Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   43851   clinical trials with a EudraCT protocol, of which   7283   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    An Open-Label, Randomized, Multicenter, Phase II, Non Comparative, Exploratory Study on Neoadjuvant Treatment With Trastuzumab Plus Docetaxel Plus Bevacizumab According to Positon Emission Tomography (PET) Value Modification in Patients With Early Stage HER2 Positive Breast Cancer

    Summary
    EudraCT number
    		 2009-013410-26
    Trial protocol
    		 FR  
    Global end of trial date
    13 Dec 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Dec 2018
    First version publication date
    21 Dec 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    ML22229
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01142778
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    13 Dec 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Feb 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Dec 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This was an open-label, randomized, multicenter, phase II, non comparative, exploratory study to assess the effect of adding bevacizumab to trastuzumab plus docetaxel in neoadjuvant therapy in participants with early stage human epidermal growth factor receptor 2 (HER2)-positive breast cancer. The main objective was to assess the complete pathological response rates (evaluation according to Chevallier’s criteria, review by an independent Committee) in patients with a relative change in [18F]-FDG tumoral uptake < 70% and randomized in the arm with trastuzumab plus docetaxel plus bevacizumab.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 May 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 4 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 152
    Worldwide total number of subjects
    152
    EEA total number of subjects
    152
    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)
    139
    From 65 to 84 years
    13
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 152 subjects met the inclusion criteria and were enrolled into the study. All participants received 2 cycles of trastuzumab and docetaxel once every 3 weeks. 142 participants were randomized or assigned to a treatment arm. 10 subjects were not allocated or randomized to a treatment arm.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Trastuzumab, Docetaxel, and Bevacizumab
    Arm description
    		 Participants with a response of <70% will receive trastuzumab and docetaxel along with bevacizumab in Cycles 3 to 6. All participants will receive trastuzumab alone in Cycle 7, and will undergo surgery after Cycle 7 and between 4 and 6 weeks after the bevacizumab infusion in Cycle 6. After surgery, all participants will receive a further 11 cycles of trastuzumab plus radiotherapy with or without hormonal therapy as per site's standard practice, and will be followed for up to 5 years from start of neoadjuvant treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Concentrate for dispersion for infusion, Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab at a dose of 15 mg/kg will be administered as IV infusion over 90 minutes from Cycles 3-6 (1 Cycle=21 days).

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Herceptin
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab will be administered as a loading dose of 8 mg/kg as IV infusion in Cycle 1, then administered as a dose of 6 mg/kg as IV infusion in Cycles 2 to 7, and during additional 11 cycles post surgery (1 Cycle=21 days).

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Taxotere
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Docetaxel at a dose of 100 mg/m^2 will be administered as IV infusion from Cycles 1-6 (1 Cycle=21 days).

    Arm title
    		 Trastuzumab and Docetaxel
    Arm description
    		 Participants with a response of <70% will receive trastuzumab and docetaxel in Cycles 3 to 6. All participants will receive trastuzumab alone in Cycle 7, and will undergo surgery after Cycle 7 and between 4 and 6 weeks after the study treatment perfusion in Cycle 6. After surgery, all participants will receive a further 11 cycles of trastuzumab plus radiotherapy with or without hormonal therapy as per site's standard practice, and will be followed for up to 5 years from start of neoadjuvant treatment.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Taxotere
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Docetaxel at a dose of 100 mg/m^2 will be administered as IV infusion from Cycles 1-6 (1 Cycle=21 days).

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Herceptin
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab will be administered as a loading dose of 8 mg/kg as IV infusion in Cycle 1, then administered as a dose of 6 mg/kg as IV infusion in Cycles 2 to 7, and during additional 11 cycles post surgery (1 Cycle=21 days).

    Arm title
    		 Trastuzumab and Docetaxel (Standard Regimen)
    Arm description
    		 Participants with a response of >/=70% will receive trastuzumab and docetaxel in Cycles 3 to 6. All participants will receive trastuzumab alone in Cycle 7, and will undergo surgery after Cycle 7 and between 4 and 6 weeks after the study treatment perfusion in Cycle 6. After surgery, all participants will receive a further 11 cycles of trastuzumab plus radiotherapy with or without hormonal therapy as per site's standard practice, and will be followed for up to 5 years from start of neoadjuvant treatment.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Taxotere
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Docetaxel at a dose of 100 mg/m^2 will be administered as IV infusion from Cycles 1-6 (1 Cycle=21 days).

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Herceptin
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab will be administered as a loading dose of 8 mg/kg as IV infusion in Cycle 1, then administered as a dose of 6 mg/kg as IV infusion in Cycles 2 to 7, and during additional 11 cycles post surgery (1 Cycle=21 days).

    Arm title
    		 Not allocated or randomized
    Arm description
    		 Participants will receive 2 cycles of trastuzumab and docetaxel once every 3 weeks prior to assignment to a treatment arm.
    Arm type
    		 Prior to randomization

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Taxotere
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Docetaxel at a dose of 100 mg/m^2 will be administered as IV infusion in Cycles 1 and 2 (1 Cycle=21 days).

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Herceptin
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab will be administered as a loading dose of 8 mg/kg as IV infusion in Cycle 1, followed by subsequent dose of 6 mg/kg as IV infusion in Cycle 2 (1 Cycle=21 days).

    Number of subjects in period 1
    		Trastuzumab, Docetaxel, and Bevacizumab Trastuzumab and Docetaxel Trastuzumab and Docetaxel (Standard Regimen) Not allocated or randomized
    Started
    48
    25
    69
    10
    Completed
    38
    22
    61
    4
    Not completed
    10
    3
    8
    6
         Consent withdrawn by subject
    5
    -
    1
    -
         Adverse event, non-fatal
    -
    -
    -
    1
         Death
    2
    1
    -
    -
         Lost to follow-up
    1
    -
    1
    -
         Multiple reasons
    1
    2
    4
    4
         Missing data
    -
    -
    1
    -
         Protocol deviation
    1
    -
    1
    1

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Trastuzumab, Docetaxel, and Bevacizumab
    Reporting group description
    		 Participants with a response of <70% will receive trastuzumab and docetaxel along with bevacizumab in Cycles 3 to 6. All participants will receive trastuzumab alone in Cycle 7, and will undergo surgery after Cycle 7 and between 4 and 6 weeks after the bevacizumab infusion in Cycle 6. After surgery, all participants will receive a further 11 cycles of trastuzumab plus radiotherapy with or without hormonal therapy as per site's standard practice, and will be followed for up to 5 years from start of neoadjuvant treatment.

    Reporting group title
    Trastuzumab and Docetaxel
    Reporting group description
    		 Participants with a response of <70% will receive trastuzumab and docetaxel in Cycles 3 to 6. All participants will receive trastuzumab alone in Cycle 7, and will undergo surgery after Cycle 7 and between 4 and 6 weeks after the study treatment perfusion in Cycle 6. After surgery, all participants will receive a further 11 cycles of trastuzumab plus radiotherapy with or without hormonal therapy as per site's standard practice, and will be followed for up to 5 years from start of neoadjuvant treatment.

