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    Clinical Trial Results:
    A randomized, open-label, 2-arm, multicentre, phase III study to evaluate the efficacy and safety of bevacizumab in combination with trastuzumab / docetaxel compared with trastuzumab/docetaxel alone as first line treatment for patients with HER2 positive locally recurrent or metastatic breast cancer

    Summary
    EudraCT number
    		 2006-001365-42
    Trial protocol
    		 AT   IT   CZ   ES   GB  
    Global end of trial date

    Results information
    Results version number
    		 v2(current)
    This version publication date
    02 Jun 2016
    First version publication date
    06 Aug 2015
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    We have performed an internal QC of the record and findings have been identified which need to be rectified inthe record.

    Trial information

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    Trial identification
    Sponsor protocol code
    BO20231
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00391092
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    30 Jun 2011
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Jun 2011
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    To evaluate efficacy and safety of bevacizumab in combination with trastuzumab/docetaxel versus compared with trastuzumab/docetaxel alone as first line treatment.
    Protection of trial subjects
    The investigator ensured that this study was conducted in full conformance with the principles of the “Declaration of Helsinki” or with the laws and regulations of the country in which the research was conducted, whichever afforded the greater protection to the individual. The study fully adhered to the principles outlined in “Guideline for Good Clinical Practice” ICH Tripartite Guideline (January 1997) or with local law if it afforded greater protection to the patient. For EU/EEA countries, the investigator ensured compliance with the EU Clinical Trial Directive (2001/20/EC). In other countries where “Guideline for Good Clinical Practice” existed Roche and the investigators strictly ensured adherence to the stated provisions.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Sep 2006
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 1 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 1
    Country: Number of subjects enrolled
    Russian Federation: 90
    Country: Number of subjects enrolled
    Australia: 26
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 10
    Country: Number of subjects enrolled
    Brazil: 43
    Country: Number of subjects enrolled
    Canada: 21
    Country: Number of subjects enrolled
    Mexico: 10
    Country: Number of subjects enrolled
    Romania: 18
    Country: Number of subjects enrolled
    Turkey: 7
    Country: Number of subjects enrolled
    Uruguay: 3
    Country: Number of subjects enrolled
    Spain: 14
    Country: Number of subjects enrolled
    United Kingdom: 45
    Country: Number of subjects enrolled
    Austria: 16
    Country: Number of subjects enrolled
    Czech Republic: 3
    Country: Number of subjects enrolled
    France: 79
    Country: Number of subjects enrolled
    Italy: 38
    Worldwide total number of subjects
    424
    EEA total number of subjects
    213
    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)
    347
    From 65 to 84 years
    77
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The participants were randomized 1:1 using a block design randomization procedure with stratification (for prior adjuvant/neo-adjuvant taxane, trastuzumab as part of adjuvant treatment versus no trastuzumab, ER/PgR hormone receptor status and measurable disease) to avoid an imbalance of important prognostic factors.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was an open-label study. However, the Independent Review Committee (IRC) assessment was blinded to treatment assignment.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Trastuzumab + Docetaxel
    Arm description
    		 Trastuzumab 8 milligrams per kilogram (mg/kg) loading dose administered intravenously on Day 1 of Cycle 1, followed by docetaxel 100 milligrams per square meter (mg/m^2) on Day 2 of Cycle 1. Then a maintenance dose of trastuzumab at 6 mg/kg and docetaxel at 100 mg/m^2 were administered intravenously on Day 1 of each 3-weekly cycle until disease progression, unacceptable toxicity (requiring discontinuation of study treatment), or withdrawal of participant's consent, and for a minimum of 6 cycles, respectively.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received 8 mg/kg trastuzumab intravenously on Cycle 1 Day 1, and thereafter 6 mg/kg trastuzumab on Day 1 of each 3-week cycle.

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received 100 mg/m^2 docetaxel intravenously on Cycle 1 Day 2, and thereafter on Day 1 of each 3-week cycle.

    Arm title
    		 Trastuzumab + Bevacizumab + Docetaxel
    Arm description
    		 Trastuzumab 8 mg/kg loading dose administered intravenously on Day 1 of Cycle 1, followed by bevacizumab 15 mg/kg and docetaxel 100 mg/m^2 on Day 2 of Cycle 1. Then a maintenance dose of trastuzumab at 6 mg/kg, bevacizumab 15 mg/kg and docetaxel at 100 mg/m^2 were administered intravenously on Day 1 of each 3-weekly cycle until disease progression, unacceptable toxicity (requiring discontinuation of study treatment), or withdrawal of participant's consent.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received 8 mg/kg trastuzumab intravenously on Cycle 1 Day 1, and thereafter 6 mg/kg trastuzumab on Day 1 of each 3-week cycle.

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received 100 mg/m^2 docetaxel intravenously on Cycle 1 Day 2, and thereafter 100 mg/m^2 docetaxel on Day 1 of each 3-week cycle.

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received 15 mg/kg bevacizumab intravenously on Cycle 1 Day 2, and thereafter 15 mg/kg bevacizumab on Day 1 of each 3-week cycle.

    Number of subjects in period 1
    		Trastuzumab + Docetaxel Trastuzumab + Bevacizumab + Docetaxel
    Started
    208
    216
    Received Treatment
    206
    215
    Completed
    0
    0
    Not completed
    208
    216
         Death
    78
    81
         Lost to follow-up
    13
    18
         Alive on treatment
    29
    33
         Alive in follow-up
    88
    84

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Trastuzumab + Docetaxel
    Reporting group description
    		 Trastuzumab 8 milligrams per kilogram (mg/kg) loading dose administered intravenously on Day 1 of Cycle 1, followed by docetaxel 100 milligrams per square meter (mg/m^2) on Day 2 of Cycle 1. Then a maintenance dose of trastuzumab at 6 mg/kg and docetaxel at 100 mg/m^2 were administered intravenously on Day 1 of each 3-weekly cycle until disease progression, unacceptable toxicity (requiring discontinuation of study treatment), or withdrawal of participant's consent, and for a minimum of 6 cycles, respectively.

