and the expected completion date were changed (last patient last visit by third quarter 2015 including the 5-year follow-up period, with a duration of 84 months) so that data on PFS and cardiac insufficiency were collected for 3 more years. • The number of study visits was updated to include additional visits during the extended posttreatment follow-up period and the study flowchart was updated accordingly. • The description of study periods requiring AEs and SAEs reporting was clarified. • The description of study periods requiring SAEs reporting was clarified. • The duration of follow-up for LVEF was changed from 2 to 5 years.
    29 Nov 2012
    Amendment 6 (dated 29 November 2012) to the protocol was issued after 125 patients were enrolled. • The sponsor was changed from Cephalon to Teva. • Administrative changes in personnel were 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
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