    Reporting group title
    Trastuzumab and Docetaxel (Standard Regimen)
    Reporting group description
    		 Participants with a response of >/=70% will receive trastuzumab and docetaxel in Cycles 3 to 6. All participants will receive trastuzumab alone in Cycle 7, and will undergo surgery after Cycle 7 and between 4 and 6 weeks after the study treatment perfusion in Cycle 6. After surgery, all participants will receive a further 11 cycles of trastuzumab plus radiotherapy with or without hormonal therapy as per site's standard practice, and will be followed for up to 5 years from start of neoadjuvant treatment.

    Reporting group title
    Not allocated or randomized
    Reporting group description
    		 Participants will receive 2 cycles of trastuzumab and docetaxel once every 3 weeks prior to assignment to a treatment arm.

    Reporting group values
    		 Trastuzumab, Docetaxel, and Bevacizumab Trastuzumab and Docetaxel Trastuzumab and Docetaxel (Standard Regimen) Not allocated or randomized Total
    Number of subjects
    		 48 25 69 10 152
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 45 24 62 8 139
        From 65-84 years
    		 3 1 7 2 13
        85 years and over
    		 0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 50.4 ( 11.1 ) 47.8 ( 8.9 ) 49.5 ( 10.7 ) 52.9 ( 14.0 ) -
    Gender categorical
    Units: Subjects
        Female
    		 48 25 69 10 152
        Male
    		 0 0 0 0 0

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Trastuzumab, Docetaxel, and Bevacizumab
    Reporting group description
    		 Participants with a response of <70% will receive trastuzumab and docetaxel along with bevacizumab in Cycles 3 to 6. All participants will receive trastuzumab alone in Cycle 7, and will undergo surgery after Cycle 7 and between 4 and 6 weeks after the bevacizumab infusion in Cycle 6. After surgery, all participants will receive a further 11 cycles of trastuzumab plus radiotherapy with or without hormonal therapy as per site's standard practice, and will be followed for up to 5 years from start of neoadjuvant treatment.

    Reporting group title
    Trastuzumab and Docetaxel
    Reporting group description
    		 Participants with a response of <70% will receive trastuzumab and docetaxel in Cycles 3 to 6. All participants will receive trastuzumab alone in Cycle 7, and will undergo surgery after Cycle 7 and between 4 and 6 weeks after the study treatment perfusion in Cycle 6. After surgery, all participants will receive a further 11 cycles of trastuzumab plus radiotherapy with or without hormonal therapy as per site's standard practice, and will be followed for up to 5 years from start of neoadjuvant treatment.

    Reporting group title
    Trastuzumab and Docetaxel (Standard Regimen)
    Reporting group description
    		 Participants with a response of >/=70% will receive trastuzumab and docetaxel in Cycles 3 to 6. All participants will receive trastuzumab alone in Cycle 7, and will undergo surgery after Cycle 7 and between 4 and 6 weeks after the study treatment perfusion in Cycle 6. After surgery, all participants will receive a further 11 cycles of trastuzumab plus radiotherapy with or without hormonal therapy as per site's standard practice, and will be followed for up to 5 years from start of neoadjuvant treatment.

    Reporting group title
    Not allocated or randomized
    Reporting group description
    		 Participants will receive 2 cycles of trastuzumab and docetaxel once every 3 weeks prior to assignment to a treatment arm.

    Primary: Percentage of Participants With Pathological Complete Response (pCR) in the Trastuzumab, Docetaxel, and Bevacizumab Treatment Arm as per Chevallier’s Classification as Reviewed by an Independent Committee

    		 Close Top of page
    End point title
    		 Percentage of Participants With Pathological Complete Response (pCR) in the Trastuzumab, Docetaxel, and Bevacizumab Treatment Arm as per Chevallier’s Classification as Reviewed by an Independent Committee [1] [2]
    End point description
    Pathological Complete Response (pCR) was assessed in surgical specimens of mammary tissue and lymph nodes of participants in the Trastuzumab, Docetaxel, and Bevacizumab Treatment Arm according to Chevallier's classification and reviewed by an independent committee. The Chevallier's classification for grading of therapeutic effect related to the tumor site and lymph nodes was defined by microscopic changes as follows - Grade 1: Disappearance of all tumors either in the breast or in the nodes, Grade 2: Persistence of carcinoma in situ in the breast only and no nodal invasion, Grade 3: Presence of invasive carcinoma with stromal alteration, Grade 4: Presence of invasive carcinoma without modification. Grade 1 and Grade 2 response were considered as pCR. Results are presented for the Intent to treat (ITT) population, which is described as all participants that were assigned to a treatment group according to change in Standard uptake value (SUV).
    End point type
    Primary
    End point timeframe
    After 6 cycles (18 weeks) of neoadjuvant therapy (cycle length=21 days)
    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 analyses were planned for the primary end point.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The primary analysis only included participants in the ITT population.
    End point values
    		 Trastuzumab, Docetaxel, and Bevacizumab
    Number of subjects analysed
    48
    Units: percentage of participants
    number (confidence interval 90%)
        Missing data considered as “failure”
    43.8 (31.5 to 56.6)
        Sensitivity analysis excluding missing values
    51.2 (37.4 to 64.9)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Pathological Complete Response According to Chevallier’s Classification as per Local Procedures

    		 Close Top of page
    End point title
    		 Percentage of Participants With Pathological Complete Response According to Chevallier’s Classification as per Local Procedures [3]
    End point description
    PCR was assessed in surgical specimens of mammary tissue and lymph nodes according to Chevallier's classification and reviewed according to local procedures. The Chevallier's classification for grading of therapeutic effect related to the tumor site and lymph nodes was defined by microscopic changes as follows - Grade 1: Disappearance of all tumors either in the breast or in the nodes, Grade 2: Persistence of carcinoma in situ in the breast only and no nodal invasion, Grade 3: Presence of invasive carcinoma with stromal alteration, Grade 4: Presence of invasive carcinoma without modification. Grade 1 and Grade 2 response were considered as pCR. Results are presented for the ITT population, which is described as all participants that were assigned to a treatment group according to change in SUV.
    End point type
    Secondary
    End point timeframe
    After 6 cycles (18 weeks) of neoadjuvant therapy (cycle length=21 days)
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The primary analysis only included participants in the ITT population.
    End point values
    		 Trastuzumab, Docetaxel, and Bevacizumab Trastuzumab and Docetaxel Trastuzumab and Docetaxel (Standard Regimen)
    Number of subjects analysed
    48
    25
    69
    Units: percentage of participants
    number (confidence interval 95%)
        Missing data considered as “failure”
    50.0 (35.2 to 64.8)
    36.0 (18.0 to 57.5)
    62.3 (49.8 to 73.7)
        Sensitivity analysis excluding missing values
    57.1 (41.0 to 72.3)
    37.5 (18.8 to 59.4)
    65.2 (52.4 to 76.5)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Pathological Complete Response (pCR) as per Chevallier’s Classification as Reviewed by an Independent Committee

