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    Clinical Trial Results:
    A Phase III, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of Bevacizumab, and Associated Biomarkers, in Combination With Paclitaxel Compared With Paclitaxel Plus Placebo as First-Line Treatment of Patients With HER2-Negative Metastatic Breast Cancer

    Summary
    EudraCT number
    		 2011-005335-97
    Trial protocol
    		 DE   BE   GB   IT   BG  
    Global end of trial date
    21 Nov 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Dec 2018
    First version publication date
    29 Apr 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GO25632
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01663727
    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
    21 Nov 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Nov 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Nov 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of bevacizumab + paclitaxel compared with placebo + paclitaxel as first-line treatment in participants with HER2-negative metastatic breast cancer (MBC) as measured by: - Progression-free survival (PFS) based on investigator tumor assessment in the intent-to-treat (ITT) participants population (co-primary endpoint). - PFS based on investigator tumor assessment in ITT participants with high baseline plasma VEGF-A levels (co-primary endpoint).
    Protection of trial subjects
    The study was conducted in accordance with the principles of the “Declaration of Helsinki” and Good Clinical Practice (GCP) according to the regulations and procedures. This study was conducted in accordance with GCP and investigators were trained according to applicable Sponsor Standard Operating Procedures.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Aug 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 16
    Country: Number of subjects enrolled
    Belgium: 24
    Country: Number of subjects enrolled
    Bulgaria: 14
    Country: Number of subjects enrolled
    Chile: 7
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    Italy: 11
    Country: Number of subjects enrolled
    Japan: 54
    Country: Number of subjects enrolled
    Korea, Republic of: 38
    Country: Number of subjects enrolled
    Panama: 28
    Country: Number of subjects enrolled
    Romania: 27
    Country: Number of subjects enrolled
    Russian Federation: 46
    Country: Number of subjects enrolled
    South Africa: 16
    Country: Number of subjects enrolled
    Ukraine: 57
    Country: Number of subjects enrolled
    United Kingdom: 33
    Country: Number of subjects enrolled
    United States: 104
    Worldwide total number of subjects
    481
    EEA total number of subjects
    115
    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)
    378
    From 65 to 84 years
    102
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 596 participants were screened of whom 115 were screen failures and 481 participants were randomized.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Paclitaxel+Placebo
    Arm description
    		 Participants received paclitaxel 90 mg/m^2 IV on Days 1, 8 and 15 and placebo matched to bevacizumab IV infusion on Days 1 and 15 of a 28 day cycle until progressive disease, treatment limiting toxicity or death.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The dose of paclitaxel was based on the participant’s weight at each administration.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The placebo dose was based on the participant’s most recent weight taken within 7 days of the first study drug dose (Cycle 1, Day 1) and remained the same throughout the study.

    Arm title
    		 Paclitaxel+ Bevacizumab
    Arm description
    		 Participants received paclitaxel 90 mg/m^2 IV on Days 1, 8 and 15 and bevacizumab IV 10 mg/kg on Days 1 and 15 of a 28 day cycle until progressive disease, treatment limiting toxicity or death.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin®
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The bevacizumab dose was based on the participant’s most recent weight taken within 7 days of the first study drug dose (Cycle 1, Day 1) and remained the same throughout the study.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The dose of paclitaxel was based on the participant’s weight at each administration.

    Number of subjects in period 1
    		Paclitaxel+Placebo Paclitaxel+ Bevacizumab
    Started
    242
    239
    Completed
    0
    1
    Not completed
    242
    238
         Consent withdrawn by subject
    18
    25
         Death
    161
    155
         Withdrawal prior to dosing.
    1
    -
         Participant Withdrawal and Adverse Event.
    1
    -
         Study Terminated
    51
    50
         Lost to follow-up
    10
    8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Paclitaxel+Placebo
    Reporting group description
    		 Participants received paclitaxel 90 mg/m^2 IV on Days 1, 8 and 15 and placebo matched to bevacizumab IV infusion on Days 1 and 15 of a 28 day cycle until progressive disease, treatment limiting toxicity or death.

    Reporting group title
    Paclitaxel+ Bevacizumab
    Reporting group description
    		 Participants received paclitaxel 90 mg/m^2 IV on Days 1, 8 and 15 and bevacizumab IV 10 mg/kg on Days 1 and 15 of a 28 day cycle until progressive disease, treatment limiting toxicity or death.

    Reporting group values
    		 Paclitaxel+Placebo Paclitaxel+ Bevacizumab Total
    Number of subjects
    		 242 239 481
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 196 182 378
        From 65-84 years
    		 46 56 102
        85 years and over
    		 0 1 1
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 54.7 ± 10.7 55.8 ± 11.5 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 237 236 473
        Male
    		 5 3 8

    End points

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    End points reporting groups
    Reporting group title
    Paclitaxel+Placebo
    Reporting group description
    		 Participants received paclitaxel 90 mg/m^2 IV on Days 1, 8 and 15 and placebo matched to bevacizumab IV infusion on Days 1 and 15 of a 28 day cycle until progressive disease, treatment limiting toxicity or death.

