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    Clinical Trial Results:
    Randomized comparison of adjuvant Docetaxel / Cyclophosphamide with sequential adjuvant EC / Docetaxel chemotherapy in patients with HER2/neu negative early breast cancer – 6 x TC vs. 4 x EC -> 4 x Doc

    Summary
    EudraCT number
    		 2008-004263-19
    Trial protocol
    		 DE  
    Global end of trial date
    01 Mar 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Mar 2020
    First version publication date
    22 Mar 2020
    Other versions
    Summary report(s)
    		 PlanB - Clinical Study Report

    Trial information

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    Trial identification
    Sponsor protocol code
    WSGAM04
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01049425
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Westdeutsche Studiengruppe
    Sponsor organisation address
    Wallstraße 10, Mönchengladbach, Germany,
    Public contact
    Studienzentrale, Westdeutsche Studiengruppe, 0049 2161566230, wsg@wsg-online.com
    Scientific contact
    Studienzentrale, Westdeutsche Studiengruppe, 0049 2161566230, wsg@wsg-online.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    15 May 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Mar 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Mar 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Compare event-free survival in patients treated with either 6 cycles of Docetaxel / Cyclophosphamide chemotherapy or 4 cycles of EC followed by 4 cycles of Docetaxel as adjuvant treatment.
    Protection of trial subjects
    Dose delay and dose adjustment in case of severe or unacceptable toxicity. Patients with hormone sensitive disease (estrogen and/or progesterone receptor positive) will receive antihormonal therapy according to national standards as defined by AGO guidelines. Supportive Treatment: Dexamethasone according to SmPC docetaxel G-CSF according to AGO guidelines to avoid dose delay and dose adjustment due to febrile neutropenia and infection. It is highly recommended to use Neulasta® as G-CSF treatment.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Feb 2009
    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
    Germany: 2449
    Worldwide total number of subjects
    2449
    EEA total number of subjects
    2449
    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)
    1850
    From 65 to 84 years
    599
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 From 2009 to 2011, 3198 patients were registered in 90 German sites. The intent-to-treat population included 2,449 patients (EC-T/TC).

    Pre-assignment
    Screening details
    		 HER2/neu negative eartly breast cancer; The following patients will be randomised to receive chemotherapy within the planB trial: • Patients with HR positive disease and either RS>11 and 0-3 positive nodes • Patients with HR positive disease and 4 or more positive nodes regardless of RS • Patients with HR negative disease

    Pre-assignment period milestones
    Number of subjects started
    		 2449
    Number of subjects completed
    		 2449

    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
    		 Docetaxel - Cyclophosphamide TC)
    Arm description
    		 TC Treatment will consist of 6 cycles of docetaxel and cyclophosphamid. Docetaxel will be given first 75 mg/m² at day 1 q3w. Followed by Cyclophosphamid 600 mg/m² at day 1 q3w.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    75 mg/m² on day 1 q3w for 6 cycles

    Investigational medicinal product name
    Cyclophosphamid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate and solution for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    600 mg/m² on day 1 q3w for 6 cycles

    Arm title
    		 EC --> DOC (EC-DOC)
    Arm description
    		 EC treatment will consist of 4 cycles of epirubicin and cyclophosphamide. Patients will receive 4 cycles of adjuvant therapy; each cycle will last for 3 weeks. The duration of the study treatment during adjuvant therapy is 12 weeks from cycle 1 to 4. Following completion of 4 cycles, the patient will enter the docetaxel segment for this arm of treatment. Patients will receive 4 cycles of adjuvant therapy; each cycle will last for 3 weeks. The duration of the study treatment during adjuvant therapy is 12 weeks from cycle 1 to 4.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Epirubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    90 mg/m² on day 1 q3w for 4 cycles

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    600 mg/m² on day 1 q3w for 4 cycles

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Three weeks after the last cycle of Epirubicine/Cyclophosphamide, Docetaxel will be given 100 mg/m² on day 1 q3w for additional 4 cycles.

    Number of subjects in period 1
    		Docetaxel - Cyclophosphamide TC) EC --> DOC (EC-DOC)
    Started
    1222
    1227
    Completed
    1217
    1226
    Not completed
    5
    1
         Adverse event, serious fatal
    5
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall Trial Total
    Number of subjects
    		 2449 2449
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 1850 1850
        From 65-84 years
    		 599 599
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 55 (25 to 77) -
    Gender categorical
    Units: Subjects
        Female
    		 2449 2449
        Male
    		 0 0
    Subject analysis sets

    Subject analysis set title
    IIT population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Among patients treated with ECDoc in the NSABP B27 trial, 71.1 % of patients were disease-free at 5 years. In this study, an accrual period of 3 years and an additionally follow up of 5 years will be planed. The one–sided equivalence test will be done at the significance levels of false positive outcome  = 5 % and false negative outcome = 20 % i.e. the power of the trial is set to 80 % for the difference of clinical interest. The study treatment will be regarded as equivalent to the reference treatment, if the difference in the 5 years disease-free survival between both study arms will not be greater as 4.4 %. A total of 2x1224 = 2448 patients are necessary to have sufficient power to show equivalence between ECDoc and TC for all randomised patients, assuming an anticipated drop-out rate of 10 %.