    		 Close Top of page
    End point title
    		 Percentage of Participants With Pathological Complete Response (pCR) as per Chevallier’s Classification as Reviewed by an Independent Committee [4]
    End point description
    Pathological Complete Response (pCR) was assessed in surgical specimens of mammary tissue and lymph nodes according to Chevallier's classification and reviewed by an independent committee. The Chevallier's classification for grading of therapeutic effect related to the tumor site and lymph nodes was defined by microscopic changes as follows - Grade 1: Disappearance of all tumors either in the breast or in the nodes, Grade 2: Persistence of carcinoma in situ in the breast only and no nodal invasion, Grade 3: Presence of invasive carcinoma with stromal alteration, Grade 4: Presence of invasive carcinoma without modification. Grade 1 and Grade 2 response were considered as pCR. Results are presented for the Intent to treat (ITT) population, which is described as all participants that were assigned to a treatment group according to change in Standard uptake value (SUV).
    End point type
    Secondary
    End point timeframe
    After 6 cycles (18 weeks) of neoadjuvant therapy (cycle length=21 days)
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The primary analysis only included participants in the ITT population.
    End point values
    		 Trastuzumab, Docetaxel, and Bevacizumab Trastuzumab and Docetaxel Trastuzumab and Docetaxel (Standard Regimen)
    Number of subjects analysed
    48
    25
    69
    Units: percentage of participants
    number (confidence interval 95%)
        Missing data considered as “failure”
    43.8 (29.5 to 58.8)
    24.0 (9.4 to 45.1)
    53.6 (41.2 to 65.7)
        Sensitivity analysis excluding missing values
    51.2 (35.1 to 67.1)
    25.0 (9.8 to 46.7)
    56.1 (43.3 to 68.3)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Pathological Complete Response According to Sataloff's Classification as Reviewed by an Independent Committee

    		 Close Top of page
    End point title
    		 Percentage of Participants With Pathological Complete Response According to Sataloff's Classification as Reviewed by an Independent Committee [5]
    End point description
    PCR was assessed in surgical specimens of mammary tissue and lymph nodes according to Sataloff classification and reviewed by an independent committee. Pathological response was defined based on the therapeutic response at the tumor site and lymph nodes. Tumor response criteria were as follows: T-A (Total / near total therapeutic effect), T-B (Subjectively greater than [>] 50 percent [%] therapeutic effect but less than [<] T-A), T-C (<50% therapeutic effect, but effect evident), T-D (No therapeutic effect). Lymph node response: N-A (Evidence of therapeutic effect, no metastases), N-B (No therapeutic effect, no nodal metastases), N-C (Nodal metastasis but evident therapeutic effect), N-D (Nodal metastasis with no therapeutic effect). T-A and N-A or T-A and N-B responses were defined as PCR. Results are presented for the ITT population, which is described as all participants that were assigned to a treatment group according to change in SUV.
    End point type
    Secondary
    End point timeframe
    After 6 cycles (18 weeks) of neoadjuvant therapy (cycle length=21 days)
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The primary analysis only included participants in the ITT population.
    End point values
    		 Trastuzumab, Docetaxel, and Bevacizumab Trastuzumab and Docetaxel Trastuzumab and Docetaxel (Standard Regimen)
    Number of subjects analysed
    48
    25
    69
    Units: percentage of participants
    number (confidence interval 95%)
        Missing data considered as “failure”
    50.0 (35.2 to 64.8)
    28.0 (12.1 to 49.4)
    65.2 (52.8 to 76.3)
        Sensitivity analysis excluding missing values
    58.5 (42.1 to 73.7)
    30.4 (13.2 to 52.9)
    68.2 (55.6 to 79.1)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Ultrasound Response According to Modified Response Evaluation Criteria in Solid Tumors (RECIST)

    		 Close Top of page
    End point title
    		 Percentage of Participants With Ultrasound Response According to Modified Response Evaluation Criteria in Solid Tumors (RECIST) [6]
    End point description
    A complete Ultrasound Response (UR) was defined as the disappearance of all measurable and assessable disease (based on RECIST criteria) with no lesion. A complete UR was considered if the largest diameter is equal to 0, during the tumoral evaluation at Cycles 3, 6 or 7, by cycle.
    End point type
    Secondary
    End point timeframe
    Neodajuvant treatment period (21 weeks)
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The primary analysis only included participants in the ITT population.
    End point values
    		 Trastuzumab, Docetaxel, and Bevacizumab Trastuzumab and Docetaxel Trastuzumab and Docetaxel (Standard Regimen)
    Number of subjects analysed
    48
    25
    69
    Units: percentage of participants
    number (not applicable)
        Cycle 3
    21.2
    21.1
    34.2
        Cycle 6
    72.0
    50.0
    81.6
        Cycle 7
    29.4
    15.0
    37.7
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Conservative Surgery Post Neoadjuvant Treatment

    		 Close Top of page
    End point title
    		 Percentage of Participants With Conservative Surgery Post Neoadjuvant Treatment [7]
    End point description
    Results were presented for the ITT population, which were described as all participants that were assigned to a treatment group according to change in SUV.
    End point type
    Secondary
    End point timeframe
    Week 20 (between Day 28 and Day 35 after the Cycle 6, cycle length=21 days)
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The primary analysis only included participants in the ITT population.
    End point values
    		 Trastuzumab, Docetaxel, and Bevacizumab Trastuzumab and Docetaxel Trastuzumab and Docetaxel (Standard Regimen)
    Number of subjects analysed
    48
    25
    69
    Units: percentage of participants
    number (confidence interval 95%)
        Missing data considered as “failure”
    60.4 (45.3 to 74.2)
    60.0 (38.7 to 78.9)
    81.2 (69.9 to 89.6)
        Sensitivity analysis excluding missing values
    67.4 (51.5 to 80.9)
    62.5 (40.6 to 81.2)
    84.8 (73.9 to 92.5)
    No statistical analyses for this end point

    Secondary: Local Relapse-Free Interval (LRFI) According to Modified RECIST Criteria

    		 Close Top of page
    End point title
    		 Local Relapse-Free Interval (LRFI) According to Modified RECIST Criteria [8]
    End point description
    LRFI was defined as time to local recurrence following first administration of neoadjuvant treatment, local recurrence in the ipsilateral or controlateral breast following lumpectomy. Probability to have LRFI at Month 12, Month 36 and Month 60 was estimated.
    End point type
    Secondary
    End point timeframe
    From baseline to occurrence of relapse/disease or death of any cause (up to 5 years)
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The primary analysis only included participants in the ITT population.
    End point values
    		 Trastuzumab, Docetaxel, and Bevacizumab Trastuzumab and Docetaxel Trastuzumab and Docetaxel (Standard Regimen)
    Number of subjects analysed
    48
    25
    69
    Units: probability of events
    number (confidence interval 95%)
        Month 12
    0.000 (0.000 to 0.000)
    0.000 (0.000 to 0.000)
    0.000 (0.000 to 0.000)
        Month 36
    0.000 (0.000 to 0.000)
    0.000 (0.000 to 0.000)
    0.000 (0.000 to 0.000)
        Month 60
    0.024 (0.003 to 0.161)
    0.091 (0.024 to 0.317)
    0.052 (0.017 to 0.154)
    No statistical analyses for this end point