    Reporting group title
    Paclitaxel+ Bevacizumab
    Reporting group description
    		 Participants received paclitaxel 90 mg/m^2 IV on Days 1, 8 and 15 and bevacizumab IV 10 mg/kg on Days 1 and 15 of a 28 day cycle until progressive disease, treatment limiting toxicity or death.

    Primary: Percentage of participants with Progression or death in Intent-to-Treat (ITT) Population

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    End point title
    		 Percentage of participants with Progression or death in Intent-to-Treat (ITT) Population [1]
    End point description
    Tumor assessment was performed as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by investigator. Disease progression was defined as at least 20 percent (%) increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study and absolute increase of at least 5 millimeter (mm), unequivocal progression of existing non-target lesions, or presence of new lesions. ITT population included all participants randomized to study treatment irrespective of whether the assigned treatment was actually received.
    End point type
    Primary
    End point timeframe
    Baseline, every 8 weeks until documented disease progression, death or clinical cut-off (up to 117.7 weeks)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The endpoint was qualitative in nature. Hence, no statistical analysis is provided.
    End point values
    		 Paclitaxel+Placebo Paclitaxel+ Bevacizumab
    Number of subjects analysed
    242
    239
    Units: percentage of participants
        number (not applicable)
    69.4
    63.6
    No statistical analyses for this end point

    Primary: Progression free survival (PFS) in ITT Population

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    End point title
    		 Progression free survival (PFS) in ITT Population
    End point description
    PFS was defined as the interval between the date of randomization and the first documentation of progressive disease or death from any cause. Tumor assessment was performed as per RECIST v1.1 by investigator. Disease progression was defined as at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study and absolute increase of at least 5 mm, unequivocal progression of existing non-target lesions, or presence of new lesions. PFS was estimated using Kaplan Meier method. ITT population included all participants randomized to study treatment irrespective of whether the assigned treatment was actually received.
    End point type
    Primary
    End point timeframe
    Baseline, every 8 weeks until documented disease progression, death or clinical cut-off (up to 117.7 weeks)
    End point values
    		 Paclitaxel+Placebo Paclitaxel+ Bevacizumab
    Number of subjects analysed
    242
    239
    Units: months
        median (confidence interval 95%)
    8.8 (7.4 to 9.3)
    11.0 (9.5 to 12.2)
    Statistical analysis title
    		 Paclitaxel+Bevacizumab vs. Paclitaxel+Placebo
    Statistical analysis description
    Stratified analysis: Stratification factors were plasma VEGF-A level (low/high), prior adjuvant chemotherapy (yes/no) and estrogen receptor / progesterone receptor status (positive, negative). Hazards ratio was estimated by Cox regression.
    Comparison groups
    Paclitaxel+ Bevacizumab v Paclitaxel+Placebo
    Number of subjects included in analysis
    481
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0007
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.68
    Confidence interval
         level
    		 99%
         sides
    2-sided
         lower limit
    		 0.51
         upper limit
    		 0.91
    Statistical analysis title
    		 Paclitaxel+ Bevacizumab vs. Paclitaxel+Placebo
    Statistical analysis description
    Unstratified Analysis. Hazards ratio was estimated by Cox regression.
    Comparison groups
    Paclitaxel+Placebo v Paclitaxel+ Bevacizumab
    Number of subjects included in analysis
    481
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0046
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.73
    Confidence interval
         level
    		 99%
         sides
    2-sided
         lower limit
    		 0.55
         upper limit
    		 0.97
    Statistical analysis title
    		 Paclitaxel+ Bevacizumab vs. Paclitaxel+Placebo
    Statistical analysis description
    A stratified multivariate Cox regression model, including treatment, VEGF-A level, and interaction between treatment and VEGF-A level (low, high) as factors was used to estimate the interaction p-value of the treatment with VEGF-A level for PFS. Analysis for the interaction of treatment effect with the plasma VEGF-A levels was a secondary objective.
    Comparison groups
    Paclitaxel+Placebo v Paclitaxel+ Bevacizumab
    Number of subjects included in analysis
    481
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4619
    Method
    		 Wald Test
    Confidence interval

    Primary: Percentage of participants with Progression or death in high baseline plasma vascular endothelial growth factor-A (VEGF-A) ITT population