    Subject analysis sets values
    		 IIT population
    Number of subjects
    2449
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    1850
        From 65-84 years
    599
        85 years and over
    0
    Age continuous
    Units: years
        median (full range (min-max))
    55 (25 to 77)
    Gender categorical
    Units: Subjects
        Female
    2449
        Male
    0

    End points

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    End points reporting groups
    Reporting group title
    Docetaxel - Cyclophosphamide TC)
    Reporting group description
    		 TC Treatment will consist of 6 cycles of docetaxel and cyclophosphamid. Docetaxel will be given first 75 mg/m² at day 1 q3w. Followed by Cyclophosphamid 600 mg/m² at day 1 q3w.

    Reporting group title
    EC --> DOC (EC-DOC)
    Reporting group description
    		 EC treatment will consist of 4 cycles of epirubicin and cyclophosphamide. Patients will receive 4 cycles of adjuvant therapy; each cycle will last for 3 weeks. The duration of the study treatment during adjuvant therapy is 12 weeks from cycle 1 to 4. Following completion of 4 cycles, the patient will enter the docetaxel segment for this arm of treatment. Patients will receive 4 cycles of adjuvant therapy; each cycle will last for 3 weeks. The duration of the study treatment during adjuvant therapy is 12 weeks from cycle 1 to 4.

    Subject analysis set title
    IIT population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Among patients treated with ECDoc in the NSABP B27 trial, 71.1 % of patients were disease-free at 5 years. In this study, an accrual period of 3 years and an additionally follow up of 5 years will be planed. The one–sided equivalence test will be done at the significance levels of false positive outcome  = 5 % and false negative outcome = 20 % i.e. the power of the trial is set to 80 % for the difference of clinical interest. The study treatment will be regarded as equivalent to the reference treatment, if the difference in the 5 years disease-free survival between both study arms will not be greater as 4.4 %. A total of 2x1224 = 2448 patients are necessary to have sufficient power to show equivalence between ECDoc and TC for all randomised patients, assuming an anticipated drop-out rate of 10 %.

    Primary: 5 year disease-free survival

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    End point title
    		 5 year disease-free survival
    End point description
    End point type
    Primary
    End point timeframe
    date of randomization to the date of local, regional or metastaic relapse or the date of second Primary Cancer or death
    End point values
    		 Docetaxel - Cyclophosphamide TC) EC --> DOC (EC-DOC)
    Number of subjects analysed
    1222
    1227
    Units: yes vs no
        number (confidence interval 95%)
    89.6 (87.8 to 91.5)
    89.8 (87.9 to 91.6)
    Statistical analysis title
    		 Statistics PlanB
    Comparison groups
    Docetaxel - Cyclophosphamide TC) v EC --> DOC (EC-DOC)
    Number of subjects included in analysis
    2449
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [1]
    P-value
    		 = 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 0.044
         upper limit
    		 -
    Variability estimate
    Standard deviation
    Dispersion value
    0.1
    Notes
    [1] - one-size equivalence test

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    End point type
    Secondary
    End point timeframe
    time from randomization until survial after 5 year follow-up
    End point values
    		 Docetaxel - Cyclophosphamide TC) EC --> DOC (EC-DOC)
    Number of subjects analysed
    1222
    1227
    Units: number
    1149
    1104
    No statistical analyses for this end point

    Secondary: Safety - Dose reduction

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    End point title
    		 Safety - Dose reduction
    End point description
    End point type
    Secondary
    End point timeframe
    number of Patient with dose reduction during chemotherapy
    End point values
    		 Docetaxel - Cyclophosphamide TC) EC --> DOC (EC-DOC)
    Number of subjects analysed
    1222
    1227
    Units: number
    78
    230
    No statistical analyses for this end point

    Secondary: Safety - Dose delay

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    End point title
    		 Safety - Dose delay
    End point description
    End point type
    Secondary
    End point timeframe
    dose delay more than 7 days during chemotherapy
    End point values
    		 Docetaxel - Cyclophosphamide TC) EC --> DOC (EC-DOC)
    Number of subjects analysed
    1222
    1227
    Units: number
    47
    78
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    from time of ranomization until end of 5 year follow-up
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18
    Frequency threshold for reporting non-serious adverse events: 5%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: Such a detailed statistical evaluation of AE results was not done. For further AE evaluation please refer to the attached Clinical Study Report.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Jun 2009
    new protocol Version V2.0
    24 May 2011
    new protocol Version 3.0 and Patient Information sheet Version 3.0

    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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