    Secondary: Disease-Free Survival (DFS) According to Modified RECIST Criteria

    		 Close Top of page
    End point title
    		 Disease-Free Survival (DFS) According to Modified RECIST Criteria [9]
    End point description
    DFS was defined as the time from first administration of neoadjuvant treatment to local recurrence, local recurrence in the ipsilateral breast following lumpectomy, regional recurrence, occurrence of distant metastases, controlateral breast cancer, second primary cancer (other than squamous or basal cell carcinoma of the skin, melanoma in situ, carcinoma in situ of the cervix, colon carcinoma in situ, or lobular carcinoma in situ of the breast), or death from any cause. Probability to have DFS at Month 12, Month 36 and Month 60 was estimated.
    End point type
    Secondary
    End point timeframe
    From baseline to occurrence of relapse/disease or death of any cause (up to 5 years)
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The primary analysis only included participants in the ITT population.
    End point values
    		 Trastuzumab, Docetaxel, and Bevacizumab Trastuzumab and Docetaxel Trastuzumab and Docetaxel (Standard Regimen)
    Number of subjects analysed
    48
    25
    69
    Units: probability of events
    number (confidence interval 95%)
        Month 12
    0.000 (0.000 to 0.000)
    0.000 (0.000 to 0.000)
    0.030 (0.007 to 0.113)
        Month 36
    0.000 (0.000 to 0.000)
    0.080 (0.021 to 0.284)
    0.045 (0.015 to 0.133)
        Month 60
    0.098 (0.038 to 0.241)
    0.240 (0.116 to 0.458)
    0.095 (0.044 to 0.200)
    No statistical analyses for this end point

    Secondary: Distant Disease-Free Interval (DDFI) According to Modified RECIST Criteria

    		 Close Top of page
    End point title
    		 Distant Disease-Free Interval (DDFI) According to Modified RECIST Criteria [10]
    End point description
    DDFI was defined as time to distant recurrence following first administration of neoadjuvant treatment. The probability to have DDFI at Month 12, Month 36 and Month 60 following first administration of neoadjuvant treatment was estimated.
    End point type
    Secondary
    End point timeframe
    From baseline to occurrence of relapse/disease or death of any cause (up to 5 years)
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The primary analysis only included participants in the ITT population.
    End point values
    		 Trastuzumab, Docetaxel, and Bevacizumab Trastuzumab and Docetaxel Trastuzumab and Docetaxel (Standard Regimen)
    Number of subjects analysed
    48
    25
    69
    Units: probability of events
    number (confidence interval 95%)
        Month 12
    0.000 (0.000 to 0.000)
    0.000 (0.000 to 0.000)
    0.030 (0.007 to 0.113)
        Month 36
    0.000 (0.000 to 0.000)
    0.040 (0.006 to 0.252)
    0.045 (0.015 to 0.133)
        Month 60
    0.000 (0.000 to 0.000)
    0.131 (0.044 to 0.355)
    0.045 (0.015 to 0.133)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

    		 Close Top of page
    End point title
    		 Overall Survival (OS) [11]
    End point description
    OS was defined as time from first administration of study treatment to death from any cause. The probability of dying at Month 12, Month 36 and Month 60 after first administration of study treatment was estimated.
    End point type
    Secondary
    End point timeframe
    Baseline up to occurrence of death (up to 5 years)
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The primary analysis only included participants in the ITT population.
    End point values
    		 Trastuzumab, Docetaxel, and Bevacizumab Trastuzumab and Docetaxel Trastuzumab and Docetaxel (Standard Regimen)
    Number of subjects analysed
    48
    25
    69
    Units: probability of events
    number (confidence interval 95%)
        Month 12
    0.000 (0.000 to 0.000)
    0.000 (0.000 to 0.000)
    0.000 (0.000 to 0.000)
        Month 36
    0.000 (0.000 to 0.000)
    0.000 (0.000 to 0.000)
    0.000 (0.000 to 0.000)
        Month 60
    0.049 (0.013 to 0.183)
    0.042 (0.006 to 0.261)
    0.000 (0.000 to 0.000)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Adverse Events

    		 Close Top of page
    End point title
    		 Percentage of Participants With Adverse Events
    End point description
    Analysis of safety was performed on the Safety population (SAF), which included all participants who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline up to 5 years
    End point values
    		 Trastuzumab, Docetaxel, and Bevacizumab Trastuzumab and Docetaxel Trastuzumab and Docetaxel (Standard Regimen) Not allocated or randomized
    Number of subjects analysed
    48
    25
    69
    10
    Units: percentage of participants
        number (not applicable)
    100
    100
    98.6
    70.0
    No statistical analyses for this end point

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    Baseline to the data cut-off of 13 December 2017 (up to approximately 7.5 years)
    Adverse event reporting additional description
    Serious adverse events (SAEs) causality was only evaluated for bevacizumab in the Trastuzumab, Docetaxel, and Bevacizumab arm.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    Trastuzumab, Docetaxel, and Bevacizumab
    Reporting group description
    		 Participants with a response of <70% will receive trastuzumab and docetaxel along with bevacizumab in Cycles 3 to 6. All participants will receive trastuzumab alone in Cycle 7, and will undergo surgery after Cycle 7 and between 4 and 6 weeks after the bevacizumab infusion in Cycle 6. After surgery, all participants will receive a further 11 cycles of trastuzumab plus radiotherapy with or without hormonal therapy as per site's standard practice, and will be followed for up to 5 years from start of neoadjuvant treatment.

    Reporting group title
    Trastuzumab and Docetaxel
    Reporting group description
    		 Participants with a response of <70% will receive trastuzumab and docetaxel in Cycles 3 to 6. All participants will receive trastuzumab alone in Cycle 7, and will undergo surgery after Cycle 7 and between 4 and 6 weeks after the study treatment perfusion in Cycle 6. After surgery, all participants will receive a further 11 cycles of trastuzumab plus radiotherapy with or without hormonal therapy as per site's standard practice, and will be followed for up to 5 years from start of neoadjuvant treatment.

    Reporting group title
    Trastuzumab and Docetaxel (Standard Regimen)
    Reporting group description
    		 Participants with a response of >/=70% will receive trastuzumab and docetaxel in Cycles 3 to 6. All participants will receive trastuzumab alone in Cycle 7, and will undergo surgery after Cycle 7 and between 4 and 6 weeks after the study treatment perfusion in Cycle 6. After surgery, all participants will receive a further 11 cycles of trastuzumab plus radiotherapy with or without hormonal therapy as per site's standard practice, and will be followed for up to 5 years from start of neoadjuvant treatment.

    Reporting group title
    Not allocated or randomized
    Reporting group description
    		 Participants will receive 2 cycles of trastuzumab and docetaxel once every 3 weeks prior to assignment to a treatment arm.