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    End point title
    		 Percentage of participants with Progression or death in high baseline plasma vascular endothelial growth factor-A (VEGF-A) ITT population [2]
    End point description
    Tumor assessment was performed as per RECIST v1.1 by investigator. Disease progression was defined as at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study and absolute increase of at least 5 mm, unequivocal progression of existing non-target lesions, or presence of new lesions. High baseline plasma VEGF-A ITT population: All participants randomized to study treatment with high baseline plasma VEGF-A levels (VEGF-A levels greater than or equal to 5.05 picograms per milliliter), irrespective of whether the assigned treatment was actually received.
    End point type
    Primary
    End point timeframe
    Baseline, every 8 weeks until documented disease progression, death or clinical cut-off (up to 111.3 weeks)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The endpoint was qualitative in nature. Hence, no statistical analysis is provided.
    End point values
    		 Paclitaxel+Placebo Paclitaxel+ Bevacizumab
    Number of subjects analysed
    124
    120
    Units: percentage of participants
        number (not applicable)
    75.0
    70.8
    No statistical analyses for this end point

    Primary: PFS in high baseline plasma VEGF-A ITT population

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    End point title
    		 PFS in high baseline plasma VEGF-A ITT population
    End point description
    PFS was defined as the interval between the date of randomization and the first documentation of progressive disease or death from any cause. Tumor assessment was performed as per RECIST v1.1 by investigator. Disease progression was defined as at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study and absolute increase of at least 5 mm, unequivocal progression of existing non-target lesions, or presence of new lesions. PFS was estimated using Kaplan Meier method.
    End point type
    Primary
    End point timeframe
    Baseline, every 8 weeks until documented disease progression, death or clinical cut-off (up to 111.3 weeks)
    End point values
    		 Paclitaxel+Placebo Paclitaxel+ Bevacizumab
    Number of subjects analysed
    124
    120
    Units: months
        median (confidence interval 95%)
    7.3 (5.6 to 8.7)
    9.6 (9.0 to 11.0)
    Statistical analysis title
    		 Paclitaxel+ Bevacizumab vs. Paclitaxel+Placebo
    Statistical analysis description
    Stratified analysis: Stratification factors were prior adjuvant chemotherapy (yes/no) and estrogen receptor / progesterone receptor status (positive, negative). Hazards ratio was estimated by Cox regression.
    Comparison groups
    Paclitaxel+Placebo v Paclitaxel+ Bevacizumab
    Number of subjects included in analysis
    244
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0038
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.64
    Confidence interval
         level
    		 96%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 0.88
    Statistical analysis title
    		 Paclitaxel+ Bevacizumab vs. Paclitaxel+Placebo
    Statistical analysis description
    Unstratified analysis. Hazards ratio was estimated by Cox regression.
    Comparison groups
    Paclitaxel+Placebo v Paclitaxel+ Bevacizumab
    Number of subjects included in analysis
    244
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0101
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.68
    Confidence interval
         level
    		 96%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 0.93

    Secondary: Percentage of Participants Who Died - ITT population

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    End point title
    		 Percentage of Participants Who Died - ITT population
    End point description
    End point type
    Secondary
    End point timeframe
    From randomization till death or clinical cut-off (up to 244 weeks)
    End point values
    		 Paclitaxel+Placebo Paclitaxel+ Bevacizumab
    Number of subjects analysed
    242
    239
    Units: percentage of participants
        number (not applicable)
    64.9
    64.0
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) - ITT Population

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    End point title
    		 Overall Survival (OS) - ITT Population
    End point description
    OS was defined as the interval between the date of randomization and death from any cause. OS was estimated using Kaplan Meier method. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    From randomization till death or clinical cut-off (up to 244 weeks)
    End point values
    		 Paclitaxel+Placebo Paclitaxel+ Bevacizumab
    Number of subjects analysed
    242
    239
    Units: months
        median (confidence interval 95%)
    25.8 (21.8 to 30.2)
    28.8 (22.8 to 32.8)
    Statistical analysis title
    		 Paclitaxel+ Bevacizumab vs. Paclitaxel+Placebo
    Statistical analysis description
    Stratified analysis: Stratified analysis: Stratification factors were plasma VEGF-A level (low/high), prior adjuvant chemotherapy (yes/no) and estrogen receptor / progesterone receptor status (positive, negative).
    Comparison groups
    Paclitaxel+Placebo v Paclitaxel+ Bevacizumab
    Number of subjects included in analysis
    481
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5877
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 1.18
    Statistical analysis title
    		 Paclitaxel+ Bevacizumab vs. Paclitaxel+Placebo
    Statistical analysis description
    Unstratified analysis.
    Comparison groups
    Paclitaxel+Placebo v Paclitaxel+ Bevacizumab
    Number of subjects included in analysis
    481
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8004
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 1.21

    Secondary: Percentage of Participants Who Died - High Baseline Plasma VEGF-A ITT Population

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    End point title
    		 Percentage of Participants Who Died - High Baseline Plasma VEGF-A ITT Population
    End point description
    Analysis was performed on high baseline plasma VEGF-A ITT Population.
    End point type
    Secondary
    End point timeframe
    From randomization till death or clinical cut-off (up to 244 weeks)
    End point values
    		 Paclitaxel+Placebo Paclitaxel+ Bevacizumab
    Number of subjects analysed
    124
    120
    Units: percentage of participants
        number (not applicable)
    74.2
    71.1
    No statistical analyses for this end point