    Reporting group title
    Trastuzumab + Bevacizumab + Docetaxel
    Reporting group description
    		 Trastuzumab 8 mg/kg loading dose administered intravenously on Day 1 of Cycle 1, followed by bevacizumab 15 mg/kg and docetaxel 100 mg/m^2 on Day 2 of Cycle 1. Then a maintenance dose of trastuzumab at 6 mg/kg, bevacizumab 15 mg/kg and docetaxel at 100 mg/m^2 were administered intravenously on Day 1 of each 3-weekly cycle until disease progression, unacceptable toxicity (requiring discontinuation of study treatment), or withdrawal of participant's consent.

    Reporting group values
    		 Trastuzumab + Docetaxel Trastuzumab + Bevacizumab + Docetaxel Total
    Number of subjects
    		 208 216 424
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 54 ( 11.71 ) 53.5 ( 10.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 208 216 424
        Male
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Trastuzumab + Docetaxel
    Reporting group description
    		 Trastuzumab 8 milligrams per kilogram (mg/kg) loading dose administered intravenously on Day 1 of Cycle 1, followed by docetaxel 100 milligrams per square meter (mg/m^2) on Day 2 of Cycle 1. Then a maintenance dose of trastuzumab at 6 mg/kg and docetaxel at 100 mg/m^2 were administered intravenously on Day 1 of each 3-weekly cycle until disease progression, unacceptable toxicity (requiring discontinuation of study treatment), or withdrawal of participant's consent, and for a minimum of 6 cycles, respectively.

    Reporting group title
    Trastuzumab + Bevacizumab + Docetaxel
    Reporting group description
    		 Trastuzumab 8 mg/kg loading dose administered intravenously on Day 1 of Cycle 1, followed by bevacizumab 15 mg/kg and docetaxel 100 mg/m^2 on Day 2 of Cycle 1. Then a maintenance dose of trastuzumab at 6 mg/kg, bevacizumab 15 mg/kg and docetaxel at 100 mg/m^2 were administered intravenously on Day 1 of each 3-weekly cycle until disease progression, unacceptable toxicity (requiring discontinuation of study treatment), or withdrawal of participant's consent.

    Primary: Progression-Free Survival (PFS)

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    End point title
    		 Progression-Free Survival (PFS)
    End point description
    PFS was defined as the time from randomization to time of first documented disease progression (unequivocal progression of existing non-target lesions) or death, whichever occurred first as assessed by Response Evaluation Criteria in Solid Tumors version 1.0 (RECIST v1.0). Primary PFS variable was defined based on the investigators’ assessments and the statistical conclusions on the primary efficacy end point were based on investigator assessed PFS. PFS was estimated using Kaplan-Meier methods. Intent-to-treat (ITT) population: All randomized participants, regardless of whether they actually received study treatment or not.
    End point type
    Primary
    End point timeframe
    Every 9 weeks up to Week 36, thereafter every 12 weeks until disease progression (up to the clinical cutoff of 30 June 2011, up to 4.75 years)
    End point values
    		 Trastuzumab + Docetaxel Trastuzumab + Bevacizumab + Docetaxel
    Number of subjects analysed
    208
    216
    Units: months
        median (confidence interval 95%)
    13.7 (11.4 to 16.3)
    16.5 (14.1 to 19.1)
    Statistical analysis title
    		 Progression-Free Survival (PFS)
    Comparison groups
    Trastuzumab + Bevacizumab + Docetaxel v Trastuzumab + Docetaxel
    Number of subjects included in analysis
    424
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0775
    Method
    		 Logrank (unstratified)
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 1.02

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS was defined as the time from randomization to the date of death, regardless of the cause of death. OS was estimated using Kaplan-Meier methods. ITT population. Here '99999' was used as the upper range of 95% confidence interval (CI) was not calculable due to immature OS data as greater than 50% of participants were censored at the time of clinical cutoff (30 June 2011).
    End point type
    Secondary
    End point timeframe
    Every 9 weeks up to Week 36, thereafter every 12 weeks until disease progression (up to the clinical cutoff of 30 June 2011, up to 4.75 years)
    End point values
    		 Trastuzumab + Docetaxel Trastuzumab + Bevacizumab + Docetaxel
    Number of subjects analysed
    208
    216
    Units: months
        median (confidence interval 95%)
    38.3 (34.3 to 99999)
    38.5 (32.1 to 99999)
    Statistical analysis title
    		 Overall Suvival (OS)
    Comparison groups
    Trastuzumab + Docetaxel v Trastuzumab + Bevacizumab + Docetaxel
    Number of subjects included in analysis
    424
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9543
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 1.38

    Secondary: Percentage of Participants With a Best Overall Response (OR) of Confirmed Complete Response (CR) or Partial Response (PR) in Participants with Measurable Disease at Baseline

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    End point title
    		 Percentage of Participants With a Best Overall Response (OR) of Confirmed Complete Response (CR) or Partial Response (PR) in Participants with Measurable Disease at Baseline
    End point description
    Best OR was assessed using RECIST v1.0 criteria. Participants were classified as responders if their best OR was either confirmed CR (disappearance of all target lesions) or confirmed PR (at least a 30% decrease in the sum of the longest diameter [LD] of target lesions, taking as reference the baseline sum LD). Participants without any post-baseline assessments were regarded as non-responders. The 95% CI for the one sample binomial using Pearson-Clopper method. ITT population.
    End point type
    Secondary
    End point timeframe
    Every 9 weeks up to Week 36, thereafter every 12 weeks until disease progression (up to clinical data cutoff of 30 June 2011, up to 4.75 years)
    End point values
    		 Trastuzumab + Docetaxel Trastuzumab + Bevacizumab + Docetaxel
    Number of subjects analysed
    176 [1]
    183 [2]
    Units: Percentage of participants
    number (confidence interval 95%)
        Responders
    69.9 (62.5 to 76.6)
    74.3 (67.4 to 80.5)
    Notes
    [1] - Only participants with measurable disease at baseline were included in the analysis.
    [2] - only participants with measurable disease at baseline were included in the analysis.
    Statistical analysis title
    		 % of Participants With Confirmed CR and PR
    Comparison groups
    Trastuzumab + Docetaxel v Trastuzumab + Bevacizumab + Docetaxel
    Number of subjects included in analysis
    359
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3492
    Method
    		 Chi-squared
    Parameter type
    		 Difference in Response rates
    Point estimate
    4.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.2
         upper limit
    		 14

    Secondary: Duration of Response (DR)

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    End point title
    		 Duration of Response (DR)
    End point description
    DR was defined as the time when response (CR or PR per RECIST v1.0) was first documented to the date of disease progression per RECIST v1.0 (unequivocal progression of existing non-target lesions) or death. ITT population.
    End point type
    Secondary
    End point timeframe
    Every 9 weeks up to Week 36, thereafter every 12 weeks until disease progression (up to clinical cutoff of 30 June 2011, up to 4.75 years)
    End point values
    		 Trastuzumab + Docetaxel Trastuzumab + Bevacizumab + Docetaxel
    Number of subjects analysed
    123 [3]
    136 [4]
    Units: months
        median (confidence interval 95%)
    11.4 (9.1 to 13.2)
    14.6 (12 to 17.1)
    Notes
    [3] - Only participants with a best OR of CR or PR were included in the analysis.
    [4] - Only participants with a best OR of CR or PR were included in the analysis.
    Statistical analysis title
    		 Duration of Response (DR)
    Comparison groups
    Trastuzumab + Docetaxel v Trastuzumab + Bevacizumab + Docetaxel
    Number of subjects included in analysis
    259
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.56
         upper limit
    		 0.98

    Secondary: Time to Treatment Failure (TTF)

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    End point title
    		 Time to Treatment Failure (TTF)
    End point description
    TTF was defined as the time between randomization and date of disease progression (per RECIST v1.0; unequivocal progression of existing non-target lesions), death, or withdrawal of treatment due to adverse events, withdrawal of informed consent, insufficient therapeutic response, refusal of treatment/failure to co-operate, or failure to return, whichever occurred first. ITT population.
    End point type
    Secondary
    End point timeframe
    Every 9 weeks up to Week 36, thereafter every 12 weeks until disease progression (up to clinical cutoff of 30 June 2011, up to 4.75 years)
    End point values
    		 Trastuzumab + Docetaxel Trastuzumab + Bevacizumab + Docetaxel
    Number of subjects analysed
    208
    216
    Units: months
        median (confidence interval 95%)
    7.7 (6.3 to 8.6)
    9.8 (7.9 to 10.9)
    Statistical analysis title
    		 Time to Treatment Failure (TTF)
    Comparison groups
    Trastuzumab + Docetaxel v Trastuzumab + Bevacizumab + Docetaxel
    Number of subjects included in analysis
    424
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5392
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.76
         upper limit
    		 1.15

    Secondary: Functional Assessment of Cancer Therapy-Generic (FACT-G) and Functional Assessment of Cancer Therapy-Breast (FACT-B) Subscale Scores

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    End point title
    		 Functional Assessment of Cancer Therapy-Generic (FACT-G) and Functional Assessment of Cancer Therapy-Breast (FACT-B) Subscale Scores
    End point description
    FACT-G is core questionnaire of Functional Assessment of Chronic Illness Therapy (FACIT) measurement system to evaluate quality of life (QoL) in cancer population. FACT-G consisted of 27 questions grouped in 4 domains of general Health-Related QoL (HRQoL): Physical Well-being (PWB), Social/Family Well-Being (SWB), Emotional Well-Being (EWB) and Functional Well-Being (FWB); each ranged from 0 (not at all) to 4 (very much). FACT-G ranged between 0-108. Since questions could be reversed coded, as appropriate, before calculating FACT-G, 0 and 108 could be considered worst and best health states. FACT-B is used for assessment of HRQoL in participants with breast cancer. It consists of 36 items, summarized to 5 subscales: 7 items for each physical, functional, social/family; all 3 ranged from 0-28, emotional (6 items) ranged from 0-24, and breast cancer subscale (9 items) ranged from 0-36. All single-item measures ranges from 0-144. High score represents a better QoL. ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Cycles 3, 5, 11, and post progressive disease (PD; 14 to 28 days after disease progression [up to clinical cutoff of 30 June 2011, up to 4.75 years])
    End point values
    		 Trastuzumab + Docetaxel Trastuzumab + Bevacizumab + Docetaxel
    Number of subjects analysed
    173 [5]
    189 [6]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Physical Well-Being: Baseline (n=173,189)
    21.2 ( 5.74 )
    21.47 ( 5.07 )
        Social Well-Being: Baseline (n=173,189)
    20.59 ( 5.75 )
    20.88 ( 5.77 )
        Emotional Well-Being: Baseline (n=173,189)
    14.95 ( 4.95 )
    15.54 ( 4.44 )
        Functional Well-Being: Baseline (n=173,189)
    16.34 ( 5.83 )
    16.36 ( 5.57 )
        Total FACT-G Score: Baseline (n=173,189)
    73.3 ( 16.6 )
    74.49 ( 14.5 )
        Breast Specific: Baseline (n=173,189)
    21.67 ( 6.43 )
    22.84 ( 5.85 )
        Total FACT-B Score: Baseline (n=173,189)
    94.97 ( 20.5 )
    97.46 ( 17.71 )
        Trial Outcome Index: Baseline (n=173,189)
    59.54 ( 14.03 )
    60.85 ( 12.61 )
        Physical Well-Being: Cycle 3 (n=145,173)
    20.19 ( 4.89 )
    19.96 ( 5.05 )
        Social Well-Being: Cycle 3 (n=145,173)
    20.64 ( 5.32 )
    21.19 ( 5.44 )
        Emotional Well-Being: Cycle 3 (n=145,173)
    16.47 ( 4.19 )
    16.7 ( 4.36 )
        Functional Well-Being: Cycle 3 (n=145, 173)
    15.43 ( 5.33 )
    16.2 ( 5.22 )
        Total FACT-G Score: Cycle 3 (n=145,173)
    72.94 ( 14.81 )
    74.05 ( 14.35 )
        Breast Specific: Cycle 3 (n=145,173)
    22.29 ( 5.78 )
    23.17 ( 5.34 )
        Total FACT-B Score: Cycle 3 (n=145,173)
    95.26 ( 18.52 )
    97.23 ( 17.81 )
        Trial Outcome Index: Cycle 3 (n=145,173)
    58.04 ( 12.8 )
    59.33 ( 12.49 )
        Physical Well-Being: Cycle 5 (n=139, 166)
    19.51 ( 4.83 )
    19.67 ( 4.56 )
        Social Well-Being: Cycle 5 (n=139, 166)
    19.36 ( 5.26 )
    20.68 ( 4.92 )
        Emotional Well-Being: Cycle 5 (n=139, 166)
    16.05 ( 4.44 )
    17.07 ( 4.3 )
        Functional Well-Being: Cycle 5 (n=139, 166)
    14.81 ( 5.45 )
    15.78 ( 4.77 )
        Total FACT-G Score: Cycle 5 (n=139, 166)
    69.78 ( 15.04 )
    73.21 ( 12.49 )
        Breast Specific: Cycle 5 (n=139, 166)
    21.65 ( 5.83 )
    23.15 ( 4.9 )
        Total FACT-B Score: Cycle 5 (n=139, 166)
    91.43 ( 18.81 )
    96.36 ( 15.63 )
        Trial Outcome Index: Cycle 5 (n=139, 166)
    55.99 ( 13.09 )
    58.59 ( 11.01 )
        Physical Well-Being: Cycle 11 (n=100, 133)
    21.71 ( 4.54 )
    21.56 ( 4.53 )
        Social Well-Being: Cycle 11 (n=100, 133)
    19.71 ( 5.74 )
    20.78 ( 4.92 )
        Emotional Well-Being: Cycle 11 (n=100, 133)
    15.96 ( 4.5 )
    17.46 ( 3.7 )
        Functional Well-Being: Cycle 11 (n=100, 133)
    16.25 ( 5.16 )
    16.98 ( 4.92 )
        Total FACT-G Score: Cycle 11 (n=100, 133)
    73.26 ( 15.24 )
    76.55 ( 13.56 )
        Breast Specific: Cycle 11 (n=100, 133)
    21.29 ( 5.55 )
    23.8 ( 4.92 )
        Total FACT-B Score: Cycle 11 (n=100, 133)
    94.57 ( 18.58 )
    100.43 ( 16.97 )
        Trial Outcome Index: Cycle 11 (n=100, 133)
    59.19 ( 12 )
    62.34 ( 11.79 )
        Physical Well-Being: Post PD (n=33, 39)
    19.94 ( 4.99 )
    20.35 ( 5.37 )
        Social Well-Being: Post PD (n=33, 39)
    19.02 ( 5.61 )
    19.68 ( 4.77 )
        Emotional Well-Being: Post PD (n=33, 39)
    14.76 ( 4.83 )
    14.77 ( 4.64 )
        Functional Well-Being: Post PD (n=33, 39)
    14.13 ( 5.57 )
    15.08 ( 5.16 )
        Total FACT-G Score: Post PD (n=33, 39)
    67.84 ( 14.21 )
    70.04 ( 15.08 )
        Breast Specific: Post PD (n=33, 39)
    22.9 ( 4.48 )
    22.87 ( 5.14 )
        Total FACT-B Score: Post PD (n=33, 39)
    90.74 ( 16.59 )
    92.92 ( 18.47 )
        Trial Outcome Index: Post PD (n=33, 39)
    56.97 ( 11.16 )
    58.47 ( 12.43 )
    Notes
    [5] - n (number) = number of participants assessed for the given parameter at the specified visit.
    [6] - n (number) = number of participants assessed for the given parameter at the specified visit.
    No statistical analyses for this end point

    Secondary: Change From Baseline for FACT-G and FACT-B

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    End point title
    		 Change From Baseline for FACT-G and FACT-B
    End point description
    FACT-G is core questionnaire of FACIT measurement system to evaluate QoL in cancer population. FACT-G consisted of 27 questions grouped in 4 domains of general HRQoL: PWB, SWB, EWB and FWB; each ranged from 0 (not at all) to 4 (very much). FACT-G ranged between 0-108. Since questions could be reversed coded, as appropriate, before calculating FACT-G, 0 and 108 could be considered worst and best health states. FACT -B is used for assessment of HRQoL in participants with breast cancer. It consists of 36 items, summarized to 5 subscales: 7 items for each physical, functional, social/family; all 3 ranged from 0-28, emotional (6 items) ranged from 0-24, and breast cancer subscale (9 items) ranged from 0-36. All single-item measures ranges from 0-144. High score represents a better QoL. ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Cycles 3, 5, 11, and post PD (14 to 28 days after disease progression [up to clinical cutoff of 30 June 2011, up to 4.75 years])
    End point values
    		 Trastuzumab + Docetaxel Trastuzumab + Bevacizumab + Docetaxel
    Number of subjects analysed
    145 [7]
    173 [8]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Physical Well-Being: Cycle 3 (n=145,173)
    -1.01 ( 7.54 )
    -1.51 ( 7.16 )
        Social Well-Being: Cycle 3 (n=145,173)
    0.05 ( 7.83 )
    0.32 ( 7.93 )
        Emotional Well-Being: Cycle 3 (n=145,173)
    1.52 ( 6.49 )
    1.16 ( 6.22 )
        Functional Well-Being: Cycle 3 (n=145, 173)
    -0.91 ( 7.9 )
    -0.16 ( 7.63 )
        Total FACT-G Score: Cycle 3 (n=145,173)
    -0.36 ( 22.25 )
    -0.44 ( 20.4 )
        Breast Specific: Cycle 3 (n=145,173)
    0.61 ( 8.65 )
    0.34 ( 7.92 )
        Total FACT-B Score: Cycle 3 (n=145,173)
    0.29 ( 27.63 )
    -0.24 ( 25.12 )
        Trial Outcome Index: Cycle 3 (n=145,173)
    -1.5 ( 18.99 )
    -1.52 ( 17.75 )
        Physical Well-Being: Cycle 5 (n=139, 166)
    -1.69 ( 7.5 )
    -1.8 ( 6.82 )
        Social Well-Being: Cycle 5 (n=139, 166)
    -1.23 ( 7.79 )
    -0.2 ( 7.58 )
        Emotional Well-Being: Cycle 5 (n=139, 166)
    1.09 ( 6.65 )
    1.53 ( 6.18 )
        Functional Well-Being: Cycle 5 (n=139, 166)
    -1.53 ( 7.98 )
    -0.58 ( 7.33 )
        Total FACT-G Score: Cycle 5 (n=139, 166)
    -3.53 ( 22.4 )
    -1.28 ( 19.14 )
        Breast Specific: Cycle 5 (n=139, 166)
    -0.03 ( 8.68 )
    0.31 ( 7.63 )
        Total FACT-B Score: Cycle 5 (n=139, 166)
    -3.55 ( 27.82 )
    -1.1 ( 23.62 )
        Trial Outcome Index: Cycle 5 (n=139,166)
    -3.55 ( 19.19 )
    -2.26 ( 16.74 )
        Physical Well-Being: Cycle 11 (n=100, 133)
    0.51 ( 7.32 )
    0.09 ( 6.8 )
        Social Well-Being: Cycle 11 (n=100, 133)
    -0.89 ( 8.13 )
    -0.1 ( 7.58 )
        Emotional Well-Being: Cycle 11 (n=100, 133)
    1 ( 6.69 )
    1.92 ( 5.78 )
        Functional Well-Being: Cycle 11 (n=100, 133)
    -0.09 ( 7.79 )
    0.62 ( 7.43 )
        Total FACT-G Score: Cycle 11 (n=100, 133)
    -0.05 ( 22.54 )
    2.06 ( 19.85 )
        Breast Specific: Cycle 11 (n=100, 133)
    -0.38 ( 8.49 )
    0.96 ( 7.64 )
        Total FACT-B Score: Cycle 11 (n=100, 133)
    -0.41 ( 27.67 )
    2.97 ( 24.53 )
        Trial Outcome Index: Cycle 11 (n=100, 133)
    -0.35 ( 18.46 )
    1.49 ( 17.26 )
        Physical Well-Being: Post PD (n=33, 39)
    -1.25 ( 7.61 )
    -1.12 ( 7.39 )
        Social Well-Being: Post PD (n=33, 39)
    -1.58 ( 8.03 )
    -1.19 ( 7.48 )
        Emotional Well-Being: Post PD (n=33, 39)
    -0.2 ( 6.92 )
    -0.78 ( 6.42 )
        Functional Well-Being: Post PD (n=33, 39)
    -2.22 ( 8.06 )
    -1.28 ( 7.59 )
        Total FACT-G Score: Post PD (n=33, 39)
    -5.46 ( 21.85 )
    -4.44 ( 20.92 )
        Breast Specific: Post PD (n=33, 39)
    1.22 ( 7.84 )
    0.03 ( 7.79 )
        Total FACT-B Score: Post PD (n=33, 39)
    -4.23 ( 26.37 )
    -4.55 ( 25.59 )
        Trial Outcome Index: Post PD (n=33, 39)
    -2.57 ( 17.92 )
    -2.38 ( 17.7 )
    Notes
    [7] - n (number) = number of participants assessed for the given parameter at the specified visit.
    [8] - n (number) = number of participants assessed for the given parameter at the specified visit.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From time of first drug intake up to 28 days after last dose study treatment (up to 4.75 years)
    Adverse event reporting additional description
    Safety population included all participants who had received at least 1 dose of the trial medication, whether withdrawn prematurely or not.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    Trastuzumab + Docetaxel
    Reporting group description
    		 Trastuzumab 8 mg/kg loading dose administered intravenously on Day 1 of Cycle 1, followed by docetaxel 100 mg/m^2 on Day 2 of Cycle 1. Then a maintenance dose of trastuzumab at 6 mg/kg and docetaxel at 100 mg/m^2 were administered intravenously on Day 1 of each 3-weekly cycle until disease progression, unacceptable toxicity (requiring discontinuation of study treatment), or withdrawal of participant's consent, and for a minimum of 6 cycles, respectively.

    Reporting group title
    Trastuzumab + Bevacizumab + Docetaxel
    Reporting group description
    		 Trastuzumab 8 mg/kg loading dose administered intravenously on Day 1 of Cycle 1, followed by bevacizumab 15 mg/kg and docetaxel 100 mg/m^2 on Day 2 of Cycle 1. Then a maintenance dose of trastuzumab at 6 mg/kg, bevacizumab 15 mg/kg and docetaxel at 100 mg/m^2 were administered intravenously on Day 1 of each 3-weekly cycle until disease progression, unacceptable toxicity (requiring discontinuation of study treatment), or withdrawal of participant's consent.

    Serious adverse events
    		 Trastuzumab + Docetaxel Trastuzumab + Bevacizumab + Docetaxel
    Total subjects affected by serious adverse events
         subjects affected / exposed
    63 / 206 (30.58%)
    72 / 215 (33.49%)
         number of deaths (all causes)
    78
    81
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Thyroid cancer
         subjects affected / exposed
    1 / 206 (0.49%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    0 / 206 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 206 (0.00%)
    2 / 215 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 206 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 206 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    0 / 206 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    1 / 206 (0.49%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 206 (0.49%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    2 / 206 (0.97%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 206 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 206 (0.97%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Performance status decreased
         subjects affected / exposed
    1 / 206 (0.49%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 206 (0.49%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 206 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    1 / 206 (0.49%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Bartholinitis
         subjects affected / exposed
    0 / 206 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast discharge
         subjects affected / exposed
    1 / 206 (0.49%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Female genital tract fistula
         subjects affected / exposed
    0 / 206 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    2 / 206 (0.97%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 206 (0.49%)
    3 / 215 (1.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 206 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 206 (0.97%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 206 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 206 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphonia
         subjects affected / exposed
    0 / 206 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 206 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 206 (0.49%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    Bipolar I disorder
         subjects affected / exposed
    1 / 206 (0.49%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    0 / 206 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    General physical condition abnormal
         subjects affected / exposed
    1 / 206 (0.49%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Comminuted fracture
         subjects affected / exposed
    1 / 206 (0.49%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    1 / 206 (0.49%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    0 / 206 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular access complication
         subjects affected / exposed
    0 / 206 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    1 / 206 (0.49%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    1 / 206 (0.49%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 206 (0.00%)
    2 / 215 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 206 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 206 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    1 / 206 (0.49%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    0 / 206 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 206 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    1 / 206 (0.49%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    0 / 206 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery thrombosis
         subjects affected / exposed
    0 / 206 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 206 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    0 / 206 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 206 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    0 / 206 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    14 / 206 (6.80%)
    18 / 215 (8.37%)
         occurrences causally related to treatment / all
    14 / 14
    18 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    9 / 206 (4.37%)
    6 / 215 (2.79%)
         occurrences causally related to treatment / all
    9 / 9
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 206 (0.49%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 206 (0.49%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    4 / 206 (1.94%)
    6 / 215 (2.79%)
         occurrences causally related to treatment / all
    3 / 4
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 206 (0.00%)
    3 / 215 (1.40%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    0 / 206 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 206 (0.49%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal wall haematoma
         subjects affected / exposed
    1 / 206 (0.49%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aphthous stomatitis
         subjects affected / exposed
    0 / 206 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer perforation
         subjects affected / exposed
    1 / 206 (0.49%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 206 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 206 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 206 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 206 (0.49%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 206 (0.49%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 206 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 206 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal perforation
         subjects affected / exposed
    1 / 206 (0.49%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 206 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic vein thrombosis
         subjects affected / exposed
    1 / 206 (0.49%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    1 / 206 (0.49%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular injury
         subjects affected / exposed
    1 / 206 (0.49%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Exfoliative rash
         subjects affected / exposed
    1 / 206 (0.49%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 206 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 206 (0.49%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Neutropenic sepsis
         subjects affected / exposed
    3 / 206 (1.46%)
    6 / 215 (2.79%)
         occurrences causally related to treatment / all
    3 / 3
    6 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    2 / 206 (0.97%)
    4 / 215 (1.86%)
         occurrences causally related to treatment / all
    2 / 2
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal Abscess
         subjects affected / exposed
    0 / 206 (0.00%)
    4 / 215 (1.86%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 206 (0.49%)
    2 / 215 (0.93%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    3 / 206 (1.46%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 206 (0.97%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 206 (0.49%)
    2 / 215 (0.93%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 206 (0.49%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 206 (0.49%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess soft tissue
         subjects affected / exposed
    1 / 206 (0.49%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina gangrenous
         subjects affected / exposed
    1 / 206 (0.49%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    0 / 206 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 206 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis C
         subjects affected / exposed
    1 / 206 (0.49%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mastitis
         subjects affected / exposed
    0 / 206 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphangitis
         subjects affected / exposed
    1 / 206 (0.49%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 206 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Viral infection
         subjects affected / exposed
    0 / 206 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 206 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Trastuzumab + Docetaxel Trastuzumab + Bevacizumab + Docetaxel
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    198 / 206 (96.12%)
    202 / 215 (93.95%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    27 / 206 (13.11%)
    79 / 215 (36.74%)
         occurrences all number
    41
    115
    Hot flush
         subjects affected / exposed
    16 / 206 (7.77%)
    12 / 215 (5.58%)
         occurrences all number
    19
    15
    Lymphoedema
         subjects affected / exposed
    17 / 206 (8.25%)
    8 / 215 (3.72%)
         occurrences all number
    17
    8
    Flushing
         subjects affected / exposed
    10 / 206 (4.85%)
    12 / 215 (5.58%)
         occurrences all number
    19
    20
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    76 / 206 (36.89%)
    75 / 215 (34.88%)
         occurrences all number
    154
    139
    Fatigue
         subjects affected / exposed
    48 / 206 (23.30%)
    69 / 215 (32.09%)
         occurrences all number
    87
    183
    Oedema peripheral
         subjects affected / exposed
    72 / 206 (34.95%)
    37 / 215 (17.21%)
         occurrences all number
    113
    43
    Pyrexia
         subjects affected / exposed
    41 / 206 (19.90%)
    51 / 215 (23.72%)
         occurrences all number
    53
    82
    Influenza like illness
         subjects affected / exposed
    18 / 206 (8.74%)
    17 / 215 (7.91%)
         occurrences all number
    31
    36
    Spinal pain
         subjects affected / exposed
    4 / 206 (1.94%)
    11 / 215 (5.12%)
         occurrences all number
    4
    13
    Chills
         subjects affected / exposed
    11 / 206 (5.34%)
    15 / 215 (6.98%)
         occurrences all number
    12
    18
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    14 / 206 (6.80%)
    10 / 215 (4.65%)
         occurrences all number
    19
    12
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    43 / 206 (20.87%)
    43 / 215 (20.00%)
         occurrences all number
    65
    55
    Epistaxis
         subjects affected / exposed
    35 / 206 (16.99%)
    109 / 215 (50.70%)
         occurrences all number
    59
    251
    Rhinorrhoea
         subjects affected / exposed
    18 / 206 (8.74%)
    26 / 215 (12.09%)
         occurrences all number
    31
    36
    Dyspnoea
         subjects affected / exposed
    46 / 206 (22.33%)
    36 / 215 (16.74%)
         occurrences all number
    61
    44
    Dysphonia
         subjects affected / exposed
    8 / 206 (3.88%)
    21 / 215 (9.77%)
         occurrences all number
    8
    24
    Oropharyngeal pain
         subjects affected / exposed
    13 / 206 (6.31%)
    26 / 215 (12.09%)
         occurrences all number
    19
    39
    Respiratory disorder
         subjects affected / exposed
    8 / 206 (3.88%)
    11 / 215 (5.12%)
         occurrences all number
    9
    18
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    21 / 206 (10.19%)
    19 / 215 (8.84%)
         occurrences all number
    24
    34
    Depression
         subjects affected / exposed
    15 / 206 (7.28%)
    13 / 215 (6.05%)
         occurrences all number
    16
    15
    Anxiety
         subjects affected / exposed
    16 / 206 (7.77%)
    12 / 215 (5.58%)
         occurrences all number
    17
    13
    Investigations
    Weight decreased
         subjects affected / exposed
    6 / 206 (2.91%)
    20 / 215 (9.30%)
         occurrences all number
    6
    22
    Weight increased
         subjects affected / exposed
    13 / 206 (6.31%)
    8 / 215 (3.72%)
         occurrences all number
    14
    8
    Cardiac disorders
    Left ventricular dysfunction
         subjects affected / exposed
    17 / 206 (8.25%)
    24 / 215 (11.16%)
         occurrences all number
    20
    28
    Nervous system disorders
    Headache
         subjects affected / exposed
    40 / 206 (19.42%)
    66 / 215 (30.70%)
         occurrences all number
    67
    129
    Peripheral sensory neuropathy
         subjects affected / exposed
    52 / 206 (25.24%)
    46 / 215 (21.40%)
         occurrences all number
    73
    71
    Paraesthesia
         subjects affected / exposed
    28 / 206 (13.59%)
    37 / 215 (17.21%)
         occurrences all number
    36
    40
    Dysgeusia
         subjects affected / exposed
    32 / 206 (15.53%)
    37 / 215 (17.21%)
         occurrences all number
    47
    60
    Neuropathy peripheral
         subjects affected / exposed
    18 / 206 (8.74%)
    22 / 215 (10.23%)
         occurrences all number
    21
    29
    Dizziness
         subjects affected / exposed
    16 / 206 (7.77%)
    14 / 215 (6.51%)
         occurrences all number
    22
    18
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    51 / 206 (24.76%)
    44 / 215 (20.47%)
         occurrences all number
    108
    76
    Anaemia
         subjects affected / exposed
    24 / 206 (11.65%)
    16 / 215 (7.44%)
         occurrences all number
    28
    20
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    13 / 206 (6.31%)
    3 / 215 (1.40%)
         occurrences all number
    17
    3
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    59 / 206 (28.64%)
    75 / 215 (34.88%)
         occurrences all number
    75
    88
    Dry eye
         subjects affected / exposed
    6 / 206 (2.91%)
    12 / 215 (5.58%)
         occurrences all number
    6
    13
    Conjunctivitis
         subjects affected / exposed
    9 / 206 (4.37%)
    22 / 215 (10.23%)
         occurrences all number
    14
    25
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    85 / 206 (41.26%)
    107 / 215 (49.77%)
         occurrences all number
    158
    265
    Stomatitis
         subjects affected / exposed
    61 / 206 (29.61%)
    95 / 215 (44.19%)
         occurrences all number
    95
    182
    Nausea
         subjects affected / exposed
    76 / 206 (36.89%)
    82 / 215 (38.14%)
         occurrences all number
    163
    187
    Constipation
         subjects affected / exposed
    47 / 206 (22.82%)
    54 / 215 (25.12%)
         occurrences all number
    65
    88
    Dyspepsia
         subjects affected / exposed
    18 / 206 (8.74%)
    34 / 215 (15.81%)
         occurrences all number
    26
    58
    Vomiting
         subjects affected / exposed
    37 / 206 (17.96%)
    42 / 215 (19.53%)
         occurrences all number
    72
    60
    Abdominal pain
         subjects affected / exposed
    15 / 206 (7.28%)
    27 / 215 (12.56%)
         occurrences all number
    20
    45
    Abdominal pain upper
         subjects affected / exposed
    24 / 206 (11.65%)
    23 / 215 (10.70%)
         occurrences all number
    33
    32
    Haemorrhoids
         subjects affected / exposed
    8 / 206 (3.88%)
    22 / 215 (10.23%)
         occurrences all number
    13
    35
    Toothache
         subjects affected / exposed
    7 / 206 (3.40%)
    12 / 215 (5.58%)
         occurrences all number
    7
    24
    Gastrooesophageal reflux disease
         subjects affected / exposed
    11 / 206 (5.34%)
    8 / 215 (3.72%)
         occurrences all number
    19
    17
    Gingival bleeding
         subjects affected / exposed
    1 / 206 (0.49%)
    15 / 215 (6.98%)
         occurrences all number
    2
    26
    Rectal haemorrhage
         subjects affected / exposed
    1 / 206 (0.49%)
    10 / 215 (4.65%)
         occurrences all number
    1
    14
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    141 / 206 (68.45%)
    135 / 215 (62.79%)
         occurrences all number
    142
    142
    Rash
         subjects affected / exposed
    41 / 206 (19.90%)
    37 / 215 (17.21%)
         occurrences all number
    58
    52
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    26 / 206 (12.62%)
    27 / 215 (12.56%)
         occurrences all number
    32
    34
    Nail disorder
         subjects affected / exposed
    59 / 206 (28.64%)
    68 / 215 (31.63%)
         occurrences all number
    65
    74
    Dry skin
         subjects affected / exposed
    25 / 206 (12.14%)
    28 / 215 (13.02%)
         occurrences all number
    29
    30
    Pruritus
         subjects affected / exposed
    24 / 206 (11.65%)
    19 / 215 (8.84%)
         occurrences all number
    34
    31
    Nail toxicity
         subjects affected / exposed
    24 / 206 (11.65%)
    15 / 215 (6.98%)
         occurrences all number
    27
    18
    Erythema
         subjects affected / exposed
    12 / 206 (5.83%)
    16 / 215 (7.44%)
         occurrences all number
    14
    27
    Onycholysis
         subjects affected / exposed
    5 / 206 (2.43%)
    16 / 215 (7.44%)
         occurrences all number
    5
    17
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    1 / 206 (0.49%)
    22 / 215 (10.23%)
         occurrences all number
    2
    35
    Dysuria
         subjects affected / exposed
    7 / 206 (3.40%)
    13 / 215 (6.05%)
         occurrences all number
    8
    14
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    60 / 206 (29.13%)
    59 / 215 (27.44%)
         occurrences all number
    115
    137
    Musculoskeletal pain
         subjects affected / exposed
    32 / 206 (15.53%)
    39 / 215 (18.14%)
         occurrences all number
    46
    61
    Arthralgia
         subjects affected / exposed
    41 / 206 (19.90%)
    63 / 215 (29.30%)
         occurrences all number
    86
    109
    Pain in extremity
         subjects affected / exposed
    37 / 206 (17.96%)
    35 / 215 (16.28%)
         occurrences all number
    54
    53
    Neck pain
         subjects affected / exposed
    10 / 206 (4.85%)
    17 / 215 (7.91%)
         occurrences all number
    13
    17
    Back pain
         subjects affected / exposed
    26 / 206 (12.62%)
    32 / 215 (14.88%)
         occurrences all number
    37
    39
    Bone pain
         subjects affected / exposed
    25 / 206 (12.14%)
    23 / 215 (10.70%)
         occurrences all number
    35
    27
    Musculoskeletal chest pain
         subjects affected / exposed
    7 / 206 (3.40%)
    14 / 215 (6.51%)
         occurrences all number
    8
    15
    Muscle spasms
         subjects affected / exposed
    8 / 206 (3.88%)
    18 / 215 (8.37%)
         occurrences all number
    10
    33
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    33 / 206 (16.02%)
    27 / 215 (12.56%)
         occurrences all number
    58
    43
    Cystitis
         subjects affected / exposed
    17 / 206 (8.25%)
    19 / 215 (8.84%)
         occurrences all number
    21
    27
    Rhinitis
         subjects affected / exposed
    16 / 206 (7.77%)
    17 / 215 (7.91%)
         occurrences all number
    22
    20
    Nasopharyngitis
         subjects affected / exposed
    20 / 206 (9.71%)
    18 / 215 (8.37%)
         occurrences all number
    25
    26
    Upper respiratory tract infection
         subjects affected / exposed
    11 / 206 (5.34%)
    21 / 215 (9.77%)
         occurrences all number
    15
    47
    Bronchitis
         subjects affected / exposed
    15 / 206 (7.28%)
    9 / 215 (4.19%)
         occurrences all number
    18
    14
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    25 / 206 (12.14%)
    39 / 215 (18.14%)
         occurrences all number
    41
    58

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Jan 2007
    - Implemented central human epidermal growth factor receptor 2 (HER2) testing to ensure greater consistency in determination of HER2 status. - Increased sample size to accommodate an assessment of PFS by an Independent Review Committee (not all participants could be assessed by such a procedure) for an intended US filing. - Reversible posterior leukoencephalopathy syndrome (RPLS) was listed as an adverse event of special interest to ensure instances of this rare event were properly detected. - Inclusion criterion for participants who had received adjuvant trastuzumab treatment was modified to better reflect the clinical reality after the earlier than expected approval of this treatment. The washout period for prior hormone treatment was also extended. - The definition of inadequate liver function in the exclusion criteria was changed for better alignment with the labeling for docetaxel and the duration of subsequent trastuzumab administration was extended for greater compliance with the dosing recommendations at the time. - Further clarifications and correction of typographical errors.
    06 Mar 2009
    - Monitoring of left ventricular ejection fraction (LVEF) was extended on the recommendation of the Data Safety Monitoring Board (DSMB). - Exploratory interim analyses on PFS and OS were added on the request of the DSMB to enable an assessment of the risk/benefit ratio. - Provision was made for participants randomized to the Trastuzumab+Docetaxel arm to receive bevacizumab after the end of the study if considered appropriate by DSMB on the basis of the interim analyses. - Further clarifications were made and typographical errors were corrected.

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

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