    Serious adverse events
    		 Trastuzumab, Docetaxel, and Bevacizumab Trastuzumab and Docetaxel Trastuzumab and Docetaxel (Standard Regimen) Not allocated or randomized
    Total subjects affected by serious adverse events
         subjects affected / exposed
    19 / 48 (39.58%)
    6 / 25 (24.00%)
    18 / 69 (26.09%)
    1 / 10 (10.00%)
         number of deaths (all causes)
    2
    1
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 25 (4.00%)
    1 / 69 (1.45%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Lymphocele
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    0 / 69 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Phlebitis deep
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    1 / 69 (1.45%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Breast operation
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    0 / 69 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast prosthesis removal
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 25 (4.00%)
    0 / 69 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Salpingo-oophorectomy bilateral
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    1 / 69 (1.45%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Impaired healing
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 25 (0.00%)
    0 / 69 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    0 / 69 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    0 / 69 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    1 / 69 (1.45%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    0 / 69 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    1 / 69 (1.45%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Bronchogenic cyst
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    1 / 69 (1.45%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    1 / 69 (1.45%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    1 / 69 (1.45%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Neuralgia
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    1 / 69 (1.45%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    0 / 69 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    1 / 69 (1.45%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    0 / 69 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    1 / 69 (1.45%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    3 / 48 (6.25%)
    2 / 25 (8.00%)
    3 / 69 (4.35%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 25 (0.00%)
    4 / 69 (5.80%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile bone marrow aplasia
         subjects affected / exposed
    3 / 48 (6.25%)
    0 / 25 (0.00%)
    2 / 69 (2.90%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Agranulocytosis
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    0 / 69 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    0 / 69 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    0 / 69 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    1 / 69 (1.45%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 25 (4.00%)
    0 / 69 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    0 / 69 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 25 (4.00%)
    0 / 69 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    0 / 69 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    1 / 69 (1.45%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fibromyalgia
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    0 / 69 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Postoperative wound infection
         subjects affected / exposed
    3 / 48 (6.25%)
    0 / 25 (0.00%)
    0 / 69 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    2 / 69 (2.90%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridial infection
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    0 / 69 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    1 / 69 (1.45%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    0 / 69 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    0 / 69 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mycoplasma infection
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    0 / 69 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic abscess
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    0 / 69 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    0 / 69 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 25 (4.00%)
    0 / 69 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    0 / 69 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis syndrome
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    1 / 69 (1.45%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    0 / 69 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    1 / 69 (1.45%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Trastuzumab, Docetaxel, and Bevacizumab Trastuzumab and Docetaxel Trastuzumab and Docetaxel (Standard Regimen) Not allocated or randomized
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    48 / 48 (100.00%)
    25 / 25 (100.00%)
    68 / 69 (98.55%)
    7 / 10 (70.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung neoplasm
         subjects affected / exposed
    0 / 48 (0.00%)
    2 / 25 (8.00%)
    0 / 69 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Vascular disorders
    Hot flush
         subjects affected / exposed
    13 / 48 (27.08%)
    16 / 25 (64.00%)
    35 / 69 (50.72%)
    0 / 10 (0.00%)
         occurrences all number
    18
    18
    38
    0
    Lymphocele
         subjects affected / exposed
    10 / 48 (20.83%)
    9 / 25 (36.00%)
    15 / 69 (21.74%)
    0 / 10 (0.00%)
         occurrences all number
    11
    9
    15
    0
    Lymphoedema
         subjects affected / exposed
    9 / 48 (18.75%)
    5 / 25 (20.00%)
    10 / 69 (14.49%)
    0 / 10 (0.00%)
         occurrences all number
    9
    5
    10
    0
    Hypertension
         subjects affected / exposed
    7 / 48 (14.58%)
    2 / 25 (8.00%)
    3 / 69 (4.35%)
    0 / 10 (0.00%)
         occurrences all number
    7
    2
    3
    0
    Hypotension
         subjects affected / exposed
    1 / 48 (2.08%)
    2 / 25 (8.00%)
    2 / 69 (2.90%)
    0 / 10 (0.00%)
         occurrences all number
    1
    2
    2
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    35 / 48 (72.92%)
    21 / 25 (84.00%)
    51 / 69 (73.91%)
    2 / 10 (20.00%)
         occurrences all number
    57
    35
    75
    2
    Mucosal inflammation
         subjects affected / exposed
    23 / 48 (47.92%)
    8 / 25 (32.00%)
    30 / 69 (43.48%)
    3 / 10 (30.00%)
         occurrences all number
    29
    8
    42
    3
    Pyrexia
         subjects affected / exposed
    15 / 48 (31.25%)
    7 / 25 (28.00%)
    20 / 69 (28.99%)
    2 / 10 (20.00%)
         occurrences all number
    21
    14
    24
    2
    Oedema peripheral
         subjects affected / exposed
    13 / 48 (27.08%)
    10 / 25 (40.00%)
    28 / 69 (40.58%)
    1 / 10 (10.00%)
         occurrences all number
    18
    11
    30
    1
    Fatigue