    Secondary: OS - High Baseline Plasma VEGF-A ITT Population

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    End point title
    		 OS - High Baseline Plasma VEGF-A ITT Population
    End point description
    OS was defined as the interval between the date of randomization and death from any cause. OS was estimated using Kaplan Meier method.
    End point type
    Secondary
    End point timeframe
    From randomization till death or clinical cut-off (up to 244 weeks)
    End point values
    		 Paclitaxel+Placebo Paclitaxel+ Bevacizumab
    Number of subjects analysed
    124
    120
    Units: months
        median (confidence interval 95%)
    19.4 (16.5 to 25.0)
    22.8 (18.2 to 31.6)
    Statistical analysis title
    		 Paclitaxel+ Bevacizumab vs. Paclitaxel+Placebo
    Statistical analysis description
    Stratified analysis: Stratification factors were prior adjuvant chemotherapy (yes/no) and estrogen receptor / progesterone receptor status (positive, negative).
    Comparison groups
    Paclitaxel+Placebo v Paclitaxel+ Bevacizumab
    Number of subjects included in analysis
    244
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2745
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.63
         upper limit
    		 1.14
    Statistical analysis title
    		 Paclitaxel+ Bevacizumab vs. Paclitaxel+Placebo
    Statistical analysis description
    Unstratified analysis. Hazards ratio was estimated by Cox regression.
    Comparison groups
    Paclitaxel+Placebo v Paclitaxel+ Bevacizumab
    Number of subjects included in analysis
    244
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3616
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 1.17

    Secondary: Percentage of Participants With an Objective Response - ITT population

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    End point title
    		 Percentage of Participants With an Objective Response - ITT population
    End point description
    Objective response was defined as having a Complete Response (CR) or Partial Response (PR) according to a RECIST criteria v 1.1. CR was defined as disappearance of all target and non-target lesions and no new lesions, all pathological lymph nodes must have decreased to <10 mm in short axis and normalization of tumor marker level. PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters), no progression in non-target lesions, and no new lesions. Measurable disease was defined by the presence of at least one measurable lesion by clinical measurement, chest x-ray, computed tomography (CT), or magnetic resonance imaging (MRI). Number of participants analyzed=participants from ITT population with measurable disease at baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, every 8 weeks until documented disease progression, death or clinical cut-off (up to 117.7 weeks)
    End point values
    		 Paclitaxel+Placebo Paclitaxel+ Bevacizumab
    Number of subjects analysed
    214
    202
    Units: percentage of participants
        number (confidence interval 95%)
    33.2 (26.87 to 39.49)
    54.0 (47.09 to 60.83)
    Statistical analysis title
    		 Paclitaxel+ Bevacizumab vs. Paclitaxel+Placebo
    Comparison groups
    Paclitaxel+Placebo v Paclitaxel+ Bevacizumab
    Number of subjects included in analysis
    416
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Fisher
    Parameter type
    		 Difference in Response Rates
    Point estimate
    20.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 11.45
         upper limit
    		 30.11

    Secondary: Percentage of Participants With an Objective Response - High Baseline Plasma VEGF-A ITT Population

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    End point title
    		 Percentage of Participants With an Objective Response - High Baseline Plasma VEGF-A ITT Population
    End point description
    Objective response was defined as having a CR or PR according to a RECIST criteria v 1.1. CR was defined as disappearance of all target and non-target lesions and no new lesions, all pathological lymph nodes must have decreased to <10 mm in short axis and normalization of tumor marker level. PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters), no progression in non-target lesions, and no new lesions. Measurable disease was defined by the presence of at least one measurable lesion by clinical measurement, chest x-ray, CT, or MRI. Number of participants analyzed=participants from high baseline plasma VEGF-A ITT population with measurable disease at baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, every 8 weeks until documented disease progression, death or clinical cut-off (up to 111.3 weeks)
    End point values
    		 Paclitaxel+Placebo Paclitaxel+ Bevacizumab
    Number of subjects analysed
    116
    105
    Units: percentage of participants
        number (confidence interval 95%)
    32.8 (24.22 to 41.30)
    54.3 (44.76 to 63.81)
    Statistical analysis title
    		 Paclitaxel+ Bevacizumab vs. Paclitaxel+Placebo
    Comparison groups
    Paclitaxel+Placebo v Paclitaxel+ Bevacizumab
    Number of subjects included in analysis
    221
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0017
    Method
    		 Fisher
    Parameter type
    		 Difference in Response Rates
    Point estimate
    21.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 8.73
         upper limit
    		 34.32

    Secondary: Duration of Response - ITT Population

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    End point title
    		 Duration of Response - ITT Population
    End point description
    Duration of response was defined as the time from the initial date of the objective response to documented disease progression or death (whichever occurred first). Objective response was defined as having a CR or PR according to a RECIST criteria v 1.1. CR was defined as disappearance of all target and non-target lesions and no new lesions, all pathological lymph nodes must have decreased to <10 mm in short axis and normalization of tumor marker level. PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters), no progression in non-target lesions, and no new lesions. Disease progression was defined as at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study and absolute increase of at least 5 mm, unequivocal progression of existing non-target lesions, or presence of new lesions. Analysis was performed using Kaplan Meier method.
    End point type
    Secondary
    End point timeframe
    Baseline, every 8 weeks until documented disease progression or clinical cut-off (up to 117.7 weeks)
    End point values
    		 Paclitaxel+Placebo Paclitaxel+ Bevacizumab
    Number of subjects analysed
    71
    109
    Units: months
        median (confidence interval 95%)
    9.2 (7.4 to 11.5)
    9.5 (7.8 to 12.4)
    Statistical analysis title
    		 Paclitaxel+ Bevacizumab vs. Paclitaxel+Placebo
    Statistical analysis description
    Stratified analysis: Stratification factors were plasma VEGF-A level (low/high), prior adjuvant chemotherapy (yes/no) and estrogen receptor / progesterone receptor status (positive, negative).
    Comparison groups
    Paclitaxel+Placebo v Paclitaxel+ Bevacizumab
    Number of subjects included in analysis
    180
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2737
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 1.19
    Statistical analysis title
    		 Paclitaxel+ Bevacizumab vs. Paclitaxel+Placebo
    Statistical analysis description
    Unstratified analysis. Hazards ratio was estimated by Cox regression.
    Comparison groups
    Paclitaxel+Placebo v Paclitaxel+ Bevacizumab
    Number of subjects included in analysis
    180
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2959
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.56
         upper limit
    		 1.19

    Secondary: Duration of Response - High Baseline Plasma VEGF-A ITT Population

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    End point title
    		 Duration of Response - High Baseline Plasma VEGF-A ITT Population
    End point description
    Duration of response was defined as the time from the initial date of the objective response to documented disease progression or death (whichever occurred first). Objective response was defined as having a CR or PR according to a RECIST criteria v 1.1. CR was defined as disappearance of all target and non-target lesions and no new lesions, all pathological lymph nodes must have decreased to <10 mm in short axis and normalization of tumor marker level. PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters), no progression in non-target lesions, and no new lesions. Disease progression was defined at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study and absolute increase of at least 5 mm, unequivocal progression of existing non-target lesions, or presence of new lesions. Analysis was performed using Kaplan Meier method.
    End point type
    Secondary
    End point timeframe
    Baseline, every 8 weeks until documented disease progression or clinical cut-off (up to 111.3 weeks)
    End point values
    		 Paclitaxel+Placebo Paclitaxel+ Bevacizumab
    Number of subjects analysed
    38
    57
    Units: months
        median (confidence interval 95%)
    7.2 (5.6 to 9.5)
    8.1 (7.1 to 11.1)
    Statistical analysis title
    		 Paclitaxel+ Bevacizumab vs. Paclitaxel+Placebo
    Statistical analysis description
    Stratified analysis: Stratification factors were prior adjuvant chemotherapy (yes/no) and estrogen receptor / progesterone receptor status (positive, negative). Hazards ratio was estimated by Cox regression.
    Comparison groups
    Paclitaxel+Placebo v Paclitaxel+ Bevacizumab
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1783
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.41
         upper limit
    		 1.18
    Statistical analysis title
    		 Paclitaxel+ Bevacizumab vs. Paclitaxel+Placebo
    Statistical analysis description
    Unstratified analysis. Hazards ratio was estimated by Cox regression.
    Comparison groups
    Paclitaxel+Placebo v Paclitaxel+ Bevacizumab
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2429
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.45
         upper limit
    		 1.22

    Secondary: Percentage of Participants Who were Alive at 1 Year - ITT Population

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    End point title
    		 Percentage of Participants Who were Alive at 1 Year - ITT Population
    End point description
    End point type
    Secondary
    End point timeframe
    1 year
    End point values
    		 Paclitaxel+Placebo Paclitaxel+ Bevacizumab
    Number of subjects analysed
    242
    239
    Units: percentage of participants
        number (not applicable)
    80.94
    82.47
    No statistical analyses for this end point

    Secondary: Secondary: Percentage of Participants Who were Alive at 1 Year - High Baseline Plasma VEGF-A ITT Population

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    End point title
    		 Secondary: Percentage of Participants Who were Alive at 1 Year - High Baseline Plasma VEGF-A ITT Population
    End point description
    End point type
    Secondary
    End point timeframe
    1 year
    End point values
    		 Paclitaxel+Placebo Paclitaxel+ Bevacizumab
    Number of subjects analysed
    124
    120
    Units: percentage of participants
        number (not applicable)
    69.27
    80.96
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of study drug through 30 days after the last dose of study drug or clinical cut-off (up to 115.1 weeks)
    Adverse event reporting additional description
    Safety population: All randomized participants who received at least one full or partial dose of any component of the study treatment (bevacizumab, placebo, or paclitaxel).
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Paclitaxel+Placebo
    Reporting group description
    		 Participants received paclitaxel 90 mg/m^2 IV on Days 1, 8 and 15 and placebo matched to bevacizumab IV infusion on Days 1 and 15 of a 28 day cycle until progressive disease, treatment limiting toxicity or death.

    Reporting group title
    Paclitaxel+ Bevacizumab
    Reporting group description
    		 Participants received paclitaxel 90 mg/m^2 IV on Days 1, 8 and 15 and bevacizumab IV 10 mg/kg on Days 1 and 15 of a 28 day cycle until progressive disease, treatment limiting toxicity or death.

    Serious adverse events
    		 Paclitaxel+Placebo Paclitaxel+ Bevacizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    45 / 233 (19.31%)
    66 / 238 (27.73%)
         number of deaths (all causes)
    162
    161
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    2 / 233 (0.86%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism venous
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ARTERIAL THROMBOSIS
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Asthenia
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    CATHETER SITE ERYTHEMA
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ANAPHYLACTIC REACTION
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 233 (0.86%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 233 (0.86%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 233 (0.00%)
    4 / 238 (1.68%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    2 / 233 (0.86%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Urine output decreased
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 233 (0.00%)
    2 / 238 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 233 (0.00%)
    2 / 238 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ROAD TRAFFIC ACCIDENT
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    STERNAL FRACTURE
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    WOUND DEHISCENCE
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ACUTE CORONARY SYNDROME
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIAC FAILURE CONGESTIVE
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral ischaemia
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dementia
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Speech disorder
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 233 (0.43%)
    3 / 238 (1.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 233 (0.86%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    2 / 3
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 233 (0.43%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 233 (0.00%)
    4 / 238 (1.68%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Optic nerve disorder
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Visual acuity reduced
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CATARACT
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    4 / 233 (1.72%)
    2 / 238 (0.84%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 233 (0.43%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 233 (0.00%)
    2 / 238 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal obstruction
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric varices haemorrhage
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 233 (0.00%)
    4 / 238 (1.68%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 233 (1.29%)
    4 / 238 (1.68%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct obstruction
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallbladder pain
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 233 (0.00%)
    3 / 238 (1.26%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    2 / 2
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Skin and subcutaneous tissue disorders
    Pain of skin
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin haemorrhage
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Cystitis haemorrhagic
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 233 (0.00%)
    4 / 238 (1.68%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal wall abscess
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 233 (0.00%)
    2 / 238 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 233 (0.00%)
    4 / 238 (1.68%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colonic abscess
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    2 / 233 (0.86%)
    3 / 238 (1.26%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 233 (0.00%)
    2 / 238 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngotonsillitis
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 233 (1.29%)
    4 / 238 (1.68%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 233 (0.43%)
    2 / 238 (0.84%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia necrotising
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis syndrome
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection bacterial
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 233 (0.43%)
    2 / 238 (0.84%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VIRAL INFECTION
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CATHETER SITE INFECTION
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    KLEBSIELLA SEPSIS
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SOFT TISSUE INFECTION
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URINARY TRACT INFECTION BACTERIAL
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 233 (0.86%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOKALAEMIA
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPONATRAEMIA
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LACTIC ACIDOSIS
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Paclitaxel+Placebo Paclitaxel+ Bevacizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    225 / 233 (96.57%)
    230 / 238 (96.64%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    30 / 233 (12.88%)
    73 / 238 (30.67%)
         occurrences all number
    83
    109
    Hot flush
         subjects affected / exposed
    10 / 233 (4.29%)
    15 / 238 (6.30%)
         occurrences all number
    30
    17
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    36 / 233 (15.45%)
    32 / 238 (13.45%)
         occurrences all number
    50
    62
    Fatigue
         subjects affected / exposed
    74 / 233 (31.76%)
    88 / 238 (36.97%)
         occurrences all number
    123
    156
    Pyrexia
         subjects affected / exposed
    28 / 233 (12.02%)
    34 / 238 (14.29%)
         occurrences all number
    37
    59
    Oedema peripheral
         subjects affected / exposed
    42 / 233 (18.03%)
    41 / 238 (17.23%)
         occurrences all number
    57
    56
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    30 / 233 (12.88%)
    33 / 238 (13.87%)
         occurrences all number
    33
    41
    Cough
         subjects affected / exposed
    30 / 233 (12.88%)
    43 / 238 (18.07%)
         occurrences all number
    38
    59
    Epistaxis
         subjects affected / exposed
    48 / 233 (20.60%)
    97 / 238 (40.76%)
         occurrences all number
    77
    158
    Dysphonia
         subjects affected / exposed
    5 / 233 (2.15%)
    19 / 238 (7.98%)
         occurrences all number
    5
    24
    Oropharyngeal pain
         subjects affected / exposed
    14 / 233 (6.01%)
    18 / 238 (7.56%)
         occurrences all number
    15
    23
    Rhinorrhoea
         subjects affected / exposed
    3 / 233 (1.29%)
    20 / 238 (8.40%)
         occurrences all number
    4
    26
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    15 / 233 (6.44%)
    8 / 238 (3.36%)
         occurrences all number
    15
    8
    Insomnia
         subjects affected / exposed
    20 / 233 (8.58%)
    35 / 238 (14.71%)
         occurrences all number
    24
    46
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    16 / 233 (6.87%)
    21 / 238 (8.82%)
         occurrences all number
    19
    32
    Alanine aminotransferase increased
         subjects affected / exposed
    17 / 233 (7.30%)
    21 / 238 (8.82%)
         occurrences all number
    21
    37
    Neutrophil count decreased
         subjects affected / exposed
    20 / 233 (8.58%)
    15 / 238 (6.30%)
         occurrences all number
    100
    56
    White blood cell count decreased
         subjects affected / exposed
    16 / 233 (6.87%)
    21 / 238 (8.82%)
         occurrences all number
    84
    87
    WEIGHT DECREASED
         subjects affected / exposed
    5 / 233 (2.15%)
    12 / 238 (5.04%)
         occurrences all number
    5
    13
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    22 / 233 (9.44%)
    33 / 238 (13.87%)
         occurrences all number
    24
    43
    Headache
         subjects affected / exposed
    44 / 233 (18.88%)
    51 / 238 (21.43%)
         occurrences all number
    71
    85
    Dizziness
         subjects affected / exposed
    24 / 233 (10.30%)
    28 / 238 (11.76%)
         occurrences all number
    25
    33
    Neuropathy peripheral
         subjects affected / exposed
    50 / 233 (21.46%)
    47 / 238 (19.75%)
         occurrences all number
    67
    72
    Paraesthesia
         subjects affected / exposed
    17 / 233 (7.30%)
    12 / 238 (5.04%)
         occurrences all number
    21
    14
    Peripheral sensory neuropathy
         subjects affected / exposed
    84 / 233 (36.05%)
    92 / 238 (38.66%)
         occurrences all number
    107
    129
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    14 / 233 (6.01%)
    17 / 238 (7.14%)
         occurrences all number
    42
    41
    Anaemia
         subjects affected / exposed
    39 / 233 (16.74%)
    39 / 238 (16.39%)
         occurrences all number
    82
    63
    Neutropenia
         subjects affected / exposed
    50 / 233 (21.46%)
    77 / 238 (32.35%)
         occurrences all number
    124
    254
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    17 / 233 (7.30%)
    20 / 238 (8.40%)
         occurrences all number
    30
    27
    Abdominal pain upper
         subjects affected / exposed
    13 / 233 (5.58%)
    13 / 238 (5.46%)
         occurrences all number
    14
    16
    Diarrhoea
         subjects affected / exposed
    72 / 233 (30.90%)
    88 / 238 (36.97%)
         occurrences all number
    128
    189
    Constipation
         subjects affected / exposed
    50 / 233 (21.46%)
    67 / 238 (28.15%)
         occurrences all number
    70
    108
    Dyspepsia
         subjects affected / exposed
    16 / 233 (6.87%)
    23 / 238 (9.66%)
         occurrences all number
    20
    40
    Toothache
         subjects affected / exposed
    8 / 233 (3.43%)
    15 / 238 (6.30%)
         occurrences all number
    9
    16
    Nausea
         subjects affected / exposed
    75 / 233 (32.19%)
    99 / 238 (41.60%)
         occurrences all number
    205
    310
    Stomatitis
         subjects affected / exposed
    26 / 233 (11.16%)
    42 / 238 (17.65%)
         occurrences all number
    35
    75
    Vomiting
         subjects affected / exposed
    36 / 233 (15.45%)
    47 / 238 (19.75%)
         occurrences all number
    63
    96
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    145 / 233 (62.23%)
    140 / 238 (58.82%)
         occurrences all number
    159
    149
    Nail discolouration
         subjects affected / exposed
    18 / 233 (7.73%)
    33 / 238 (13.87%)
         occurrences all number
    18
    37
    Nail disorder
         subjects affected / exposed
    13 / 233 (5.58%)
    13 / 238 (5.46%)
         occurrences all number
    13
    14
    Dry skin
         subjects affected / exposed
    7 / 233 (3.00%)
    18 / 238 (7.56%)
         occurrences all number
    7
    20
    Onychomadesis
         subjects affected / exposed
    6 / 233 (2.58%)
    15 / 238 (6.30%)
         occurrences all number
    6
    17
    Pruritis
         subjects affected / exposed
    10 / 233 (4.29%)
    15 / 238 (6.30%)
         occurrences all number
    12
    17
    Rash
         subjects affected / exposed
    31 / 233 (13.30%)
    58 / 238 (24.37%)
         occurrences all number
    36
    113
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    26 / 233 (11.16%)
    32 / 238 (13.45%)
         occurrences all number
    33
    53
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    53 / 233 (22.75%)
    53 / 238 (22.27%)
         occurrences all number
    86
    91
    Bone pain
         subjects affected / exposed
    20 / 233 (8.58%)
    11 / 238 (4.62%)
         occurrences all number
    32
    17
    Pain in extremity
         subjects affected / exposed
    21 / 233 (9.01%)
    23 / 238 (9.66%)
         occurrences all number
    23
    32
    Back pain
         subjects affected / exposed
    31 / 233 (13.30%)
    26 / 238 (10.92%)
         occurrences all number
    42
    32
    Myalgia
         subjects affected / exposed
    28 / 233 (12.02%)
    43 / 238 (18.07%)
         occurrences all number
    60
    83
    NECK PAIN
         subjects affected / exposed
    3 / 233 (1.29%)
    12 / 238 (5.04%)
         occurrences all number
    5
    13
    MUSCULOSKELETAL PAIN
         subjects affected / exposed
    5 / 233 (2.15%)
    12 / 238 (5.04%)
         occurrences all number
    8
    14
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    36 / 233 (15.45%)
    24 / 238 (10.08%)
         occurrences all number
    65
    54
    Bronchitis
         subjects affected / exposed
    12 / 233 (5.15%)
    11 / 238 (4.62%)
         occurrences all number
    12
    14
    Paronychia
         subjects affected / exposed
    7 / 233 (3.00%)
    13 / 238 (5.46%)
         occurrences all number
    9
    13
    Upper respiratory tract infection
         subjects affected / exposed
    11 / 233 (4.72%)
    25 / 238 (10.50%)
         occurrences all number
    14
    26
    Urinary tract infection
         subjects affected / exposed
    16 / 233 (6.87%)
    35 / 238 (14.71%)
         occurrences all number
    22
    47
    SINUSITIS
         subjects affected / exposed
    8 / 233 (3.43%)
    12 / 238 (5.04%)
         occurrences all number
    12
    15
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    10 / 233 (4.29%)
    15 / 238 (6.30%)
         occurrences all number
    13
    22
    Decreased appetite
         subjects affected / exposed
    42 / 233 (18.03%)
    55 / 238 (23.11%)
         occurrences all number
    65
    91

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Apr 2012
    The protocol was amended to reflect the updated development plans for the VEGF-A assay. In Study GO25632, the IMPACT platform and assay was to be used to support participant enrollment while the new in vitro diagnostic (IVD) assay for clinical use was being developed and validated in parallel with the study. A bridging study was to be conducted to validate the newly developed IVD assay using the IMPACT measurements from Study BO17708 (AVADO) as a reference. - A list of possible VEGF-A testing sites was added in order to clarify which countries the samples might be sent to for VEGF-A testing. - To clarify treatment guidelines in that bevacizumab/placebo treatment could continue until disease progression in the event that paclitaxel was discontinued.
    04 Oct 2012
    To clarify regarding contraceptive use and the designation of paclitaxel as a study drug. Paclitaxel specific exclusion criteria to reflect IMP designation. Thus, depending on local classification, paclitaxel could either be considered a NIMP or an IMP. - A section was added on the addition of an IRF to demonstrate, through a sensitivity analysis, the robustness of the investigator-determined PFS according to RECIST. - Modifications were made to the internal monitoring committee (replaced by the iDMC), with details of the periodic review of unblinded safety data.
    18 Oct 2013
    The definition of the end of the study was amended to the date when 394 deaths in the ITT population have been observed. This follow-up OS analysis is expected to occur approximately 5.2 years after 326 progression-free survival events have occurred (i.e., approximately 6.5 years after the first participant was randomized). - An interaction test of treatment effect (PFS) with the VEGF-A level was included as a secondary endpoint. - Participants who were still receiving bevacizumab at the end of the study were to be offered participation in the Avastin Long-Term Extension study (AvaLTE. Protocol MO25757) if this study was approved in the participant’s country. The objectives of Study MO25757 are to provide continued bevacizumab therapy as a single agent or in combination with an anti-cancer drug to participants with cancer who were previously enrolled in a bevacizumab study sponsored by F Hoffmann-La Roche Ltd. and Genentech Inc. and who derived benefit from the therapy administered.
    14 Sep 2015
    The protocol was amended to include an additional interim analysis for overall survival (OS) when the original projected number of events at the time of the primary progression free survival (PFS) analysis has been observed.

    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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