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    Clinical Trial Results:
    A Randomized Phase III Clinical Study of Bevacizumab Plus Capecitabine vs. Bevacizumab Alone as Maintenance Therapy in Patients with HER2-Negative Metastatic Breast Cancer That Has Not Progressed During First-Line Docetaxel Plus Bevacizumab Therapy

    Summary
    EudraCT number
    		 2008-006872-31
    Trial protocol
    		 ES   FR   IT  
    Global end of trial date
    14 Jun 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Jul 2016
    First version publication date
    06 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MO22223
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00929240
    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
    Final
    Date of interim/final analysis
    14 Jun 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Jun 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate whether maintenance therapy with bevacizumab plus capecitabine, compared to bevacizumab alone, can further increase Progression-Free Survival (PFS) in patients showing objective response or stable disease following initial therapy with bevacizumab plus (+) docetaxel.
    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 described in the following sections of the protocol.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Jul 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 9
    Country: Number of subjects enrolled
    Spain: 31
    Country: Number of subjects enrolled
    France: 54
    Country: Number of subjects enrolled
    Italy: 30
    Country: Number of subjects enrolled
    Brazil: 40
    Country: Number of subjects enrolled
    China: 25
    Country: Number of subjects enrolled
    Egypt: 13
    Country: Number of subjects enrolled
    India: 48
    Country: Number of subjects enrolled
    Turkey: 25
    Country: Number of subjects enrolled
    Hong Kong: 12
    Worldwide total number of subjects
    287
    EEA total number of subjects
    124
    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)
    238
    From 65 to 84 years
    49
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Screening was performed from Day -28 to Day 1 (Baseline).

    Period 1
    Period 1 title
    Initial Treatment Phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Initial Treatment Phase: Bevacizumab Plus (+) Docetaxel
    Arm description
    		 During the Initial Phase all participants received bevacizumab 15 milligrams per kilogram (mg/kg) intravenously (IV) on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or participant request for withdrawal, whichever occurred first. Participants also received docetaxel, a recommended dose of 100 milligrams per square meter (mg/m^2) IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m^2 of docetaxel could be administered at investigator's discretion. At the end of the Initial Treatment Phase, participants with an objective response (partial response [PR] or complete response [CR]) or stable disease (SD) following 3-6 cycles of bevacizumab + docetaxel were randomized to receive maintenance therapy with either bevacizumab alone or bevacizumab + capecitabine.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    During the Initial Phase all participants received bevacizumab 15 mg/kg IV on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or participant request for withdrawal, whichever occurred first.

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion in pre-filled syringe
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received docetaxel, a recommended dose of 100 mg/m^2 IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m^2 of docetaxel could be administered at investigator's discretion for a minimum of 3 cycles and a maximum of 6 cycles.

    Number of subjects in period 1
    		Initial Treatment Phase: Bevacizumab Plus (+) Docetaxel
    Started
    287
    Completed
    185
    Not completed
    102
         Adverse event, serious fatal
    2
         Consent withdrawn by subject
    13
         Physician decision
    4
         Disease progression
    41
         Health authority/Study termination
    3
         Adverse event, non-fatal
    31
         Participants who received no treatment
    3
         Protocol deviation
    5
    Period 2
    Period 2 title
    Maintenance Phase
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Maintenance Phase: Bevacizumab
    Arm description
    		 During the Initial Phase all participants received bevacizumab 15 mg/kg IV on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or participant request for withdrawal, whichever occurred first along with docetaxel, a recommended dose of 100 mg/m^2 IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m^2 of docetaxel could be administered at investigator's discretion. At the end of the Initial Phase, participants with an objective response (PR or CR) or SD received 15 mg/kg bevacizumab IV on Day 1 of each 3 week cycle until disease progression, unacceptable toxicity, participant request for withdrawal or end of study, whichever occurred first.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    During the Initial Phase all participants received bevacizumab 15 mg/kg IV on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or participant request for withdrawal, whichever occurred first.

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received docetaxel, a recommended dose of 100 mg/m^2 IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m^2 of docetaxel could be administered at investigator's discretion.

    Arm title
    		 Maintenance Phase: Bevacizumab + Capecitabine
    Arm description
    		 During the Initial Phase participants received bevacizumab 15 mg/kg IV on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or withdrawal, whichever occurred first, along with docetaxel, a recommended dose of 100 mg/m^2 IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m^2 of docetaxel could be administered at investigator's discretion. At the end of the Initial Phase, participants with an objective response were randomized to receive bevacizumab 15 mg/kg IV on Day 1 of each 3-week cycle plus capecitabine 1000 mg/m^2 twice daily on Days 1 to 14 of each 3 week cycle until disease progression, unacceptable toxicity, request for withdrawal or end of study, whichever occurred first. If one of the drugs was discontinued before disease progression, treatment was continued with the second drug until disease progression, unacceptable toxicity, withdrawal or end of study, whichever occurred first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    During the Initial Phase all participants received bevacizumab 15 milligrams per kilogram (mg/kg) intravenously (IV) on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or participant request for withdrawal, whichever occurred first.

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received docetaxel, a recommended dose of 100 mg/m^2 IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m^2 of docetaxel could be administered at investigator's discretion.

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received capecitabine 1000 mg/m^2 twice daily on Days 1 to 14 of each 3 week cycle until disease progression, unacceptable toxicity, request for withdrawal or end of study, whichever occurred first.

    Number of subjects in period 2
    		Maintenance Phase: Bevacizumab Maintenance Phase: Bevacizumab + Capecitabine
    Started
    94
    91
    Completed
    0
    0
    Not completed
    94
    91
         Consent withdrawn by subject
    2
    6
         Physician decision
    2
    1
         Disease progression
    73
    60
         Adverse event, non-fatal
    9
    12
         Health authority/Study termination
    1
    2
         Treatment ongoing at study termination
    -
    10
         Change of treatment
    4
    -
         Participant not treated
    2
    -
         Protocol deviation
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Initial Treatment Phase
    Reporting group description
    		 During the Initial Phase all participants received bevacizumab 15 mg/kg IV on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or participant request for withdrawal, whichever occurred first. Participants also received docetaxel, a recommended dose of 100 mg/m^2 IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m^2 of docetaxel could be administered at investigator's discretion. At the end of the Initial Treatment Phase, participants with an objective response (PR or CR) or SD following 3-6 cycles of bevacizumab + docetaxel were randomized to receive maintenance therapy with either bevacizumab alone or bevacizumab + capecitabine.

    Reporting group values
    		 Initial Treatment Phase Total
    Number of subjects
    		 287 287
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 52.5 ( 11.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 287 287
        Male
    		 0 0

    End points

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    End points reporting groups
    Reporting group title
    Initial Treatment Phase: Bevacizumab Plus (+) Docetaxel
    Reporting group description
    		 During the Initial Phase all participants received bevacizumab 15 milligrams per kilogram (mg/kg) intravenously (IV) on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or participant request for withdrawal, whichever occurred first. Participants also received docetaxel, a recommended dose of 100 milligrams per square meter (mg/m^2) IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m^2 of docetaxel could be administered at investigator's discretion. At the end of the Initial Treatment Phase, participants with an objective response (partial response [PR] or complete response [CR]) or stable disease (SD) following 3-6 cycles of bevacizumab + docetaxel were randomized to receive maintenance therapy with either bevacizumab alone or bevacizumab + capecitabine.
    Reporting group title
    Maintenance Phase: Bevacizumab
    Reporting group description
    		 During the Initial Phase all participants received bevacizumab 15 mg/kg IV on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or participant request for withdrawal, whichever occurred first along with docetaxel, a recommended dose of 100 mg/m^2 IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m^2 of docetaxel could be administered at investigator's discretion. At the end of the Initial Phase, participants with an objective response (PR or CR) or SD received 15 mg/kg bevacizumab IV on Day 1 of each 3 week cycle until disease progression, unacceptable toxicity, participant request for withdrawal or end of study, whichever occurred first.

    Reporting group title
    Maintenance Phase: Bevacizumab + Capecitabine
    Reporting group description
    		 During the Initial Phase participants received bevacizumab 15 mg/kg IV on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or withdrawal, whichever occurred first, along with docetaxel, a recommended dose of 100 mg/m^2 IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m^2 of docetaxel could be administered at investigator's discretion. At the end of the Initial Phase, participants with an objective response were randomized to receive bevacizumab 15 mg/kg IV on Day 1 of each 3-week cycle plus capecitabine 1000 mg/m^2 twice daily on Days 1 to 14 of each 3 week cycle until disease progression, unacceptable toxicity, request for withdrawal or end of study, whichever occurred first. If one of the drugs was discontinued before disease progression, treatment was continued with the second drug until disease progression, unacceptable toxicity, withdrawal or end of study, whichever occurred first.

    Primary: Percentage of Participants With Disease Progression or Death (Maintenance Phase Data Cutoff October 4, 2013)

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    End point title
    		 Percentage of Participants With Disease Progression or Death (Maintenance Phase Data Cutoff October 4, 2013) [1]
    End point description
    Progression Free Survival (PFS) was defined as the time from first study drug dosing (during the maintenance treatment phase) to the first documented disease progression or death, whichever occurred first. Progression was based on tumor assessment made by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST). Progressive Disease (PD) was defined as a 20 percent (%) or greater increase in the sum of the Longest Diameter (LD) of the target lesions taking as reference the smallest sum LD recorded or appearance of new lesions.
    End point type
    Primary
    End point timeframe
    Randomization, at the end of every third cycle (every 9 weeks) until the end of maintenance phase and every 3 months until disease progression or death until data cutoff on October 4, 2013, up to 4 year
    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: Statistical analysis was performed for Progression free survival which is defined as survival without disease progression or death.
    End point values
    		 Maintenance Phase: Bevacizumab Maintenance Phase: Bevacizumab + Capecitabine
    Number of subjects analysed
    94
    91
    Units: percentage of participants
        number (not applicable)
    88.3
    75.8
    No statistical analyses for this end point

    Primary: Progression Free Survival (Maintenance Phase Data Cutoff October 4, 2013)

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    End point title
    		 Progression Free Survival (Maintenance Phase Data Cutoff October 4, 2013)
    End point description
    PFS was defined as time from first study drug during the maintenance treatment phase dosing to first documented disease progression or death, whichever occurred first. Time to progression was defined as time from randomization to first documented disease progression defined per RECIST 1.0 criteria. Participants without an event at data cut-off or who were withdrawn from study without documented progression were censored at date of last tumor assessment when participant was known to be progression free. Participants who took other non-protocol anti-cancer drugs while being on study medication, and who were still event free were censored on date of first dose of anti-cancer drug. Participants without post-randomization tumor assessments but alive were censored at the time of randomization. Participants without post-randomization assessments, who died after randomization were considered to have the PFS event at date of death. Kaplan-Meier estimation was used for median time to PFS.
    End point type
    Primary
    End point timeframe
    Randomization, at the end of every third cycle (every 9 weeks) until the end of maintenance phase and every 3 months until disease progression or death until data cutoff on October 4, 2013, up to 4 years
    End point values
    		 Maintenance Phase: Bevacizumab Maintenance Phase: Bevacizumab + Capecitabine
    Number of subjects analysed
    94
    91
    Units: months
        median (confidence interval 95%)
    4.3 (3.9 to 6.8)
    11.9 (9.8 to 15.4)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Stratified by estrogen receptor (ER) status, visceral metastasis (yes/no), response to initial phase, and lactate dehydrogenase (LDH) level.
    Comparison groups
    Maintenance Phase: Bevacizumab v Maintenance Phase: Bevacizumab + Capecitabine
    Number of subjects included in analysis
    185
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.383
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.266
         upper limit
    		 0.551

    Secondary: Percentage of Participants With Best Overall Confirmed Objective Response of CR or PR Per RECIST 1.0 (Maintenance Phase Data Cutoff October 4, 2013)

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    End point title
    		 Percentage of Participants With Best Overall Confirmed Objective Response of CR or PR Per RECIST 1.0 (Maintenance Phase Data Cutoff October 4, 2013)
    End point description
    Objective Response was determined by the investigator using modified RECIST criteria, Version 1.0. An objective response was a complete or partial overall confirmed response as determined by investigators. CR was defined as complete disappearance of all target and non-target lesions and no new lesions. PR was defined as greater than or equal to (≥) 30 % decrease in the sum of appropriate diameters of all target measurable lesions, no progress in the non-measurable disease, and no new lesions. PD was defined as 20% increase in the sum of the longest diameter of target lesions and SD was defined as small changes that do not meet above criteria. Pearson-Clopper one-sample method was used for confidence intervals (CIs).
    End point type
    Secondary
    End point timeframe
    Randomization, at the end of every third cycle (every 9 weeks) until the end of maintenance phase and every 3 months until disease progression or death until data cutoff on October 4, 2013, up to 4 years
    End point values
    		 Maintenance Phase: Bevacizumab Maintenance Phase: Bevacizumab + Capecitabine
    Number of subjects analysed
    94
    91
    Units: percentage of participants
        number (confidence interval 95%)
    76.6 (66.7 to 84.7)
    85.7 (76.8 to 92.2)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Maintenance Phase: Bevacizumab + Capecitabine v Maintenance Phase: Bevacizumab
    Number of subjects included in analysis
    185
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.113
    Method
    		 Chi-squared
    Parameter type
    		 Mean difference (final values)
    Point estimate
    9.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.1
         upper limit
    		 20.3

    Secondary: Percentage of Participants With Clinical Benefit (CR, PR and SD) Per RECIST 1.0 (Data Cutoff October 4, 2013)

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    End point title
    		 Percentage of Participants With Clinical Benefit (CR, PR and SD) Per RECIST 1.0 (Data Cutoff October 4, 2013)
    End point description
    CR was defined as complete disappearance of all target and non-target lesions and no new lesions. PR was defined as ≥30% decrease in the sum of appropriate diameters of all target measurable lesions, no progress in the non-measurable disease, and no new lesions. SD was defined as small changes that do not meet above criteria with Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.
    End point type
    Secondary
    End point timeframe
    Randomization, at the end of every third cycle (every 9 weeks) until the end of maintenance phase and every 3 months until disease progression or death until data cutoff on October 4, 2013, up to 4 years
    End point values
    		 Maintenance Phase: Bevacizumab Maintenance Phase: Bevacizumab + Capecitabine
    Number of subjects analysed
    94
    91
    Units: percentage of participants
        number (confidence interval 95%)
    97.9 (92.5 to 99.7)
    98.9 (94 to 100)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Maintenance Phase: Bevacizumab v Maintenance Phase: Bevacizumab + Capecitabine
    Number of subjects included in analysis
    185
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.58
    Method
    		 Chi-squared
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.6
         upper limit
    		 4.6

    Secondary: Percentage of Participants Who Died (Maintenance Phase Data Cutoff October 4, 2013)

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    End point title
    		 Percentage of Participants Who Died (Maintenance Phase Data Cutoff October 4, 2013)
    End point description
    End point type
    Secondary
    End point timeframe
    Randomization, at the end of every third cycle (every 9 weeks) until the end of maintenance phase and every 3 months until disease progression or death until data cutoff on October 4, 2013, up to 4 years
    End point values
    		 Maintenance Phase: Bevacizumab Maintenance Phase: Bevacizumab + Capecitabine
    Number of subjects analysed
    94
    91
    Units: percentage of participants
        number (not applicable)
    56.4
    36.3
    No statistical analyses for this end point

    Secondary: Overall Survival (Maintenance Phase Data Cutoff October 4, 2013)

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    End point title
    		 Overall Survival (Maintenance Phase Data Cutoff October 4, 2013)
    End point description
    Duration of Overall Survival (OS) was defined as the time from randomization to death of any cause. The OS data for participants for whom no death was captured in the clinical database were censored at the last time they were known to be alive. Kaplan Meier estimation was used to determine OS. A value of 999 represents that the upper limit of the confidence interval was inestimable.
    End point type
    Secondary
    End point timeframe
    Randomization, at the end of every third cycle (every 9 weeks) until the end of maintenance phase and every 3 months until disease progression or death until data cutoff on October 4, 2013, up to 4 years
    End point values
    		 Maintenance Phase: Bevacizumab Maintenance Phase: Bevacizumab + Capecitabine
    Number of subjects analysed
    94
    91
    Units: Months
        median (confidence interval 95%)
    23.7 (18.5 to 31.7)
    39 (32.3 to 999)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Maintenance Phase: Bevacizumab + Capecitabine v Maintenance Phase: Bevacizumab
    Number of subjects included in analysis
    185
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0003 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.425
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.263
         upper limit
    		 0.685
    Notes
    [2] - Stratified by ER status, visceral metastasis (yes/no), response to initial phase, and LDH level.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Maintenance Phase: Bevacizumab v Maintenance Phase: Bevacizumab + Capecitabine
    Number of subjects included in analysis
    185
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.002 [3]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.516
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.334
         upper limit
    		 0.798
    Notes
    [3] - Unstratified analysis

    Secondary: Percentage of Participants Expected to Be Alive After 1 and 2 Years on Treatment (Maintenance Phase Data Cutoff October 4, 2013)

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    End point title
    		 Percentage of Participants Expected to Be Alive After 1 and 2 Years on Treatment (Maintenance Phase Data Cutoff October 4, 2013)
    End point description
    Probability of being alive after 1 and 2 years on treatment with 95% CIs was calculated using Kaplan Meier approach with LOGLOG transformation.
    End point type
    Secondary
    End point timeframe
    Years 1 and 2
    End point values
    		 Maintenance Phase: Bevacizumab Maintenance Phase: Bevacizumab + Capecitabine
    Number of subjects analysed
    94
    91
    Units: percentage of participants
    number (confidence interval 95%)
        1 Year
    71.6 (61.1 to 79.7)
    90.4 (81.8 to 95.1)
        2 Years
    49.4 (38.5 to 59.3)
    69 (57.6 to 77.9)
    No statistical analyses for this end point

    Secondary: Percentage Of Participants With PD or Death Due to PD (Maintenance Phase Data Cutoff October 4, 2013)

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    End point title
    		 Percentage Of Participants With PD or Death Due to PD (Maintenance Phase Data Cutoff October 4, 2013)
    End point description
    PD was defined per RECIST version 1.0 as 20% increase in the sum of the longest diameter of target lesions.
    End point type
    Secondary
    End point timeframe
    Randomization, at the end of every third cycle (every 9 weeks) until the end of maintenance phase and every 3 months until disease progression or death until data cutoff on October 4, 2013
    End point values
    		 Maintenance Phase: Bevacizumab Maintenance Phase: Bevacizumab + Capecitabine
    Number of subjects analysed
    94
    91
    Units: percentage of participants
        number (not applicable)
    88.3
    74.7
    No statistical analyses for this end point

    Secondary: Time To Progression (Maintenance Phase Data Cutoff October 4, 2013)

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    End point title
    		 Time To Progression (Maintenance Phase Data Cutoff October 4, 2013)
    End point description
    Time to Progression was defined as the time from randomization to the first documented disease progression (using investigator assessments of disease progression by RECIST 1.0). PD was defined as 20% increase in the sum of the longest diameter of target lesions.
    End point type
    Secondary
    End point timeframe
    Randomization, at the end of every third cycle (every 9 weeks) until the end of maintenance phase and every 3 months until disease progression or death until data cutoff on October 4, 2013
    End point values
    		 Maintenance Phase: Bevacizumab Maintenance Phase: Bevacizumab + Capecitabine
    Number of subjects analysed
    94
    91
    Units: Months
        median (confidence interval 95%)
    4.3 (3.9 to 6.8)
    11.9 (9.8 to 15.4)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Maintenance Phase: Bevacizumab v Maintenance Phase: Bevacizumab + Capecitabine
    Number of subjects included in analysis
    185
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001 [4]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.383
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.266
         upper limit
    		 0.551
    Notes
    [4] - Stratified by ER status, visceral metastasis (yes/no), response to initial phase, and LDH level.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Maintenance Phase: Bevacizumab v Maintenance Phase: Bevacizumab + Capecitabine
    Number of subjects included in analysis
    185
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001 [5]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.425
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.305
         upper limit
    		 0.591
    Notes
    [5] - Unstratified analysis

    Secondary: Quality of Life Assessed As Change From Baseline in Global Health Status Using The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - 30 (EORTC QLQ - C30) (Maintenance Phase Data Cutoff October 4, 2013)

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    End point title
    		 Quality of Life Assessed As Change From Baseline in Global Health Status Using The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - 30 (EORTC QLQ - C30) (Maintenance Phase Data Cutoff October 4, 2013)
    End point description
    The EORTC QLQ-C30 incorporates 9 multi-item scales: 5 functional scales (physical, role, cognitive, emotional, and social); 9 symptom scales (fatigue, pain, nausea and vomiting, dyspnoea, insomnia, appetite loss, constipation, diarrhea and financial difficulties); and a global health and quality-of-life scale. Most questions used 4 point scale (1 'Not at all' to 4 'Very much'; 2 questions used 7-point scale (1 'very poor' to 7 'Excellent'). Scores were averaged and transformed to 0-100 scale; higher score=better level of functioning or greater degree of symptoms. The change in global health status was determined to be the difference in values at baseline and each specific visit. The term ‘’baseline’’ refers to the time of randomization to the maintenance phase. Only timepoints with more than 10 participants in each treatment arm are presented. n=number of participants analyzed at the specific visit.
    End point type
    Secondary
    End point timeframe
    Baseline, Randomization and Cycles 3, 6, 9 and 12
    End point values
    		 Maintenance Phase: Bevacizumab Maintenance Phase: Bevacizumab + Capecitabine
    Number of subjects analysed
    83
    86
    Units: units on a scale
    number (confidence interval 95%)
        Randomization (n= 83, 86)
    -3.51 (-9.63 to 2.6)
    -4.46 (-9.4 to 0.48)
        Cycle 3 (n= 44, 52)
    0.76 (-6.65 to 8.17)
    -3.21 (-9.99 to 3.58)
        Cycle 6 (n= 26, 54)
    4.17 (-6.49 to 14.82)
    -5.4 (-11.67 to 0.87)
        Cycle 9 (n= 18, 37)
    8.8 (-4.57 to 22.17)
    -1.8 (-8.92 to 5.32)
        Cycle 12 (n= 12, 31)
    0.69 (-17.99 to 19.37)
    0 (-8.24 to 8.24)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Best Overall Confirmed Objective Response of CR or PR Per RECIST 1.0 (Initial Treatment Phase)

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    End point title
    		 Percentage of Participants With Best Overall Confirmed Objective Response of CR or PR Per RECIST 1.0 (Initial Treatment Phase)
    End point description
    Objective Response was determined by the investigator using RECIST criteria, Version 1.0. An objective response was a complete or partial overall confirmed response as determined by investigators. CR was defined as complete disappearance of all target and non-target lesions and no new lesions. PR was defined as ≥ 30% decrease in the sum of appropriate diameters of all target measurable lesions, no progress in the non-measurable disease, and no new lesions. Pearson-Clopper one-sample method was used for CI. Only participants who were not randomized at the end of the initial treatment phase were included in this analysis
    End point type
    Secondary
    End point timeframe
    Screening and at the end of every third cycle until randomization for an average of 18 weeks
    End point values
    		 Initial Treatment Phase: Bevacizumab Plus (+) Docetaxel
    Number of subjects analysed
    102
    Units: percentage of participants
        number (confidence interval 95%)
    8.8 (4.1 to 16.1)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Clinical Benefit (CR, PR and SD) Per RECIST 1.0 (Initial Treatment Phase)

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    End point title
    		 Percentage of Participants With Clinical Benefit (CR, PR and SD) Per RECIST 1.0 (Initial Treatment Phase)
    End point description
    CR was defined as complete disappearance of all target and non-target lesions and no new lesions. PR was defined as ≥30% decrease in the sum of appropriate diameters of all target measurable lesions, no progress in the non-measurable disease, and no new lesions. SD was defined as small changes that do not meet above criteria. Only participants who were not randomized at the end of the initial treatment phase were included in this analysis.
    End point type
    Secondary
    End point timeframe
    Screening and at the end of every third cycle until randomization for an average of 18 weeks
    End point values
    		 Initial Treatment Phase: Bevacizumab Plus (+) Docetaxel
    Number of subjects analysed
    102
    Units: percentage of participants
        number (confidence interval 95%)
    56.9 (46.7 to 66.6)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events (AEs) were recorded from the date of randomization until the end of study at the cutoff date of October 4, 2013.
    Adverse event reporting additional description
    AEs were recorded for the Safety population (all participants who received at least one dose of study drug during the maintenance phase). Only Grade 3 and above AEs have been captured per protocol.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Initial Treatment Phase: Bevacizumab + Docetaxel
    Reporting group description
    		 During the Initial Phase all participants received bevacizumab 15 mg/kg IV on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or participant request for withdrawal, whichever occurred first. Participants also received docetaxel, a recommended dose of 100 mg/m^2 IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m^2 of docetaxel could be administered at investigator's discretion. At the end of the Initial Treatment Phase, participants with an objective response (PR or CR) or SD following 3-6 cycles of bevacizumab + docetaxel were randomized to receive maintenance therapy with either bevacizumab alone or bevacizumab + capecitabine.

    Reporting group title
    Maintenance Phase: Bevacizumab
    Reporting group description
    		 During the Initial Phase all participants received bevacizumab 15 mg/kg IV on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or participant request for withdrawal, whichever occurred first along with docetaxel, a recommended dose of 100 mg/m^2 IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m^2 of docetaxel could be administered at investigator's discretion. At the end of the Initial Phase, participants with an objective response (PR or CR) or SD received 15 mg/kg bevacizumab IV on Day 1 of each 3 week cycle until disease progression, unacceptable toxicity, participant request for withdrawal or end of study, whichever occurred first.

    Reporting group title
    Maintenance Phase: Bevacizumab + Capecitabine
    Reporting group description
    		 During the Initial Phase participants received bevacizumab 15 mg/kg IV on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or withdrawal, whichever occurred first, along with docetaxel, a recommended dose of 100 mg/m^2 IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m^2 of docetaxel could be administered at investigator's discretion. At the end of the Initial Phase, participants with an objective response were randomized to receive bevacizumab 15 mg/kg IV on Day 1 of each 3-week cycle plus capecitabine 1000 mg/m^2 twice daily on Days 1 to 14 of each 3 week cycle until disease progression, unacceptable toxicity, request for withdrawal or end of study, whichever occurred first. If one of the drugs was discontinued before disease progression, treatment was continued with the second drug until disease progression, unacceptable toxicity, withdrawal or end of study, whichever occurred first.

    Serious adverse events
    		 Initial Treatment Phase: Bevacizumab + Docetaxel Maintenance Phase: Bevacizumab Maintenance Phase: Bevacizumab + Capecitabine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    78 / 284 (27.46%)
    7 / 92 (7.61%)
    10 / 91 (10.99%)
         number of deaths (all causes)
    54
    51
    33
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Large cell lung cancer
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 92 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 92 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Embolism
         subjects affected / exposed
    1 / 284 (0.35%)
    1 / 92 (1.09%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Embolism arterial
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 92 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 92 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    4 / 284 (1.41%)
    0 / 92 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 284 (1.06%)
    0 / 92 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 92 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ulcer
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 92 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory distress
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 92 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 284 (0.70%)
    0 / 92 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    2 / 284 (0.70%)
    0 / 92 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 284 (0.70%)
    0 / 92 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 92 (1.09%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Toxicity to various agents
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 92 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 92 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 92 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 92 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 92 (0.00%)
    2 / 91 (2.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 92 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 92 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 92 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 92 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Depressed level of consciousness
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 92 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    VIIth nerve paralysis
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 92 (1.09%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    28 / 284 (9.86%)
    0 / 92 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    29 / 30
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    17 / 284 (5.99%)
    0 / 92 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    18 / 18
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    3 / 284 (1.06%)
    0 / 92 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    2 / 284 (0.70%)
    0 / 92 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 92 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 92 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Intestinal perforation
         subjects affected / exposed
    2 / 284 (0.70%)
    0 / 92 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    2 / 284 (0.70%)
    0 / 92 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 284 (0.35%)
    1 / 92 (1.09%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 92 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 92 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 92 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 92 (1.09%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 92 (1.09%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal ulcer haemorrhage
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 92 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 92 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 92 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 92 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 92 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 92 (1.09%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Anuria
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 92 (1.09%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 92 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 92 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 92 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    5 / 284 (1.76%)
    1 / 92 (1.09%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 92 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 284 (0.70%)
    2 / 92 (2.17%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 284 (0.70%)
    0 / 92 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 92 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 284 (0.70%)
    0 / 92 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gallbladder empyema
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 92 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 92 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 92 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 92 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 92 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 92 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 92 (1.09%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Initial Treatment Phase: Bevacizumab + Docetaxel Maintenance Phase: Bevacizumab Maintenance Phase: Bevacizumab + Capecitabine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    40 / 284 (14.08%)
    4 / 92 (4.35%)
    32 / 91 (35.16%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    5 / 284 (1.76%)
    3 / 92 (3.26%)
    7 / 91 (7.69%)
         occurrences all number
    5
    4
    9
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    29 / 284 (10.21%)
    1 / 92 (1.09%)
    2 / 91 (2.20%)
         occurrences all number
    40
    1
    5
    Skin and subcutaneous tissue disorders
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    6 / 284 (2.11%)
    0 / 92 (0.00%)
    29 / 91 (31.87%)
         occurrences all number
    7
    0
    48

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 May 2010
    • Addition of biomarker collection to explore potential single-nucleotide polymorphisms (SNPs) that may be associated with efficacy and/or safety of bevacizumab therapy in patients with locally recurrent or metastatic breast cancer. • Inclusion of new guidance for the management of proteinuria in bevacizumab studies, to make the management of proteinuria the same irrespective of whether it was a first or subsequent occurrence. • Inclusion of new guidance to clarify SAE collection throughout the study, from the time informed consent was signed onwards. In addition, the stopping rules for bevacizumab treatment were corrected to include Grade 4 venous thrombosis and a new section regarding reversible posterior leucoencephalopathy syndrome was added for consistency with other bevacizumab studies. • Updated the guidance for capecitabine dosing and dose modifications to include numbers of tablets based on the 500 mg tablet (which was the formulation provided for this study).
    12 Aug 2012
    • Updated the patient follow-up for PFS and OS to until 24 months after the last patient had been randomized rather than until at least 24 months after the last patient had been enrolled. Randomization was selected as the reference point (replacing enrolment) as this allowed for a longer follow-up, and therefore more events for the analysis. • For China only, included that assessments such as physical examination, vital signs, ECOG PS, laboratory evaluations (specified parameters) and AEs must be performed at the beginning of each treatment cycle (before study drug administration), rather than only if clinically indicated. • Updated the guidance for deaths and other SAEs to be reported to Roche within 24 hours of the investigator becoming aware of the event rather than being reported within one working day. • Updated the guidance that a pregnancy occurring up to 6 months after completion of bevacizumab must be reported to the investigator rather than the previous interval of up to 90 days. • Established an Independent Data Monitoring Committee (IDMC), to independently evaluate the safety of the patients participating in the study.
    06 Sep 2013
    Updated the end of study information to state that the study and investigational sites were to be closed as soon as approval from the regulatory authority and ethics committee occurred. At this time, patients who were still receiving study medication (bevacizumab and/or capecitabine) were to end their study participation. Based on the physician’s decision, treatment with bevacizumab and/or capecitabine could be prolonged in accordance with the standard of care and the cost was to be refunded by the Sponsor until disease progression, as initially planned in the protocol. Alternatively, if the Avastin® long-term extension study (AvaLTE / MO25757) was approved in the patients’ country, patients were to be offered participation in this study.

    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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