         subjects affected / exposed
    10 / 48 (20.83%)
    3 / 25 (12.00%)
    10 / 69 (14.49%)
    0 / 10 (0.00%)
         occurrences all number
    18
    5
    15
    0
    Pain
         subjects affected / exposed
    7 / 48 (14.58%)
    0 / 25 (0.00%)
    7 / 69 (10.14%)
    0 / 10 (0.00%)
         occurrences all number
    8
    0
    11
    0
    Oedema
         subjects affected / exposed
    3 / 48 (6.25%)
    3 / 25 (12.00%)
    9 / 69 (13.04%)
    0 / 10 (0.00%)
         occurrences all number
    3
    3
    9
    0
    Axillary pain
         subjects affected / exposed
    1 / 48 (2.08%)
    5 / 25 (20.00%)
    2 / 69 (2.90%)
    0 / 10 (0.00%)
         occurrences all number
    1
    5
    2
    0
    Chest Pain
         subjects affected / exposed
    2 / 48 (4.17%)
    2 / 25 (8.00%)
    2 / 69 (2.90%)
    0 / 10 (0.00%)
         occurrences all number
    2
    2
    2
    0
    Inflammation
         subjects affected / exposed
    1 / 48 (2.08%)
    2 / 25 (8.00%)
    0 / 69 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    4
    0
    0
    Impaired healing
         subjects affected / exposed
    3 / 48 (6.25%)
    0 / 25 (0.00%)
    0 / 69 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Generalised oedema
         subjects affected / exposed
    0 / 48 (0.00%)
    2 / 25 (8.00%)
    0 / 69 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 25 (4.00%)
    0 / 69 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    0
    1
    Reproductive system and breast disorders
    Amenorrhoea
         subjects affected / exposed
    10 / 48 (20.83%)
    9 / 25 (36.00%)
    22 / 69 (31.88%)
    0 / 10 (0.00%)
         occurrences all number
    10
    9
    22
    0
    Breast pain
         subjects affected / exposed
    7 / 48 (14.58%)
    1 / 25 (4.00%)
    5 / 69 (7.25%)
    0 / 10 (0.00%)
         occurrences all number
    9
    1
    7
    0
    Vulvovaginal dryness
         subjects affected / exposed
    4 / 48 (8.33%)
    5 / 25 (20.00%)
    4 / 69 (5.80%)
    0 / 10 (0.00%)
         occurrences all number
    4
    6
    4
    0
    Breast oedema
         subjects affected / exposed
    2 / 48 (4.17%)
    2 / 25 (8.00%)
    6 / 69 (8.70%)
    0 / 10 (0.00%)
         occurrences all number
    2
    2
    6
    0
    Metrorrhagia
         subjects affected / exposed
    2 / 48 (4.17%)
    2 / 25 (8.00%)
    3 / 69 (4.35%)
    0 / 10 (0.00%)
         occurrences all number
    2
    2
    3
    0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    27 / 48 (56.25%)
    3 / 25 (12.00%)
    18 / 69 (26.09%)
    0 / 10 (0.00%)
         occurrences all number
    49
    5
    23
    0
    Cough
         subjects affected / exposed
    9 / 48 (18.75%)
    3 / 25 (12.00%)
    14 / 69 (20.29%)
    0 / 10 (0.00%)
         occurrences all number
    10
    4
    17
    0
    Dyspnoea
         subjects affected / exposed
    9 / 48 (18.75%)
    7 / 25 (28.00%)
    5 / 69 (7.25%)
    0 / 10 (0.00%)
         occurrences all number
    11
    7
    5
    0
    Dyspnoea exertional
         subjects affected / exposed
    7 / 48 (14.58%)
    3 / 25 (12.00%)
    12 / 69 (17.39%)
    0 / 10 (0.00%)
         occurrences all number
    7
    3
    13
    0
    Rhinorrhoea
         subjects affected / exposed
    7 / 48 (14.58%)
    4 / 25 (16.00%)
    5 / 69 (7.25%)
    0 / 10 (0.00%)
         occurrences all number
    8
    5
    5
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    8 / 48 (16.67%)
    3 / 25 (12.00%)
    13 / 69 (18.84%)
    1 / 10 (10.00%)
         occurrences all number
    8
    4
    13
    1
    Anxiety
         subjects affected / exposed
    8 / 48 (16.67%)
    2 / 25 (8.00%)
    7 / 69 (10.14%)
    0 / 10 (0.00%)
         occurrences all number
    8
    2
    7
    0
    Depression
         subjects affected / exposed
    4 / 48 (8.33%)
    1 / 25 (4.00%)
    4 / 69 (5.80%)
    0 / 10 (0.00%)
         occurrences all number
    4
    1
    4
    0
    Sleep disorder
         subjects affected / exposed
    3 / 48 (6.25%)
    2 / 25 (8.00%)
    4 / 69 (5.80%)
    0 / 10 (0.00%)
         occurrences all number
    3
    2
    4
    0
    Investigations
    Weight increased
         subjects affected / exposed
    3 / 48 (6.25%)
    2 / 25 (8.00%)
    11 / 69 (15.94%)
    0 / 10 (0.00%)
         occurrences all number
    3
    2
    11
    0
    Weight decreased
         subjects affected / exposed
    3 / 48 (6.25%)
    0 / 25 (0.00%)
    3 / 69 (4.35%)
    0 / 10 (0.00%)
         occurrences all number
    5
    0
    3
    0
    Injury, poisoning and procedural complications
    Radiation skin injury
         subjects affected / exposed
    24 / 48 (50.00%)
    19 / 25 (76.00%)
    47 / 69 (68.12%)
    0 / 10 (0.00%)
         occurrences all number
    25
    19
    51
    0
    Procedural pain
         subjects affected / exposed
    1 / 48 (2.08%)
    3 / 25 (12.00%)
    1 / 69 (1.45%)
    0 / 10 (0.00%)
         occurrences all number
    1
    3
    1
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 48 (2.08%)
    2 / 25 (8.00%)
    4 / 69 (5.80%)
    0 / 10 (0.00%)
         occurrences all number
    1
    4
    4
    0
    Ventricular arrhythmia
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    0 / 69 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    16 / 48 (33.33%)
    9 / 25 (36.00%)
    25 / 69 (36.23%)
    0 / 10 (0.00%)
         occurrences all number
    18
    15
    28
    0
    Neuropathy peripheral
         subjects affected / exposed
    13 / 48 (27.08%)
    8 / 25 (32.00%)
    25 / 69 (36.23%)
    0 / 10 (0.00%)
         occurrences all number
    14
    10
    26
    0
    Paraesthesia
         subjects affected / exposed
    6 / 48 (12.50%)
    10 / 25 (40.00%)
    11 / 69 (15.94%)
    0 / 10 (0.00%)
         occurrences all number
    9
    14
    13
    0
    Headache
         subjects affected / exposed
    12 / 48 (25.00%)
    3 / 25 (12.00%)
    10 / 69 (14.49%)
    1 / 10 (10.00%)
         occurrences all number
    14
    5
    12
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    6 / 48 (12.50%)
    4 / 25 (16.00%)
    5 / 69 (7.25%)
    0 / 10 (0.00%)
         occurrences all number
    6
    4
    7
    0
    Hypoaesthesia
         subjects affected / exposed
    4 / 48 (8.33%)
    3 / 25 (12.00%)
    2 / 69 (2.90%)
    0 / 10 (0.00%)
         occurrences all number
    4
    4
    2
    0
    Neuralgia
         subjects affected / exposed
    2 / 48 (4.17%)
    2 / 25 (8.00%)
    5 / 69 (7.25%)
    0 / 10 (0.00%)
         occurrences all number
    2
    2
    5
    0
    Ageusia
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 25 (0.00%)
    5 / 69 (7.25%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    5
    0
    Dysaesthesia
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    4 / 69 (5.80%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    4
    0
    Sciatica
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 25 (0.00%)
    2 / 69 (2.90%)
    1 / 10 (10.00%)
         occurrences all number
    2
    0
    2
    1
    Presyncope
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 25 (4.00%)
    0 / 69 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    0
    1
    Disturbance in attention
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    0 / 69 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    8 / 48 (16.67%)
    3 / 25 (12.00%)
    11 / 69 (15.94%)
    0 / 10 (0.00%)
         occurrences all number
    15
    9
    16
    0
    Anaemia
         subjects affected / exposed
    7 / 48 (14.58%)
    7 / 25 (28.00%)
    12 / 69 (17.39%)
    0 / 10 (0.00%)
         occurrences all number
    7
    9
    12
    0
    Febrile neutropenia
         subjects affected / exposed
    5 / 48 (10.42%)
    3 / 25 (12.00%)
    12 / 69 (17.39%)
    2 / 10 (20.00%)
         occurrences all number
    5
    3
    12
    2
    Leukopenia
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    7 / 69 (10.14%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    11
    0
    Febrile bone marrow aplasia
         subjects affected / exposed
    3 / 48 (6.25%)
    1 / 25 (4.00%)
    1 / 69 (1.45%)
    0 / 10 (0.00%)
         occurrences all number
    4
    1
    1
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    4 / 48 (8.33%)
    1 / 25 (4.00%)
    2 / 69 (2.90%)
    0 / 10 (0.00%)
         occurrences all number
    4
    1
    3
    0
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    17 / 48 (35.42%)
    13 / 25 (52.00%)
    29 / 69 (42.03%)
    0 / 10 (0.00%)
         occurrences all number
    18
    14
    32
    0
    Conjunctivitis
         subjects affected / exposed
    7 / 48 (14.58%)
    3 / 25 (12.00%)
    10 / 69 (14.49%)
    1 / 10 (10.00%)
         occurrences all number
    9
    3
    11
    1
    Dry eye
         subjects affected / exposed
    3 / 48 (6.25%)
    1 / 25 (4.00%)
    4 / 69 (5.80%)
    0 / 10 (0.00%)
         occurrences all number
    3
    1
    4
    0
    Eyelid oedema
         subjects affected / exposed
    0 / 48 (0.00%)
    2 / 25 (8.00%)
    0 / 69 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Gastrointestinal disorders
    Diarrhoea
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    27 / 48 (56.25%)
    14 / 25 (56.00%)
    32 / 69 (46.38%)
    3 / 10 (30.00%)
         occurrences all number
    57
    26
    58
    3
    Nausea
         subjects affected / exposed
    24 / 48 (50.00%)
    11 / 25 (44.00%)
    23 / 69 (33.33%)
    0 / 10 (0.00%)
         occurrences all number
    57
    17
    31
    0
    Constipation
         subjects affected / exposed
    22 / 48 (45.83%)
    5 / 25 (20.00%)
    23 / 69 (33.33%)
    0 / 10 (0.00%)
         occurrences all number
    30
    6
    29
    0
    Vomiting
         subjects affected / exposed
    10 / 48 (20.83%)
    5 / 25 (20.00%)
    6 / 69 (8.70%)
    0 / 10 (0.00%)
         occurrences all number
    19
    7
    6
    0
    Abdominal pain upper
         subjects affected / exposed
    9 / 48 (18.75%)
    5 / 25 (20.00%)
    10 / 69 (14.49%)
    1 / 10 (10.00%)
         occurrences all number
    10
    5
    15
    1
    Abdominal pain
         subjects affected / exposed
    7 / 48 (14.58%)
    2 / 25 (8.00%)
    13 / 69 (18.84%)
    2 / 10 (20.00%)
         occurrences all number
    9
    2
    14
    2
    Dyspepsia
         subjects affected / exposed
    5 / 48 (10.42%)
    2 / 25 (8.00%)
    10 / 69 (14.49%)
    0 / 10 (0.00%)
         occurrences all number
    6
    2
    15
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    5 / 48 (10.42%)
    3 / 25 (12.00%)
    7 / 69 (10.14%)
    0 / 10 (0.00%)
         occurrences all number
    7
    6
    8
    0
    Haemorrhoids
         subjects affected / exposed
    10 / 48 (20.83%)
    1 / 25 (4.00%)
    9 / 69 (13.04%)
    0 / 10 (0.00%)
         occurrences all number
    10
    1
    10
    0
    Dysphagia
         subjects affected / exposed
    6 / 48 (12.50%)
    2 / 25 (8.00%)
    1 / 69 (1.45%)
    0 / 10 (0.00%)
         occurrences all number
    10
    3
    1
    0
    Dry mouth
         subjects affected / exposed
    6 / 48 (12.50%)
    0 / 25 (0.00%)
    6 / 69 (8.70%)
    0 / 10 (0.00%)
         occurrences all number
    6
    0
    7
    0
    Aphthous stomatitis
         subjects affected / exposed
    1 / 48 (2.08%)
    4 / 25 (16.00%)
    3 / 69 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    1
    5
    4
    1
    Stomatitis
         subjects affected / exposed
    3 / 48 (6.25%)
    0 / 25 (0.00%)
    6 / 69 (8.70%)
    0 / 10 (0.00%)
         occurrences all number
    3
    0
    7
    0
    Gingivitis
         subjects affected / exposed
    4 / 48 (8.33%)
    1 / 25 (4.00%)
    1 / 69 (1.45%)
    0 / 10 (0.00%)
         occurrences all number
    5
    2
    1
    0
    Oesophagitis
         subjects affected / exposed
    4 / 48 (8.33%)
    0 / 25 (0.00%)
    3 / 69 (4.35%)
    0 / 10 (0.00%)
         occurrences all number
    5
    0
    3
    0
    Gastrointestinal motility disorder
         subjects affected / exposed
    1 / 48 (2.08%)
    2 / 25 (8.00%)
    0 / 69 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    3
    3
    0
    0
    Anal fissure
         subjects affected / exposed
    3 / 48 (6.25%)
    0 / 25 (0.00%)
    1 / 69 (1.45%)
    0 / 10 (0.00%)
         occurrences all number
    4
    0
    1
    0
    Gingival bleeding
         subjects affected / exposed
    5 / 48 (10.42%)
    0 / 25 (0.00%)
    0 / 69 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    5
    0
    0
    0
    Abdominal rigidity
         subjects affected / exposed
    1 / 48 (2.08%)
    2 / 25 (8.00%)
    1 / 69 (1.45%)
    0 / 10 (0.00%)
         occurrences all number
    1
    2
    1
    0
    Abdominal pain lower
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    1 / 69 (1.45%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    37 / 48 (77.08%)
    21 / 25 (84.00%)
    46 / 69 (66.67%)
    1 / 10 (10.00%)
         occurrences all number
    37
    21
    47
    1
    Rash
         subjects affected / exposed
    12 / 48 (25.00%)
    8 / 25 (32.00%)
    12 / 69 (17.39%)
    0 / 10 (0.00%)
         occurrences all number
    19
    12
    17
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    12 / 48 (25.00%)
    6 / 25 (24.00%)
    11 / 69 (15.94%)
    0 / 10 (0.00%)
         occurrences all number
    15
    12
    16
    0
    Nail toxicity
         subjects affected / exposed
    12 / 48 (25.00%)
    7 / 25 (28.00%)
    20 / 69 (28.99%)
    0 / 10 (0.00%)
         occurrences all number
    12
    9
    21
    0
    Dry skin
         subjects affected / exposed
    9 / 48 (18.75%)
    7 / 25 (28.00%)
    13 / 69 (18.84%)
    0 / 10 (0.00%)
         occurrences all number
    10
    7
    16
    0
    Erythema
         subjects affected / exposed
    5 / 48 (10.42%)
    4 / 25 (16.00%)
    18 / 69 (26.09%)
    0 / 10 (0.00%)
         occurrences all number
    6
    5
    20
    0
    Pruritus
         subjects affected / exposed
    5 / 48 (10.42%)
    4 / 25 (16.00%)
    11 / 69 (15.94%)
    0 / 10 (0.00%)
         occurrences all number
    6
    4
    14
    0
    Nail disorder
         subjects affected / exposed
    6 / 48 (12.50%)
    4 / 25 (16.00%)
    9 / 69 (13.04%)
    0 / 10 (0.00%)
         occurrences all number
    6
    5
    10
    0
    Onycholysis
         subjects affected / exposed
    6 / 48 (12.50%)
    1 / 25 (4.00%)
    8 / 69 (11.59%)
    0 / 10 (0.00%)
         occurrences all number
    6
    1
    8
    0
    Skin toxicity
         subjects affected / exposed
    2 / 48 (4.17%)
    3 / 25 (12.00%)
    6 / 69 (8.70%)
    1 / 10 (10.00%)
         occurrences all number
    2
    4
    7
    1
    Eczema
         subjects affected / exposed
    5 / 48 (10.42%)
    3 / 25 (12.00%)
    0 / 69 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    5
    4
    0
    0
    Dermatitis acneiform
         subjects affected / exposed
    0 / 48 (0.00%)
    2 / 25 (8.00%)
    5 / 69 (7.25%)
    1 / 10 (10.00%)
         occurrences all number
    0
    2
    5
    1
    Rash pruritic
         subjects affected / exposed
    4 / 48 (8.33%)
    1 / 25 (4.00%)
    2 / 69 (2.90%)
    1 / 10 (10.00%)
         occurrences all number
    4
    1
    2
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 48 (2.08%)
    2 / 25 (8.00%)
    3 / 69 (4.35%)
    0 / 10 (0.00%)
         occurrences all number
    1
    2
    3
    0
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    24 / 48 (50.00%)
    17 / 25 (68.00%)
    48 / 69 (69.57%)
    2 / 10 (20.00%)
         occurrences all number
    40
    29
    74
    2
    Arthralgia
         subjects affected / exposed
    19 / 48 (39.58%)
    12 / 25 (48.00%)
    32 / 69 (46.38%)
    1 / 10 (10.00%)
         occurrences all number
    19
    22
    45
    1
    Musculoskeletal pain
         subjects affected / exposed
    11 / 48 (22.92%)
    8 / 25 (32.00%)
    12 / 69 (17.39%)
    2 / 10 (20.00%)
         occurrences all number
    21
    9
    13
    2
    Pain in extremity
         subjects affected / exposed
    13 / 48 (27.08%)
    2 / 25 (8.00%)
    6 / 69 (8.70%)
    0 / 10 (0.00%)
         occurrences all number
    15
    2
    9
    0
    Bone pain
         subjects affected / exposed
    6 / 48 (12.50%)
    3 / 25 (12.00%)
    4 / 69 (5.80%)
    1 / 10 (10.00%)
         occurrences all number
    8
    3
    6
    1
    Back pain
         subjects affected / exposed
    7 / 48 (14.58%)
    3 / 25 (12.00%)
    6 / 69 (8.70%)
    0 / 10 (0.00%)
         occurrences all number
    7
    3
    7
    0
    Muscle spasms
         subjects affected / exposed
    1 / 48 (2.08%)
    1 / 25 (4.00%)
    7 / 69 (10.14%)
    0 / 10 (0.00%)
         occurrences all number
    1
    2
    9
    0
    Musculoskeletal stiffness
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 25 (0.00%)
    4 / 69 (5.80%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    4
    0
    Joint stiffness
         subjects affected / exposed
    0 / 48 (0.00%)
    3 / 25 (12.00%)
    2 / 69 (2.90%)
    0 / 10 (0.00%)
         occurrences all number
    0
    3
    2
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    11 / 48 (22.92%)
    2 / 25 (8.00%)
    10 / 69 (14.49%)
    0 / 10 (0.00%)
         occurrences all number
    16
    4
    12
    0
    Tonsillitis
         subjects affected / exposed
    4 / 48 (8.33%)
    1 / 25 (4.00%)
    6 / 69 (8.70%)
    0 / 10 (0.00%)
         occurrences all number
    4
    1
    14
    0
    Urinary tract infection
         subjects affected / exposed
    7 / 48 (14.58%)
    3 / 25 (12.00%)
    3 / 69 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    7
    5
    3
    1
    Rhinitis
         subjects affected / exposed
    3 / 48 (6.25%)
    3 / 25 (12.00%)
    7 / 69 (10.14%)
    0 / 10 (0.00%)
         occurrences all number
    3
    4
    8
    0
    Bronchitis
         subjects affected / exposed
    3 / 48 (6.25%)
    3 / 25 (12.00%)
    4 / 69 (5.80%)
    0 / 10 (0.00%)
         occurrences all number
    3
    4
    4
    0
    Vulvovaginal mycotic infection
         subjects affected / exposed
    2 / 48 (4.17%)
    2 / 25 (8.00%)
    6 / 69 (8.70%)
    0 / 10 (0.00%)
         occurrences all number
    2
    2
    6
    0
    Cystitis
         subjects affected / exposed
    4 / 48 (8.33%)
    0 / 25 (0.00%)
    4 / 69 (5.80%)
    0 / 10 (0.00%)
         occurrences all number
    4
    0
    5
    0
    Pharyngitis
         subjects affected / exposed
    3 / 48 (6.25%)
    2 / 25 (8.00%)
    3 / 69 (4.35%)
    0 / 10 (0.00%)
         occurrences all number
    3
    2
    3
    0
    Influenza
         subjects affected / exposed
    2 / 48 (4.17%)
    3 / 25 (12.00%)
    1 / 69 (1.45%)
    0 / 10 (0.00%)
         occurrences all number
    2
    3
    1
    0
    Tracheitis
         subjects affected / exposed
    1 / 48 (2.08%)
    3 / 25 (12.00%)
    2 / 69 (2.90%)
    0 / 10 (0.00%)
         occurrences all number
    1
    3
    2
    0
    Paronychia
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    4 / 69 (5.80%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    4
    0
    Sinusitis
         subjects affected / exposed
    1 / 48 (2.08%)
    2 / 25 (8.00%)
    1 / 69 (1.45%)
    0 / 10 (0.00%)
         occurrences all number
    1
    2
    1
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    0 / 69 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    14 / 48 (29.17%)
    3 / 25 (12.00%)
    12 / 69 (17.39%)
    0 / 10 (0.00%)
         occurrences all number
    25
    4
    18
    0
    Fluid retention
         subjects affected / exposed
    1 / 48 (2.08%)
    2 / 25 (8.00%)
    5 / 69 (7.25%)
    0 / 10 (0.00%)
         occurrences all number
    1
    2
    5
    0

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Aug 2010
    Modified the clinical trial method from comparative phase II to non comparative phase II, Modified the trastuzumab administration during the neo=adjuvant treatment (discontinuation during the 4 weeks of the surgery period to no discontinuation of the treatment), Added a secondary endpoint - pathological complete response rate evaluated post-surgery, and Censored the survival analyses at the date of last assessment without event.
    09 Nov 2010
    Modified the samples calendar in the angiogenesis biomarkers study which led to an increase in the number of additional blood samples for participants.
    26 Apr 2011
    The duration of contraception for bevacizumab was update to 6 months after the last dose, the patient informed consent form was updated to warn of particular symptoms, a new adverse event of special interest was introduced (i.e. febrile neutropenia), and the blood glucose measurement requirement was updated to allow for the use of capillary blood glucose measurement in the absence of measurement made of plasma glucose.
    02 May 2012
    The informed consent form was updated with new safety information and the study exclusion criteria for bifocal tumor was expanded.
    29 Apr 2015
    Clarification was provided for the exploratory research sub-studies.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

    European Medicines Agency © 1995-Sat Apr 20 07:25:13 CEST 2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA