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    Clinical Trial Results:
    A Double-Blind, Placebo-Controlled, Randomised, Phase II Study Evaluating the Efficacy and Safety of Addition of Continuous Multiple Line Bevacizumab Treatment to Lomustine in Second (2nd)-Line Followed by Standard of Care (SOC) in Third (3rd)-Line and Beyond Compared to Addition of Placebo, Following First Progression of Disease (PD1) in Patients with Glioblastoma (GBM) After First (1st)-Line Treatment with Radiotherapy, Temozolomide and Bevacizumab

    Summary
    EudraCT number
    		 2012-003138-17
    Trial protocol
    		 AT   LT   IT   IE   EE   GB   LV   ES   FI   SE   PT   BG   GR   HR  
    Global end of trial date
    05 May 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 May 2018
    First version publication date
    12 May 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MO28347
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01860638
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Study Acronym: TAMIGA
    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 61 6878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, 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
    05 May 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 May 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To assess the efficacy of addition of continuous multiple line bevacizumab treatment to lomustine in 2nd-line followed by SOC in 3rd-line and beyond compared to addition of bevacizumab-placebo, as measured by overall survival (OS) from randomization at first-line disease progression (PD1).
    Protection of trial subjects
    This study was conducted in full conformance with the International Council for Harmonisation (ICH) E6 guideline for Good Clinical Practice (GCP) and the principles of the Declaration of Helsinki, or the laws and regulations of the country in which the research was conducted, whichever afforded the greater protection to the individual. The study complied with the requirements of the ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for Expedited Reporting). The study also complied with the European Union (EU) Clinical Trial Directive (2001/20/EC).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Aug 2013
    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
    Austria: 25
    Country: Number of subjects enrolled
    Bulgaria: 6
    Country: Number of subjects enrolled
    Croatia: 4
    Country: Number of subjects enrolled
    Estonia: 2
    Country: Number of subjects enrolled
    France: 68
    Country: Number of subjects enrolled
    Greece: 20
    Country: Number of subjects enrolled
    Italy: 62
    Country: Number of subjects enrolled
    Latvia: 4
    Country: Number of subjects enrolled
    Portugal: 3
    Country: Number of subjects enrolled
    Romania: 24
    Country: Number of subjects enrolled
    Spain: 40
    Country: Number of subjects enrolled
    Sweden: 6
    Country: Number of subjects enrolled
    Turkey: 10
    Country: Number of subjects enrolled
    United Kingdom: 22
    Worldwide total number of subjects
    296
    EEA total number of subjects
    286
    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)
    215
    From 65 to 84 years
    81
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 360 participants were screened, out of which, 296 participants were enrolled and treated at least once in this study.

    Period 1
    Period 1 title
    1st-Line (1L) Treatment
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 1L Bevacizumab
    Arm description
    		 Participants received 1L treatment with radiotherapy, temozolomide, and bevacizumab. All 3 treatments were given concurrently for the first 6 weeks, followed by maintenance therapy consisting of 6 cycles (of 28 days each) of temozolomide plus bevacizumab, followed by bevacizumab monotherapy until PD1 or unacceptable toxicity/consent withdrawal.
    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
    Bevacizumab was administered at a dose of 10 milligrams per kilogram (mg/kg) as intravenous (IV) infusion every 2 weeks (Q2W) for first 30 weeks, followed by bevacizumab at a dose of 15 mg/kg as IV infusion every 3 weeks (Q3W) as monotherapy until PD1 or unacceptable toxicity/consent withdrawal.

    Number of subjects in period 1
    		1L Bevacizumab
    Started
    296
    Completed
    123
    Not completed
    173
         Adverse Event (AE)/Serious Adverse Event (SAE)
    71
         Participant Decision
    12
         Consent withdrawn by subject
    15
         Physician decision
    24
         Non-Compliance
    9
         Death
    14
         Administrative/Other
    14
         Protocol deviation
    1
         Treatment Ongoing at data cut-off date
    13
    Period 2
    Period 2 title
    2L Treatment
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 2L: Placebo + Lomustine
    Arm description
    		 At PD1, eligible participants for 2L therapy who were randomized to this group received bevacizumab-placebo plus lomustine until PD2 or unacceptable toxicity/consent withdrawal.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bevacizumab-Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo matched to bevacizumab was administered as IV infusion Q2W until PD2 or unacceptable toxicity/consent withdrawal.

    Investigational medicinal product name
    Lomustine
    Investigational medicinal product code
    Other name
    Cecenu
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Lomustine was administered at a dose of 90 milligrams per square meter (mg/m^2) orally (PO) every 6 weeks (Q6W), with a cap of 160 mg/m^2 per dose. In the absence of hematologic toxicity following the first dose, the second and subsequent doses could be increased up to 110 mg/m^2 PO Q6W, with a cap of 200 mg/m^2 per dose until PD2 or unacceptable toxicity/consent withdrawal.

    Arm title
    		 2L: Bevacizumab + Lomustine
    Arm description
    		 At PD1, eligible participants for 2L therapy who were randomized to this group received bevacizumab plus lomustine until PD2 or unacceptable toxicity/consent withdrawal.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lomustine
    Investigational medicinal product code
    Other name
    Cecenu
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Lomustine was administered at a dose of 90 mg/m^2 PO Q6W, with a cap of 160 mg/m^2 per dose. In the absence of hematologic toxicity following the first dose, the second and subsequent doses could be increased up to 110 mg/m^2 PO Q6W, with a cap of 200 mg/m^2 per dose until PD2 or unacceptable toxicity/consent withdrawal.

    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
    Bevacizumab was administered at a dose of 10 mg/kg as IV infusion Q2W until PD2 or unacceptable toxicity/consent withdrawal.

    Number of subjects in period 2
    		2L: Placebo + Lomustine 2L: Bevacizumab + Lomustine
    Started
    62
    61
    Completed
    25
    25
    Not completed
    37
    36
         Participant Decision
    3
    4
         Consent withdrawn by subject
    6
    4
         Physician decision
    11
    10
         Non-Compliance
    -
    1
         Death
    3
    5
         Administrative/Other
    5
    4
         AE/SAE
    8
    6
         Treatment Ongoing at data cut-off date
    1
    2
    Period 3
    Period 3 title
    3L Treatment
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 3L: Placebo + SOC
    Arm description
    		 After PD2, participants continued 3L treatment as per assigned arm and received bevacizumab-placebo plus the appropriate SOC treatment (generally used to treat recurrence) at the discretion of the investigator until PD3 or unacceptable toxicity/consent withdrawal.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Bevacizumab-Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo matched to bevacizumab was administered as IV infusion Q2W until PD3 or unacceptable toxicity/consent withdrawal.

    Arm title
    		 3L: Bevacizumab + SOC
    Arm description
    		 After PD2, participants continued 3L treatment as per assigned arm and received bevacizumab plus the appropriate SOC treatment (generally used to treat recurrence) at the discretion of the investigator until PD3 or unacceptable toxicity/consent withdrawal.
    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
    Bevacizumab was administered at a dose of 10 mg/kg as IV infusion Q2W until PD3 or unacceptable toxicity/consent withdrawal.

    Number of subjects in period 3
    		3L: Placebo + SOC 3L: Bevacizumab + SOC
    Started
    25
    25
    Completed
    9
    9
    Not completed
    16
    16
         Participant Decision
    2
    3
         Consent withdrawn by subject
    1
    -
         Physician decision
    5
    7
         Death
    4
    3
         Administrative/Other
    2
    -
         AE/SAE
    -
    2
         Treatment Ongoing at data cut-off date
    1
    1
         Protocol deviation
    1
    -
    Period 4
    Period 4 title
    4L Treatment
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 4L: Placebo + SOC
    Arm description
    		 After PD3, participants continued 4L treatment as per assigned arm and received bevacizumab-placebo plus the appropriate SOC treatment (generally used to treat recurrence) at the discretion of the investigator until PD4 or unacceptable toxicity/consent withdrawal.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Bevacizumab-Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo matched to bevacizumab was administered as IV infusion Q2W until PD4 or unacceptable toxicity/consent withdrawal.

    Arm title
    		 4L: Bevacizumab + SOC
    Arm description
    		 After PD3, participants continued 4L treatment as per assigned arm and received bevacizumab plus the appropriate SOC treatment (generally used to treat recurrence) at the discretion of the investigator until PD4 or unacceptable toxicity/consent withdrawal.
    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
    Bevacizumab was administered at a dose of 10 mg/kg as IV infusion Q2W until PD4 or unacceptable toxicity/consent withdrawal.

    Number of subjects in period 4
    		4L: Placebo + SOC 4L: Bevacizumab + SOC
    Started
    9
    9
    Completed
    2
    2
    Not completed
    7
    7
         Participant Decision
    -
    2
         Physician decision
    3
    2
         Death
    -
    1
         Administrative/Other
    2
    1
         AE/SAE
    1
    1
         Treatment Ongoing at data cut-off date
    1
    -
    Period 5
    Period 5 title
    5L Treatment
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 5L: Placebo + SOC
    Arm description
    		 After PD4, participants continued 5L treatment as per assigned arm and received bevacizumab-placebo plus the appropriate SOC treatment (generally used to treat recurrence) at the discretion of the investigator until PD5 or unacceptable toxicity/consent withdrawal.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Bevacizumab-Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo matched to bevacizumab was administered as IV infusion Q2W until PD5 or unacceptable toxicity/consent withdrawal.

    Arm title
    		 5L: Bevacizumab + SOC
    Arm description
    		 After PD4, participants continued 5L treatment as per assigned arm and received bevacizumab plus the appropriate SOC treatment (generally used to treat recurrence) at the discretion of the investigator until PD5 or unacceptable toxicity/consent withdrawal.
    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
    Bevacizumab was administered at a dose of 10 mg/kg as IV infusion Q2W until PD5 or unacceptable toxicity/consent withdrawal.

    Number of subjects in period 5
    		5L: Placebo + SOC 5L: Bevacizumab + SOC
    Started
    2
    2
    Completed
    0
    1
    Not completed
    2
    1
         Physician decision
    2
    1
    Period 6
    Period 6 title
    6L Treatment
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Arm title
    		 6L: Bevacizumab + SOC
    Arm description
    		 After PD5, participants continued 6L treatment as per assigned arm and received bevacizumab plus the appropriate SOC treatment (generally used to treat recurrence) at the discretion of the investigator until PD6 or unacceptable toxicity/consent withdrawal.
    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
    Bevacizumab was administered at a dose of 10 mg/kg as IV infusion Q2W until PD6 or unacceptable toxicity/consent withdrawal.

    Number of subjects in period 6
    		6L: Bevacizumab + SOC
    Started
    1
    Completed
    0
    Not completed
    1
         Death
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    1L Bevacizumab
    Reporting group description
    		 Participants received 1L treatment with radiotherapy, temozolomide, and bevacizumab. All 3 treatments were given concurrently for the first 6 weeks, followed by maintenance therapy consisting of 6 cycles (of 28 days each) of temozolomide plus bevacizumab, followed by bevacizumab monotherapy until PD1 or unacceptable toxicity/consent withdrawal.

    Reporting group values
    		 1L Bevacizumab Total
    Number of subjects
    		 296 296
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55.9 ( 11.85 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 104 104
        Male
    		 192 192

    End points

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    End points reporting groups
    Reporting group title
    1L Bevacizumab
    Reporting group description
    		 Participants received 1L treatment with radiotherapy, temozolomide, and bevacizumab. All 3 treatments were given concurrently for the first 6 weeks, followed by maintenance therapy consisting of 6 cycles (of 28 days each) of temozolomide plus bevacizumab, followed by bevacizumab monotherapy until PD1 or unacceptable toxicity/consent withdrawal.
    Reporting group title
    2L: Placebo + Lomustine
    Reporting group description
    		 At PD1, eligible participants for 2L therapy who were randomized to this group received bevacizumab-placebo plus lomustine until PD2 or unacceptable toxicity/consent withdrawal.

    Reporting group title
    2L: Bevacizumab + Lomustine
    Reporting group description
    		 At PD1, eligible participants for 2L therapy who were randomized to this group received bevacizumab plus lomustine until PD2 or unacceptable toxicity/consent withdrawal.
    Reporting group title
    3L: Placebo + SOC
    Reporting group description
    		 After PD2, participants continued 3L treatment as per assigned arm and received bevacizumab-placebo plus the appropriate SOC treatment (generally used to treat recurrence) at the discretion of the investigator until PD3 or unacceptable toxicity/consent withdrawal.

    Reporting group title
    3L: Bevacizumab + SOC
    Reporting group description
    		 After PD2, participants continued 3L treatment as per assigned arm and received bevacizumab plus the appropriate SOC treatment (generally used to treat recurrence) at the discretion of the investigator until PD3 or unacceptable toxicity/consent withdrawal.
    Reporting group title
    4L: Placebo + SOC
    Reporting group description
    		 After PD3, participants continued 4L treatment as per assigned arm and received bevacizumab-placebo plus the appropriate SOC treatment (generally used to treat recurrence) at the discretion of the investigator until PD4 or unacceptable toxicity/consent withdrawal.

    Reporting group title
    4L: Bevacizumab + SOC
    Reporting group description
    		 After PD3, participants continued 4L treatment as per assigned arm and received bevacizumab plus the appropriate SOC treatment (generally used to treat recurrence) at the discretion of the investigator until PD4 or unacceptable toxicity/consent withdrawal.
    Reporting group title
    5L: Placebo + SOC
    Reporting group description
    		 After PD4, participants continued 5L treatment as per assigned arm and received bevacizumab-placebo plus the appropriate SOC treatment (generally used to treat recurrence) at the discretion of the investigator until PD5 or unacceptable toxicity/consent withdrawal.

    Reporting group title
    5L: Bevacizumab + SOC
    Reporting group description
    		 After PD4, participants continued 5L treatment as per assigned arm and received bevacizumab plus the appropriate SOC treatment (generally used to treat recurrence) at the discretion of the investigator until PD5 or unacceptable toxicity/consent withdrawal.
    Reporting group title
    6L: Bevacizumab + SOC
    Reporting group description
    		 After PD5, participants continued 6L treatment as per assigned arm and received bevacizumab plus the appropriate SOC treatment (generally used to treat recurrence) at the discretion of the investigator until PD6 or unacceptable toxicity/consent withdrawal.

    Subject analysis set title
    Placebo + Lomustine/SOC (ITT)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    At PD1, eligible participants for 2L therapy who were randomized to this group received bevacizumab-placebo plus lomustine until PD2. After PD2, participants continued 3L and subsequent lines of treatment with bevacizumab-placebo plus the appropriate SOC treatment (generally used to treat recurrence) at the discretion of the investigator. Participants were analyzed as randomized.

    Subject analysis set title
    Bevacizumab + Lomustine/SOC (ITT)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    At PD1, eligible participants for 2L therapy who were randomized to this group received bevacizumab plus lomustine until PD2. After PD2, participants continued 3L and subsequent lines of treatment with bevacizumab plus the appropriate SOC treatment (generally used to treat recurrence) at the discretion of the investigator. Participants were analyzed as randomized.

    Subject analysis set title
    No 2L received (Safety)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants who discontinued before randomization or who did not receive any study treatment after randomization were analyzed as 'No 2L received'.

    Subject analysis set title
    Placebo + Lomustine/SOC (Safety)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    At PD1, eligible participants for 2L therapy who were randomized to this group received bevacizumab-placebo plus lomustine until PD2. After PD2, participants continued 3L and subsequent lines of treatment with bevacizumab-placebo plus the appropriate SOC treatment (generally used to treat recurrence) at the discretion of the investigator and. Participants were analyzed as treated.

    Subject analysis set title
    Bevacizumab + Lomustine/SOC (Safety)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    At PD1, eligible participants for 2L therapy who were randomized to this group received bevacizumab plus lomustine until PD2. After PD2, participants continued 3L and subsequent lines of treatment with bevacizumab plus the appropriate SOC treatment (generally used to treat recurrence) at the discretion of the investigator. Participants were analyzed as treated.

    Subject analysis set title
    Placebo + Lomustine/SOC (Safety 2L+)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    At PD1, eligible participants for 2L therapy who were randomized to this group received bevacizumab-placebo plus lomustine until PD2. After PD2, participants continued 3L treatment with bevacizumab-placebo plus the appropriate SOC treatment (generally used to treat recurrence) at the discretion of the investigator. Analysis set included all participants who received at least one dose of 2L study treatment. Participants were analyzed as treated during 2L and 3L.

    Subject analysis set title
    Bevacizumab + Lomustine/SOC (Safety 2L+)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    At PD1, eligible participants for 2L therapy who were randomized to this group received bevacizumab plus lomustine until PD2. After PD2, participants continued 3L treatment with bevacizumab plus the appropriate SOC treatment (generally used to treat recurrence) at the discretion of the investigator. Analysis set included all participants who received at least one dose of 2L study treatment. Participants were analyzed as treated during 2L and 3L.

    Subject analysis set title
    Placebo + Lomustine/SOC (Safety 4L+)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    After PD3, participants who chose to continue their assigned treatment received 4L and later lines of treatment with bevacizumab-placebo plus the appropriate SOC treatment (generally used to treat recurrence) at the discretion of the investigator. Analysis set included all participants who received at least one dose of 4L study treatment. Participants were analyzed as treated during 4L and later lines.

    Subject analysis set title
    Bevacizumab + Lomustine/SOC (Safety 4L+)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    After PD3, participants who chose to continue their assigned treatment received 4L and later lines of treatment with bevacizumab plus the appropriate SOC treatment (generally used to treat recurrence) at the discretion of the investigator. Analysis set included all participants who received at least one dose of 4L study treatment. Participants were analyzed as treated during 4L and later lines.

    Subject analysis set title
    Cross-over (Safety 4L+)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    After PD3, participants who chose to cross-over their treatment from bevacizumab-placebo to bevacizumab received 4L and later lines of treatment with bevacizumab plus the appropriate SOC treatment (generally used to treat recurrence) at the discretion of the investigator. Analysis set included all participants who received at least one dose of 4L study treatment. Participants were analyzed as treated during 4L and later lines.

    Primary: Percentage of Participants Who Died of any Cause From Randomization until End of Study

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    End point title
    		 Percentage of Participants Who Died of any Cause From Randomization until End of Study [1]
    End point description
    Percentage of participants who died of any cause from randomization/PD1 until end of study was reported. Analysis was performed on Intent-to-treat (ITT) Population, which included all randomized participants. Participants were analyzed as randomized.
    End point type
    Primary
    End point timeframe
    From randomization at PD1 until death from any cause or end of study (overall approximately 35 months)
    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: Results were reported descriptively and were not planned to be analyzed for statistically significant differences between groups
    End point values
    		 Placebo + Lomustine/SOC (ITT) Bevacizumab + Lomustine/SOC (ITT)
    Number of subjects analysed
    62
    61
    Units: percentage of participants
        number (not applicable)
    75.8
    83.6
    No statistical analyses for this end point

    Primary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    Overall survival was defined as the time from randomization until death from any cause. Participants who were alive at the time of analysis (clinical cut-off) and participants who were lost to follow-up were censored at their last clinical assessment date. Median OS time and 95 percent (%) confidence interval (CI) were estimated using Kaplan-Meier method. Analysis was performed on ITT Population.
    End point type
    Primary
    End point timeframe
    From randomization at PD1 until death from any cause or end of study (overall approximately 35 months)
    End point values
    		 Placebo + Lomustine/SOC (ITT) Bevacizumab + Lomustine/SOC (ITT)
    Number of subjects analysed
    62
    61
    Units: months
        median (confidence interval 95%)
    5.5 (3.9 to 7.2)
    6.4 (5.1 to 8.1)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Test stratified by time to PD1 (before versus after completion of 1L maintenance therapy) and Eastern Cooperative Oncology Group Performance Status (ECOG PS) at randomization (0 versus 1/2).
    Comparison groups
    Placebo + Lomustine/SOC (ITT) v Bevacizumab + Lomustine/SOC (ITT)
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.59
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo + Lomustine/SOC (ITT) v Bevacizumab + Lomustine/SOC (ITT)
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.04
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 1.37

    Secondary: Percentage of Participants Alive at 6, 12, and 18 Months After Randomization

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    End point title
    		 Percentage of Participants Alive at 6, 12, and 18 Months After Randomization
    End point description
    Percentage of participants alive (event-free rate) and 95% CI were estimated using Kaplan-Meier method. Analysis was performed on ITT Population. Here, 'n' signifies number of participants remaining at risk at indicated time point for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    At 6, 12, and 18 months after randomization/PD1 (overall up to approximately 35 months)
    End point values
    		 Placebo + Lomustine/SOC (ITT) Bevacizumab + Lomustine/SOC (ITT)
    Number of subjects analysed
    62
    61
    Units: percentage of participants
    number (confidence interval 95%)
        6 months (n=24,30)
    46.2 (32.8 to 58.5)
    55.4 (41.4 to 67.3)
        12 months (n=7,5)
    16.5 (7.5 to 28.5)
    11.7 (4.6 to 22.5)
        18 months (n=4,2)
    9.4 (3.1 to 20.1)
    4.7 (0.9 to 13.7)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    6 Months: Two-sided log-rank test stratified by time to PD1 (before versus after completion of 1L maintenance therapy) and ECOG PS at randomization (0 versus 1/2). Correct number of subjects included in analysis=54.
    Comparison groups
    Placebo + Lomustine/SOC (ITT) v Bevacizumab + Lomustine/SOC (ITT)
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    Method
    Parameter type
    		 Difference in OS Rate
    Point estimate
    9.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.3
         upper limit
    		 27.7
    Notes
    [2] - The 95% CI was calculated using Greenwood’s formula.
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    18 Months: Two-sided log-rank test stratified by time to PD1 (before versus after completion of 1L maintenance therapy) and ECOG PS at randomization (0 versus 1/2). Correct number of subjects included in analysis=6.
    Comparison groups
    Placebo + Lomustine/SOC (ITT) v Bevacizumab + Lomustine/SOC (ITT)
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    Method
    Parameter type
    		 Difference in OS Rate
    Point estimate
    -4.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.4
         upper limit
    		 5.9
    Notes
    [3] - The 95% CI was calculated using Greenwood’s formula.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    12 Months: Two-sided log-rank test stratified by time to PD1 (before versus after completion of 1L maintenance therapy) and ECOG PS at randomization (0 versus 1/2). Correct number of subjects included in analysis=12.
    Comparison groups
    Placebo + Lomustine/SOC (ITT) v Bevacizumab + Lomustine/SOC (ITT)
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    Method
    Parameter type
    		 Difference in OS Rate
    Point estimate
    -4.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -18.9
         upper limit
    		 9.4
    Notes
    [4] - The 95% CI was calculated using Greenwood’s formula.

    Secondary: Percentage of Participants with PD2 (Assessed According to Modified Response Assessment in Neuro-Oncology [RANO] Criteria) or Death From Any Cause

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    End point title
    		 Percentage of Participants with PD2 (Assessed According to Modified Response Assessment in Neuro-Oncology [RANO] Criteria) or Death From Any Cause
    End point description
    As per the modified RANO criteria, progression was defined as: greater than or equal to (>/=) 25% increase in the sum of products of perpendicular diameters of enhancing lesions compared with the smallest tumor measurement obtained either at baseline or at best response, on stable/increasing corticosteroids dose; significant increase in non-enhancing T2/fluid attenuated inversion recovery (FLAIR) lesions, not caused by comorbid events; any new lesions; clear clinical deterioration (not attributable to other non-tumor causes or decreases in corticosteroid dose); failure to return for evaluation due to death or deteriorating condition; or clear progression of non-measurable disease. Analysis was performed on ITT Population.
    End point type
    Secondary
    End point timeframe
    From first administration of randomized treatment until PD2 or death from any cause (overall approximately 18 months)
    End point values
    		 Placebo + Lomustine/SOC (ITT) Bevacizumab + Lomustine/SOC (ITT)
    Number of subjects analysed
    62
    61
    Units: percentage of participants
        number (not applicable)
    95.2
    95.1
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS) on 2L Treatment Assessed According to Modified RANO Criteria

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    End point title
    		 Progression-Free Survival (PFS) on 2L Treatment Assessed According to Modified RANO Criteria
    End point description
    PFS on 2L treatment was defined as the time from randomization/PD1 until PD2 or death from any cause, whichever occurred first. As per the modified RANO criteria, progression was defined as: >/=25% increase in the sum of products of perpendicular diameters of enhancing lesions compared with the smallest tumor measurement obtained on study, on stable/increasing corticosteroid dose; significant increase in non-enhancing T2/FLAIR lesions, not caused by comorbid events; any new lesions; clear clinical deterioration (not attributable to other non-tumor causes or decreases in corticosteroid dose); failure to return for evaluation due to death or deteriorating condition; or clear progression of non-measurable disease. Participants without an event were censored at the date of their last evaluable tumor assessment or, if this is not available, at date of randomization. Median PFS on 2L treatment and 95% CI were estimated using Kaplan-Meier method. Analysis was performed on ITT Population.
    End point type
    Secondary
    End point timeframe
    From first administration of randomized treatment until PD2 or death from any cause (overall approximately 18 months)
    End point values
    		 Placebo + Lomustine/SOC (ITT) Bevacizumab + Lomustine/SOC (ITT)
    Number of subjects analysed
    62
    61
    Units: months
        median (confidence interval 95%)
    1.8 (1.4 to 2.1)
    2.3 (1.9 to 2.7)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Test stratified by time to PD1 (before versus after completion of 1L maintenance therapy) and ECOG PS at randomization (0 versus 1/2).
    Comparison groups
    Placebo + Lomustine/SOC (ITT) v Bevacizumab + Lomustine/SOC (ITT)
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 1.04

    Secondary: Percentage of Participants with PD3 (Assessed According to Modified RANO Criteria) or Death from any Cause

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    End point title
    		 Percentage of Participants with PD3 (Assessed According to Modified RANO Criteria) or Death from any Cause
    End point description
    As per the modified RANO criteria, progression was defined as: >/=25% increase in the sum of products of perpendicular diameters of enhancing lesions compared with the smallest tumor measurement obtained either at baseline or at best response, on stable/increasing corticosteroid dose; significant increase in non-enhancing T2/FLAIR lesions, not caused by comorbid events; any new lesions; clear clinical deterioration (not attributable to other non-tumor causes or decreases in corticosteroid dose); failure to return for evaluation due to death or deteriorating condition; or clear progression of non-measurable disease. Analysis was performed on ITT Population.
    End point type
    Secondary
    End point timeframe
    From first administration of randomized treatment until PD3 or death from any cause (overall approximately 35 months)
    End point values
    		 Placebo + Lomustine/SOC (ITT) Bevacizumab + Lomustine/SOC (ITT)
    Number of subjects analysed
    62
    61
    Units: percentage of participants
        number (not applicable)
    77.4
    65.6
    No statistical analyses for this end point

    Secondary: PFS on 3L Treatment Assessed According to Modified RANO Criteria

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    End point title
    		 PFS on 3L Treatment Assessed According to Modified RANO Criteria
    End point description
    PFS on 3L treatment: the time from randomization/PD1 until PD3 or death from any cause, whichever occurred first. As per the modified RANO criteria, progression was defined as: >/=25% increase in sum of products of perpendicular diameters of enhancing lesions compared to smallest measurements on study, on stable/increasing corticosteroid dose; significant increase in non-enhancing T2/FLAIR lesions, not caused by comorbid events; any new lesions; clear clinical deterioration (not attributable to other non-tumor causes or decreases in corticosteroid dose); failure to return for evaluation due to death or deteriorating condition; or clear progression of non-measurable disease. Participants who were alive and for whom PD3 was not observed were censored at the last time known to be alive. Participants who died (at PD2/before PD3) were censored at the date of death. Median PFS on 3L treatment and 95% CI were estimated using Kaplan-Meier method. Analysis was performed on ITT Population.
    End point type
    Secondary
    End point timeframe
    From first administration of randomized treatment until PD3 or death from any cause (overall approximately 35 months)
    End point values
    		 Placebo + Lomustine/SOC (ITT) Bevacizumab + Lomustine/SOC (ITT)
    Number of subjects analysed
    62
    61
    Units: months
        median (confidence interval 95%)
    4.2 (3.9 to 4.9)
    5.6 (3.9 to 6.2)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Test stratified by time to PD1 (before versus after completion of 1L maintenance therapy) and ECOG PS at randomization (0 versus 1/2).
    Comparison groups
    Placebo + Lomustine/SOC (ITT) v Bevacizumab + Lomustine/SOC (ITT)
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 1.28

    Secondary: Percentage of Participants with PD3 after PD2 (Assessed According to Modified RANO Criteria) or Death from any Cause

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    End point title
    		 Percentage of Participants with PD3 after PD2 (Assessed According to Modified RANO Criteria) or Death from any Cause
    End point description
    As per the modified RANO criteria, progression was defined as: >/=25% increase in the sum of products of perpendicular diameters of enhancing lesions compared with the smallest tumor measurement obtained either at baseline or at best response, on stable/increasing corticosteroid dose; significant increase in non-enhancing T2/FLAIR lesions, not caused by comorbid events; any new lesions; clear clinical deterioration (not attributable to other non-tumor causes or decreases in corticosteroid dose); failure to return for evaluation due to death or deteriorating condition; or clear progression of non-measurable disease. Analysis was performed on ITT Population. Participants without a PD2 and without the start of 3L treatment were excluded from this analysis.
    End point type
    Secondary
    End point timeframe
    From first administration of treatment after PD2 until PD3 or death from any cause (overall approximately 26 months)
    End point values
    		 Placebo + Lomustine/SOC (ITT) Bevacizumab + Lomustine/SOC (ITT)
    Number of subjects analysed
    25
    25
    Units: percentage of participants
        number (not applicable)
    96.0
    96.0
    No statistical analyses for this end point

    Secondary: Restricted PFS on 3L Treatment (PFS3R) Assessed According to Modified RANO Criteria

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    End point title
    		 Restricted PFS on 3L Treatment (PFS3R) Assessed According to Modified RANO Criteria
    End point description
    PFS3R was defined as the time from first administration of randomized treatment after PD2 until PD3 or death from any cause, whichever occurred first. As per the modified RANO criteria, progression was defined as: >/=25% increase in the sum of products of perpendicular diameters of enhancing lesions, on stable/increasing corticosteroid dose; significant increase in non-enhancing T2/FLAIR lesions; any new lesions; clear clinical deterioration; failure to return for evaluation due to death or deteriorating condition; or clear progression of non-measurable disease. Participants without an event were censored at the date of their last evaluable tumor assessment or, if this was not available, at date of first administration of randomized treatment after PD2. Median PFS3R and 95% CI were estimated using Kaplan-Meier method. Analysis was performed on ITT Population. Participants without a PD2 and without the start of 3L treatment were excluded from this analysis.
    End point type
    Secondary
    End point timeframe
    From first administration of treatment after PD2 until PD3 or death from any cause (overall approximately 26 months)
    End point values
    		 Placebo + Lomustine/SOC (ITT) Bevacizumab + Lomustine/SOC (ITT)
    Number of subjects analysed
    25
    25
    Units: months
        median (confidence interval 95%)
    2.2 (1.3 to 2.7)
    2.0 (1.8 to 2.7)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Test stratified by time to PD1 (before versus after completion of 1L maintenance therapy) and ECOG PS at randomization (0 versus 1/2).
    Comparison groups
    Placebo + Lomustine/SOC (ITT) v Bevacizumab + Lomustine/SOC (ITT)
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.37
         upper limit
    		 1.33

    Secondary: Percentage of Participants with 2L Objective Response of Complete Response (CR) or Partial Response (PR) Assessed According to Modified RANO Criteria

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    End point title
    		 Percentage of Participants with 2L Objective Response of Complete Response (CR) or Partial Response (PR) Assessed According to Modified RANO Criteria
    End point description
    2L objective response was defined as the CR/PR recorded from the date of randomization/PD1 until PD2, death, subsequent anticancer therapy, operation/re-operation for glioblastoma, or 13 weeks after last administration of 2L-treatment, whichever occurred first. Modified RANO criteria: CR was defined as complete disappearance of all enhancing disease, sustained for at least 4 weeks; no new lesions; stable or improved non-enhancing (T2/FLAIR) lesions; no corticosteroids; and clinical status of stable or improved. PR was defined as >/=50% decrease compared with baseline in all measurable enhancing lesions, sustained for at least 4 weeks; no progression of non-measurable T1-enhancing disease; no new lesions; stable/improved non-enhancing lesions on the same or lower dose of corticosteroids compared to baseline; and clinical status of stable or improved. The 95% CI was computed using Clopper-Pearson approach. Analysis was performed on ITT Population.
    End point type
    Secondary
    End point timeframe
    From randomization/PD1 until PD2, death, subsequent anticancer therapy, operation/re-operation for glioblastoma, or 13 weeks after last administration of 2L-treatment, whichever occurred first (approximately 18 months overall)
    End point values
    		 Placebo + Lomustine/SOC (ITT) Bevacizumab + Lomustine/SOC (ITT)
    Number of subjects analysed
    55 [5]
    57 [6]
    Units: percentage of participants
        number (confidence interval 95%)
    0.0 (0.0 to 6.5)
    0.0 (0.0 to 6.3)
    Notes
    [5] - Participants with a valid response assessment
    [6] - Participants with a valid response assessment
    No statistical analyses for this end point

    Secondary: Percentage of Participants with 3L Objective Response of CR or PR Assessed According to Modified RANO Criteria

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    End point title
    		 Percentage of Participants with 3L Objective Response of CR or PR Assessed According to Modified RANO Criteria
    End point description
    3L objective response was defined as the CR/PR recorded from first administration of randomized treatment after PD2 until PD3, death, subsequent anticancer therapy, operation/re-operation for glioblastoma, or 13 weeks after last administration of 3L-treatment, whichever occurred first. Modified RANO criteria: CR was defined as complete disappearance of all enhancing disease, sustained for at least 4 weeks; no new lesions; stable or improved non-enhancing (T2/FLAIR) lesions; no corticosteroids; and clinical status of stable or improved. PR was defined as >/=50% decrease compared with baseline in all measurable enhancing lesions, sustained for at least 4 weeks; no progression of non-measurable T1-enhancing disease; no new lesions; stable/improved non-enhancing lesions on the same or lower dose of corticosteroids compared to baseline; and clinical status of stable or improved. The 95% CI was computed using Clopper-Pearson approach. Analysis was performed on ITT Population.
    End point type
    Secondary
    End point timeframe
    From PD2 until PD3, death, subsequent anticancer therapy, operation/re-operation for glioblastoma, or 13 weeks after last administration of study treatment, whichever occurs first (approximately 26 months overall)
    End point values
    		 Placebo + Lomustine/SOC (ITT) Bevacizumab + Lomustine/SOC (ITT)
    Number of subjects analysed
    21 [7]
    21 [8]
    Units: percentage of participants
        number (confidence interval 95%)
    4.8 (0.1 to 23.8)
    0.0 (0.0 to 16.1)
    Notes
    [7] - Participants with PD2, start of 3L treatment, and valid response assessment
    [8] - Participants with PD2, start of 3L treatment, and valid response assessment
    No statistical analyses for this end point

    Secondary: Percentage of Participants with 2L Disease Control as CR, PR, or Stable Disease (SD) Assessed According to Modified RANO Criteria

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    End point title
    		 Percentage of Participants with 2L Disease Control as CR, PR, or Stable Disease (SD) Assessed According to Modified RANO Criteria
    End point description
    2L disease control was defined as CR, PR, or SD recorded from the date of randomization/PD1 until PD2, death, subsequent anticancer therapy, operation/re-operation for glioblastoma, or 13 weeks after last administration of 2L-treatment, whichever occurred first. Tumor response was assessed according to modified RANO criteria. CR: complete disappearance of all enhancing disease, sustained >/=4 weeks; no new lesions; stable/improved non-enhancing lesions; no corticosteroids; and clinical status of stable or improved. PR: >/=50% decrease compared with baseline in all measurable enhancing lesions, sustained >/=4 weeks; no progression of non-measurable T1-enhancing disease; no new lesions; stable/improved non-enhancing lesions; and clinical status of stable or improved. SD: absence of CR, PR, or progression; stable non-enhancing lesions; and clinical status of stable or improved. The 95% CI was computed using Clopper-Pearson approach. Analysis was performed on ITT Population.
    End point type
    Secondary
    End point timeframe
    From randomization/PD1 until PD2, death, subsequent anticancer therapy, operation/re-operation for glioblastoma, or 13 weeks after last administration of 2L-treatment, whichever occurred first (approximately 18 months overall)
    End point values
    		 Placebo + Lomustine/SOC (ITT) Bevacizumab + Lomustine/SOC (ITT)
    Number of subjects analysed
    55 [9]
    57 [10]
    Units: percentage of participants
        number (confidence interval 95%)
    10.9 (4.1 to 22.2)
    21.1 (11.4 to 33.9)
    Notes
    [9] - Participants with a valid response assessment
    [10] - Participants with a valid response assessment
    No statistical analyses for this end point

    Secondary: Percentage of Participants with 3L Disease Control as CR, PR, or SD Assessed According to Modified RANO Criteria

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    End point title
    		 Percentage of Participants with 3L Disease Control as CR, PR, or SD Assessed According to Modified RANO Criteria
    End point description
    3L disease control was defined as a CR, PR, or SD recorded from first administration of randomized treatment after PD2 until PD3, death, subsequent anticancer therapy, operation/re-operation for glioblastoma, or 13 weeks after last administration of 3L-treatment, whichever occurred first. According to modified RANO criteria, CR: complete disappearance of all enhancing disease, sustained >/=4 weeks; no new lesions; stable/improved non-enhancing lesions; no corticosteroids; and clinical status of stable or improved. PR: >/=50% decrease compared with baseline in all measurable enhancing lesions, sustained >/=4 weeks; no progression of non-measurable T1-enhancing disease; no new lesions; stable/improved non-enhancing lesions; and clinical status of stable or improved. SD: absence of CR, PR, or progression; stable non-enhancing lesions; and clinical status of stable or improved. The 95% CI was computed using Clopper-Pearson approach. Analysis was performed on ITT Population.
    End point type
    Secondary
    End point timeframe
    From PD2/start of 3L-treatment until PD3, death, subsequent anticancer therapy, operation/re-operation for glioblastoma, or 13 weeks after last administration of 3L-treatment, whichever occurred first (approximately 26 months overall)
    End point values
    		 Placebo + Lomustine/SOC (ITT) Bevacizumab + Lomustine/SOC (ITT)
    Number of subjects analysed
    21 [11]
    21 [12]
    Units: percentage of participants
        number (confidence interval 95%)
    14.3 (3.0 to 36.3)
    9.5 (1.2 to 30.4)
    Notes
    [11] - Participants with PD2, start of 3L treatment, and valid response assessment
    [12] - Participants with PD2, start of 3L treatment, and valid response assessment
    No statistical analyses for this end point

    Secondary: Duration of 2L Objective Response (DOR2) Assessed According to Modified RANO Criteria

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    End point title
    		 Duration of 2L Objective Response (DOR2) Assessed According to Modified RANO Criteria
    End point description
    Duration of 2L objective response was defined as the time interval from the first assessment of CR or PR after randomization/PD1 until PD2, death from any cause, subsequent anticancer therapy, whichever occurred first. Tumor response was assessed according to modified RANO criteria. CR: complete disappearance of all enhancing disease, sustained >/=4 weeks; no new lesions; stable/improved non-enhancing lesions; no corticosteroids; and clinical status of stable or improved. PR: >/=50% decrease compared with baseline in all measurable enhancing lesions, sustained >/=4 weeks; no progression of non-measurable T1-enhancing disease; no new lesions; stable/improved non-enhancing lesions; and clinical status of stable or improved. Median DOR2 and 95% CI were assessed using Kaplan-Meier method. Analysis was performed on ITT Population. The data ‘99999 (99999 to 99999)’ in the results signifies that median and corresponding CI could not be calculated as no participants experienced a CR or PR.
    End point type
    Secondary
    End point timeframe
    From first occurrence of CR/PR after randomization/PD1 until PD2, death from any cause, subsequent anticancer therapy, whichever occurred first (approximately 18 months overall)
    End point values
    		 Placebo + Lomustine/SOC (ITT) Bevacizumab + Lomustine/SOC (ITT)
    Number of subjects analysed
    62
    61
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Duration of 3L Objective Response (DOR3) Assessed According to Modified RANO Criteria

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    End point title
    		 Duration of 3L Objective Response (DOR3) Assessed According to Modified RANO Criteria
    End point description
    Duration of 3L objective response was defined as the time interval from the first assessment of CR or PR after PD2 until PD3, death from any cause, subsequent anticancer therapy, whichever occurred first. Tumor response was assessed according to modified RANO criteria. CR: complete disappearance of all enhancing disease, sustained >/=4 weeks; no new lesions; stable/improved non-enhancing lesions; no corticosteroids; and clinical status of stable or improved. PR: >/=50% decrease compared with baseline in all measurable enhancing lesions, sustained >/=4 weeks; no progression of non-measurable T1-enhancing disease; no new lesions; stable/improved non-enhancing lesions; and clinical status of stable or improved. Median DOR3 and 95% CI were assessed using Kaplan-Meier method. Analysis was performed on ITT Population. ‘99999 (99999 to 99999)’ = median and corresponding CI could not be calculated as insufficient number of participants (<50%) experienced a CR or PR.
    End point type
    Secondary
    End point timeframe
    From first occurrence of CR/PR after PD2 until PD3, subsequent anticancer therapy, or death from any cause, whichever occurred first (approximately 26 months overall)
    End point values
    		 Placebo + Lomustine/SOC (ITT) Bevacizumab + Lomustine/SOC (ITT)
    Number of subjects analysed
    62
    61
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: 1L Treatment: Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core 30 (C30) Global Health Status/Global QoL Scale Score

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    End point title
    		 1L Treatment: Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core 30 (C30) Global Health Status/Global QoL Scale Score
    End point description
    The EORTC QLQ-C30 is a validated self-report measure consisting of 30 questions incorporated into five functional scales (Physical, Role, Cognitive, Emotional, and Social scales), three symptom scales (fatigue, pain, nausea and vomiting scales), a global health status/global quality-of-life (QoL) scale, and single items (dyspnea, insomnia, anorexia, constipation, diarrhea, and financial impact). Most questions used 4-point scale (1='Not at all' to 4='Very much'), while 2 questions used 7-point scale (1='very poor' to 7='Excellent'). Scores were averaged, transformed to 0-100 scale; where higher score for global health status/global QoL = better health related quality of life (HRQoL). Analysis was performed on enrolled analysis set, which included all participants enrolled in the study regardless of whether they received any trial drug. 'Number of Subject Analysed'=participants evaluable for this outcome measure; 'n'=participants evaluable at specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline;Week(Wk)3,5;end of Wk6;Maintenance:Day(D)1 (Visit[V]1), D15(V2) Cycles(C)1-6 Q4W;Monotherapy:V1-V44 Q3W;Safety Follow-up(FU) (30 days after last 1L dose);PD FUs(8 Wk after Safety FU [PD FU1],then every 12 Wk until PD1) (up to 41 months overall)
    End point values
    		 1L Bevacizumab
    Number of subjects analysed
    279 [13]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=279)
    67.1 ( 22.09 )
        Change at Beginning of Wk 3 (n=245)
    2.4 ( 18.69 )
        Change at Beginning of Wk 5 (n=257)
    2.5 ( 19.52 )
        Change at end of Wk 6 (n=245)
    -1.2 ( 22.04 )
        Change at Maintenance C1V1 (n=200)
    1.7 ( 21.43 )
        Change at Maintenance C1V2 (n=221)
    0.1 ( 21.38 )
        Change at Maintenance C2V1 (n=223)
    -0.2 ( 21.25 )
        Change at Maintenance C2V2 (n=204)
    -1.6 ( 22.99 )
        Change at Maintenance C3V1 (n=201)
    -1.0 ( 22.20 )
        Change at Maintenance C3V2 (n=205)
    1.3 ( 20.66 )
        Change at Maintenance C4V1 (n=196)
    1.0 ( 19.19 )
        Change at Maintenance C4V2 (n=194)
    1.9 ( 19.35 )
        Change at Maintenance C5V1 (n=185)
    1.6 ( 21.17 )
        Change at Maintenance C5V2 (n=181)
    2.3 ( 21.58 )
        Change at Maintenance C6V1 (n=171)
    0.8 ( 22.00 )
        Change at Maintenance C6V2 (n=168)
    1.6 ( 20.04 )
        Change at Monotherapy V1 (n=161)
    0.7 ( 20.27 )
        Change at Monotherapy V2 (n=147)
    1.6 ( 19.47 )
        Change at Monotherapy V3 (n=135)
    2.0 ( 22.52 )
        Change at Monotherapy V4 (n=118)
    2.4 ( 22.54 )
        Change at Monotherapy V5 (n=109)
    0 ( 21.52 )
        Change at Monotherapy V6 (n=99)
    0.7 ( 21.55 )
        Change at Monotherapy V7 (n=91)
    0.8 ( 23.18 )
        Change at Monotherapy V8 (n=77)
    2.8 ( 21.74 )
        Change at Monotherapy V9 (n=75)
    5.1 ( 22.47 )
        Change at Monotherapy V10 (n=72)
    5.0 ( 22.28 )
        Change at Monotherapy V11 (n=71)
    3.8 ( 19.10 )
        Change at Monotherapy V12 (n=66)
    2.3 ( 21.86 )
        Change at Monotherapy V13 (n=58)
    1.4 ( 22.08 )
        Change at Monotherapy V14 (n=58)
    4.9 ( 21.00 )
        Change at Monotherapy V15 (n=56)
    2.5 ( 21.26 )
        Change at Monotherapy V16 (n=50)
    4.8 ( 23.03 )
        Change at Monotherapy V17 (n=48)
    3.3 ( 23.87 )
        Change at Monotherapy V18 (n=44)
    2.5 ( 23.54 )
        Change at Monotherapy V19 (n=41)
    2.4 ( 21.35 )
        Change at Monotherapy V20 (n=36)
    3.5 ( 21.40 )
        Change at Monotherapy V21 (n=31)
    3.0 ( 24.01 )
        Change at Monotherapy V22 (n=32)
    5.7 ( 22.64 )
        Change at Monotherapy V23 (n=30)
    3.6 ( 27.13 )
        Change at Monotherapy V24 (n=25)
    8.3 ( 23.94 )
        Change at Monotherapy V25 (n=23)
    7.2 ( 23.48 )
        Change at Monotherapy V26 (n=21)
    3.6 ( 23.95 )
        Change at Monotherapy V27 (n=21)
    8.3 ( 25.00 )
        Change at Monotherapy V28 (n=17)
    13.7 ( 26.67 )
        Change at Monotherapy V29 (n=18)
    13.4 ( 26.83 )
        Change at Monotherapy V30 (n=15)
    13.9 ( 24.93 )
        Change at Monotherapy V31 (n=15)
    15.0 ( 21.41 )
        Change at Monotherapy V32 (n=10)
    13.3 ( 31.72 )
        Change at Monotherapy V33 (n=7)
    15.5 ( 30.21 )
        Change at Monotherapy V34 (n=7)
    13.1 ( 32.58 )
        Change at Monotherapy V35 (n=4)
    -8.3 ( 15.21 )
        Change at Monotherapy V36 (n=5)
    5.0 ( 32.60 )
        Change at Monotherapy V37 (n=4)
    -8.3 ( 15.21 )
        Change at Monotherapy V38 (n=3)
    -11.1 ( 17.35 )
        Change at Monotherapy V39 (n=2)
    -20.8 ( 5.89 )
        Change at Monotherapy V40 (n=3)
    -11.1 ( 17.35 )
        Change at Monotherapy V41 (n=3)
    -11.1 ( 17.35 )
        Change at Monotherapy V42 (n=2)
    -20.8 ( 5.89 )
        Change at Monotherapy V43 (n=3)
    -11.1 ( 17.35 )
        Change at Monotherapy V44 (n=2)
    -4.2 ( 17.68 )
        Change at Safety FU (n=51)
    -0.5 ( 28.01 )
        Change at PD FU1 (n=40)
    4.2 ( 29.54 )
        Change at PD FU2 (n=19)
    4.8 ( 21.93 )
        Change at PD FU3 (n=11)
    4.5 ( 23.38 )
        Change at PD FU4 (n=5)
    3.3 ( 12.64 )
        Change at PD FU5 (n=4)
    2.1 ( 17.18 )
        Change at PD FU6 (n=3)
    11.1 ( 17.35 )
        Change at PD FU7 (n=2)
    4.2 ( 29.46 )
        Change at PD FU8 (n=1)
    25.0 ( 99999 )
    Notes
    [13] - ‘99999’=SD could not be calculated as only 1 participant was evaluable at indicated time point.
    No statistical analyses for this end point

    Secondary: 2L and 3L Treatment: Change From 2L Baseline in EORTC QLQ C30 Global Health Status/Global QoL Scale Score

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    End point title
    		 2L and 3L Treatment: Change From 2L Baseline in EORTC QLQ C30 Global Health Status/Global QoL Scale Score
    End point description
    The EORTC QLQ-C30 is a validated self-report measure consisting of 30 questions incorporated into five functional scales (Physical, Role, Cognitive, Emotional, and Social scales), three symptom scales (fatigue, pain, nausea and vomiting scales), a global health status/global quality-of-life (QoL) scale, and single items (dyspnea, insomnia, anorexia, constipation, diarrhea, and financial impact). Most questions used 4-point scale (1='Not at all' to 4='Very much'), while 2 questions used 7-point scale (1='very poor' to 7='Excellent'). Scores were averaged, transformed to 0-100 scale; where higher score for global health status/global QoL = better HRQoL. Analysis was performed on ITT population. 'n'=participants evaluable at specified time point for different arms, respectively. ‘99999’=either data were not available because no participant was evaluable or standard deviation (SD) was not available because only 1 participant was evaluable at indicated time point.
    End point type
    Secondary
    End point timeframe
    2L Baseline (2L treatment V1); 2L treatment: V2-V41 (Q2W) until PD2; 3L treatment: V1-V61 (Q2W) until PD3; Safety FU (30 days after last 3L dose); PD FU1 (8 Wk after Safety FU); end of study (up to 41 months overall)
    End point values
    		 Placebo + Lomustine/SOC (ITT) Bevacizumab + Lomustine/SOC (ITT)
    Number of subjects analysed
    62
    61
    Units: units on a scale
    arithmetic mean (standard deviation)
        2L Baseline (n=62,61)
    65.6 ( 20.66 )
    57.5 ( 23.21 )
        Change at 2L V2 (n=45,40)
    -2.4 ( 13.49 )
    3.1 ( 17.37 )
        Change at 2L V3 (n=41,39)
    -6.1 ( 15.37 )
    -0.9 ( 19.19 )
        Change at 2L V4 (n=29,31)
    -6.0 ( 16.35 )
    -2.2 ( 18.25 )
        Change at 2L V5 (n=22,19)
    -8.3 ( 17.44 )
    5.7 ( 10.04 )
        Change at 2L V6 (n=18,13)
    -8.3 ( 18.96 )
    3.8 ( 16.88 )
        Change at 2L V7 (n=7,9)
    -3.6 ( 9.45 )
    -2.8 ( 11.79 )
        Change at 2L V8 (n=4,6)
    -4.2 ( 15.96 )
    18.1 ( 18.57 )
        Change at 2L V9 (n=4,7)
    0 ( 13.61 )
    -4.8 ( 6.56 )
        Change at 2L V10 (n=4,7)
    0 ( 13.61 )
    -9.5 ( 25.20 )
        Change at 2L V11 (n=4,5)
    -2.1 ( 4.17 )
    -5.0 ( 7.45 )
        Change at 2L V12 (n=2,3)
    -8.3 ( 11.79 )
    5.6 ( 9.62 )
        Change at 2L V13 (n=3,1)
    -2.8 ( 12.73 )
    -25.0 ( 99999 )
        Change at 2L V14 (n=2,1)
    -8.3 ( 11.79 )
    16.7 ( 99999 )
        Change at 2L V15 (n=1,0)
    -16.7 ( 99999 )
    99999 ( 99999 )
        Change at 2L V16 (n=1,0)
    -16.7 ( 99999 )
    99999 ( 99999 )
        Change at 2L V17 (n=1,1)
    0 ( 99999 )
    16.7 ( 99999 )
        Change at 2L V19 (n=1,0)
    -16.7 ( 99999 )
    99999 ( 99999 )
        Change at 2L V20 (n=1,0)
    -16.7 ( 99999 )
    99999 ( 99999 )
        Change at 2L V21 (n=1,0)
    -16.7 ( 99999 )
    99999 ( 99999 )
        Change at 2L V22 (n=1,0)
    -16.7 ( 99999 )
    99999 ( 99999 )
        Change at 2L V24 (n=1,0)
    -16.7 ( 99999 )
    99999 ( 99999 )
        Change at 2L V25 (n=1,0)
    -16.7 ( 99999 )
    99999 ( 99999 )
        Change at 2L V26 (n=1,0)
    -16.7 ( 99999 )
    99999 ( 99999 )
        Change at 2L V27 (n=1,0)
    -16.7 ( 99999 )
    99999 ( 99999 )
        Change at 2L V28 (n=1,0)
    -16.7 ( 99999 )
    99999 ( 99999 )
        Change at 2L V29 (n=1,0)
    -8.3 ( 99999 )
    99999 ( 99999 )
        Change at 2L V30 (n=1,0)
    -16.7 ( 99999 )
    99999 ( 99999 )
        Change at 2L V31 (n=1,0)
    -16.7 ( 99999 )
    99999 ( 99999 )
        Change at 2L V32 (n=1,0)
    -33.3 ( 99999 )
    99999 ( 99999 )
        Change at 2L V33 (n=1,0)
    -33.3 ( 99999 )
    99999 ( 99999 )
        Change at 2L V34 (n=1,0)
    -33.3 ( 99999 )
    99999 ( 99999 )
        Change at 2L V35 (n=1,0)
    -16.7 ( 99999 )
    99999 ( 99999 )
        Change at 2L V36 (n=1,0)
    -33.3 ( 99999 )
    99999 ( 99999 )
        Change at 2L V38 (n=1,0)
    -16.7 ( 99999 )
    99999 ( 99999 )
        Change at 2L V40 (n=1,0)
    -25.0 ( 99999 )
    99999 ( 99999 )
        Change at 2L V41 (n=1,0)
    -8.3 ( 99999 )
    99999 ( 99999 )
        Change at 3L V1 (n=19,17)
    -6.6 ( 18.55 )
    0.5 ( 16.53 )
        Change at 3L V2 (n=15,14)
    -2.2 ( 12.39 )
    -6.5 ( 17.04 )
        Change at 3L V3 (n=10,14)
    0.8 ( 14.93 )
    -6.5 ( 17.96 )
        Change at 3L V4 (n=12,13)
    -8.3 ( 23.84 )
    -2.6 ( 18.13 )
        Change at 3L V5 (n=9,8)
    0 ( 16.67 )
    -9.4 ( 15.71 )
        Change at 3L V6 (n=6,3)
    -11.1 ( 12.55 )
    -13.9 ( 20.97 )
        Change at 3L V7 (n=3,4)
    -16.7 ( 28.87 )
    2.1 ( 23.94 )
        Change at 3L V8 (n=3,3)
    -2.8 ( 12.73 )
    19.4 ( 4.81 )
        Change at 3L V9 (n=3,3)
    -8.3 ( 22.05 )
    2.8 ( 12.73 )
        Change at 3L V10 (n=3,1)
    -13.9 ( 12.73 )
    0 ( 99999 )
        Change at 3L V11 (n=1,1)
    0 ( 99999 )
    16.7 ( 99999 )
        Change at 3L V12 (n=2,2)
    -8.3 ( 11.79 )
    12.5 ( 5.89 )
        Change at 3L V13 (n=2,0)
    -8.3 ( 11.79 )
    99999 ( 99999 )
        Change at 3L V14 (n=2,0)
    0 ( 0 )
    99999 ( 99999 )
        Change at 3L V15 (n=2,0)
    0 ( 0 )
    99999 ( 99999 )
        Change at 3L V16 (n=2,0)
    -8.3 ( 11.79 )
    99999 ( 99999 )
        Change at 3L V17 (n=2,0)
    0 ( 0 )
    99999 ( 99999 )
        Change at 3L V18 (n=2,0)
    -8.3 ( 11.79 )
    99999 ( 99999 )
        Change at 3L V19 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        Change at 3L V20 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        Change at 3L V21 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        Change at 3L V22 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        Change at 3L V23 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        Change at 3L V25 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        Change at 3L V27 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        Change at 3L V28 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        Change at 3L V29 (n=1,0)
    16.7 ( 99999 )
    99999 ( 99999 )
        Change at 3L V30 (n=1,0)
    16.7 ( 99999 )
    99999 ( 99999 )
        Change at 3L V31 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        Change at 3L V32 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        Change at 3L V33 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        Change at 3L V34 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        Change at 3L V35 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        Change at 3L V36 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        Change at 3L V37 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        Change at 3L V38 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        Change at 3L V39 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        Change at 3L V41 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        Change at 3L V42 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        Change at 3L V43 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        Change at 3L V44 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        Change at 3L V45 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        Change at 3L V46 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        Change at 3L V47 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        Change at 3L V48 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        Change at 3L V49 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        Change at 3L V51 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        Change at 3L V52 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        Change at 3L V53 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        Change at 3L V54 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        Change at 3L V55 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        Change at 3L V56 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        Change at 3L V57 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        Change at 3L V58 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        Change at 3L V59 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        Change at 3L V60 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        Change at 3L V61 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        Change at Safety FU (n=6,13)
    -20.8 ( 11.49 )
    -11.5 ( 14.25 )
        Change at PD FU1 (n=1,3)
    -8.3 ( 99999 )
    -25.0 ( 0 )
        Change at end of study (n=4,2)
    -16.7 ( 22.57 )
    -12.5 ( 5.89 )
    No statistical analyses for this end point

    Secondary: 1L Treatment: Change From Baseline in EORTC QLQ Brain Cancer Module 20 (BN20) Multiple Item Score

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    End point title
    		 1L Treatment: Change From Baseline in EORTC QLQ Brain Cancer Module 20 (BN20) Multiple Item Score
    End point description
    The BN20 consists of 4 multiple items scales (future uncertainty [FtUn], visual disorder [VsDr], motor dysfunction [MtDf], communication deficit [CmDf]) and 7 single items (headache, seizures, drowsiness, hair loss, itching, difficulty with bladder control, and weakness of both legs). All questions used 4-point scale (1='Not at all' to 4='Very much'). Multiple item scores were transformed to a 0-100 scale, where higher score=more severe symptoms/poor QoL. The change from baseline in multiple items scales score at different time points is reported. Analysis was performed on enrolled analysis set. 'Number of Subject Analysed'=participants evaluable for this outcome measure; 'n'=participants evaluable at specified time point; ‘99999’=SD could not be calculated as only 1 participant was evaluable at indicated time point.
    End point type
    Secondary
    End point timeframe
    Baseline; Wk 3, 5; end of Wk6; Maintenance: D1(V1), D15(V2) of C1-6 (Q4W); Monotherapy: V1-V44 (Q3W); Safety FU (30 days after last 1L dose); PD FUs (8 Wk after Safety FU [PD FU1], then every 12 Wk until PD1) (up to 41 months overall)
    End point values
    		 1L Bevacizumab
    Number of subjects analysed
    256
    Units: units on a scale
    arithmetic mean (standard deviation)
        FtUn: Baseline (n=256)
    32.3 ( 24.08 )
        FtUn: Change at Beginning of Wk 3 (n=230)
    -8.9 ( 20.21 )
        FtUn: Change at Beginning of Wk 5 (n=234)
    -8.6 ( 21.32 )
        FtUn: Change at end of Wk 6 (n=227)
    -7.5 ( 22.88 )
        FtUn: Change at Maintenance C1V1 (n=188)
    -7.9 ( 26.64 )
        FtUn: Change at Maintenance C1V2 (n=201)
    -9.4 ( 24.31 )
        FtUn: Change at Maintenance C2V1 (n=205)
    -10.8 ( 25.27 )
        FtUn: Change at Maintenance C2V2 (n=197)
    -8.8 ( 27.05 )
        FtUn: Change at Maintenance C3V1 (n=185)
    -9.9 ( 24.82 )
        FtUn: Change at Maintenance C3V2 (n=190)
    -8.9 ( 23.56 )
        FtUn: Change at Maintenance C4V1 (n=190)
    -11.7 ( 21.91 )
        FtUn: Change at Maintenance C4V2 (n=184)
    -10.6 ( 24.55 )
        FtUn: Change at Maintenance C5V1 (n=173)
    -10.7 ( 22.30 )
        FtUn: Change at Maintenance C5V2 (n=164)
    -11.1 ( 23.70 )
        FtUn: Change at Maintenance C6V1 (n=165)
    -11.7 ( 23.52 )
        FtUn: Change at Maintenance C6V2 (n=161)
    -12.8 ( 23.65 )
        FtUn: Change at Monotherapy V1 (n=154)
    -10.7 ( 23.25 )
        FtUn: Change at Monotherapy V2 (n=139)
    -10.1 ( 25.22 )
        FtUn: Change at Monotherapy V3 (n=131)
    -9.1 ( 26.31 )
        FtUn: Change at Monotherapy V4 (n=111)
    -11.2 ( 23.90 )
        FtUn: Change at Monotherapy V5 (n=101)
    -11.5 ( 23.68 )
        FtUn: Change at Monotherapy V6 (n=95)
    -10.6 ( 26.12 )
        FtUn: Change at Monotherapy V7 (n=86)
    -10.7 ( 26.73 )
        FtUn: Change at Monotherapy V8 (n=71)
    -11.2 ( 27.68 )
        FtUn: Change at Monotherapy V9 (n=70)
    -14.0 ( 24.92 )
        FtUn: Change at Monotherapy V10 (n=68)
    -15.2 ( 23.81 )
        FtUn: Change at Monotherapy V11 (n=66)
    -15.0 ( 25.29 )
        FtUn: Change at Monotherapy V12 (n=59)
    -14.8 ( 23.57 )
        FtUn: Change at Monotherapy V13 (n=53)
    -16.3 ( 20.22 )
        FtUn: Change at Monotherapy V14 (n=53)
    -14.2 ( 22.88 )
        FtUn: Change at Monotherapy V15 (n=56)
    -17.2 ( 23.10 )
        FtUn: Change at Monotherapy V16 (n=47)
    -18.8 ( 21.17 )
        FtUn: Change at Monotherapy V17 (n=43)
    -18.2 ( 24.75 )
        FtUn: Change at Monotherapy V18 (n=39)
    -14.1 ( 23.27 )
        FtUn: Change at Monotherapy V19 (n=36)
    -18.3 ( 20.68 )
        FtUn: Change at Monotherapy V20 (n=31)
    -17.7 ( 21.05 )
        FtUn: Change at Monotherapy V21 (n=28)
    -18.8 ( 18.46 )
        FtUn: Change at Monotherapy V22 (n=29)
    -21.3 ( 18.17 )
        FtUn: Change at Monotherapy V23 (n=27)
    -19.4 ( 18.20 )
        FtUn: Change at Monotherapy V24 (n=22)
    -24.5 ( 20.17 )
        FtUn: Change at Monotherapy V25 (n=22)
    -20.8 ( 20.04 )
        FtUn: Change at Monotherapy V26 (n=20)
    -19.6 ( 17.16 )
        FtUn: Change at Monotherapy V27 (n=20)
    -22.9 ( 18.90 )
        FtUn: Change at Monotherapy V28 (n=15)
    -22.2 ( 18.54 )
        FtUn: Change at Monotherapy V29 (n=16)
    -20.8 ( 23.96 )
        FtUn: Change at Monotherapy V30 (n=13)
    -22.0 ( 23.42 )
        FtUn: Change at Monotherapy V31 (n=13)
    -23.7 ( 18.59 )
        FtUn: Change at Monotherapy V32 (n=9)
    -24.1 ( 19.30 )
        FtUn: Change at Monotherapy V33 (n=6)
    -36.1 ( 18.76 )
        FtUn: Change at Monotherapy V34 (n=6)
    -23.6 ( 26.57 )
        FtUn: Change at Monotherapy V35 (n=4)
    -16.7 ( 27.22 )
        FtUn: Change at Monotherapy V36 (n=5)
    -20.0 ( 22.52 )
        FtUn: Change at Monotherapy V37 (n=4)
    -18.8 ( 27.53 )
        FtUn: Change at Monotherapy V38 (n=2)
    -25.0 ( 11.79 )
        FtUn: Change at Monotherapy V39 (n=2)
    0 ( 23.57 )
        FtUn: Change at Monotherapy V40 (n=3)
    -13.9 ( 29.27 )
        FtUn: Change at Monotherapy V41 (n=3)
    -13.9 ( 29.27 )
        FtUn: Change at Monotherapy V42 (n=2)
    -4.2 ( 17.68 )
        FtUn: Change at Monotherapy V43 (n=3)
    -13.9 ( 29.27 )
        FtUn: Change at Monotherapy V44 (n=2)
    -29.2 ( 17.68 )
        FtUn: Change at Safety FU (n=50)
    -2.6 ( 26.92 )
        FtUn: Change at PD FU1 (n=40)
    -6.0 ( 32.26 )
        FtUn: Change at PD FU2 (n=17)
    -11.8 ( 19.56 )
        FtUn: Change at PD FU3 (n=10)
    -17.5 ( 21.32 )
        FtUn: Change at PD FU4 (n=9)
    -16.0 ( 20.59 )
        FtUn: Change at PD FU5 (n=4)
    -21.5 ( 3.50 )
        FtUn: Change at PD FU6 (n=3)
    -19.4 ( 20.97 )
        FtUn: Change at PD FU7 (n=2)
    -29.2 ( 17.68 )
        FtUn: Change at PD FU8 (n=1)
    -16.7 ( 99999 )
        VsDr: Baseline (n=256)
    13.4 ( 21.64 )
        VsDr: Change at Beginning of Wk 3 (n=228)
    -2.7 ( 15.76 )
        VsDr: Change at Beginning of Wk 5 (n=234)
    -2.8 ( 16.23 )
        VsDr: Change at end of Wk 6 (n=226)
    -0.5 ( 18.04 )
        VsDr: Change at Maintenance C1V1 (n=186)
    -1.8 ( 20.25 )
        VsDr: Change at Maintenance C1V2 (n=200)
    -1.6 ( 18.68 )
        VsDr: Change at Maintenance C2V1 (n=204)
    -2.2 ( 17.74 )
        VsDr: Change at Maintenance C2V2 (n=197)
    -2.8 ( 20.37 )
        VsDr: Change at Maintenance C3V1 (n=185)
    -1.3 ( 20.82 )
        VsDr: Change at Maintenance C3V2 (n=189)
    -2.3 ( 20.71 )
        VsDr: Change at Maintenance C4V1 (n=190)
    -2.1 ( 20.69 )
        VsDr: Change at Maintenance C4V2 (n=184)
    -1.4 ( 18.61 )
        VsDr: Change at Maintenance C5V1 (n=172)
    -1.6 ( 17.17 )
        VsDr: Change at Maintenance C5V2 (n=164)
    -1.2 ( 17.27 )
        VsDr: Change at Maintenance C6V1 (n=165)
    -1.8 ( 17.06 )
        VsDr: Change at Maintenance C6V2 (n=158)
    -0.9 ( 16.28 )
        VsDr: Change at Monotherapy V1 (n=154)
    -0.8 ( 18.31 )
        VsDr: Change at Monotherapy V2 (n=140)
    -2.3 ( 17.22 )
        VsDr: Change at Monotherapy V3 (n=131)
    -2.5 ( 17.35 )
        VsDr: Change at Monotherapy V4 (n=111)
    -0.7 ( 18.86 )
        VsDr: Change at Monotherapy V5 (n=101)
    0.2 ( 20.17 )
        VsDr: Change at Monotherapy V6 (n=95)
    -0.2 ( 20.05 )
        VsDr: Change at Monotherapy V7 (n=85)
    -2.8 ( 18.89 )
        VsDr: Change at Monotherapy V8 (n=71)
    -2.4 ( 14.60 )
        VsDr: Change at Monotherapy V9 (n=70)
    -0.6 ( 16.12 )
        VsDr: Change at Monotherapy V10 (n=67)
    -2.2 ( 12.76 )
        VsDr: Change at Monotherapy V11 (n=66)
    -1.6 ( 14.77 )
        VsDr: Change at Monotherapy V12 (n=59)
    -0.1 ( 17.94 )
        VsDr: Change at Monotherapy V13 (n=54)
    -3.5 ( 15.12 )
        VsDr: Change at Monotherapy V14 (n=53)
    -0.8 ( 15.84 )
        VsDr: Change at Monotherapy V15 (n=55)
    -2.1 ( 12.85 )
        VsDr: Change at Monotherapy V16 (n=47)
    -0.4 ( 14.30 )
        VsDr: Change at Monotherapy V17 (n=43)
    -1.6 ( 15.96 )
        VsDr: Change at Monotherapy V18 (n=39)
    0.4 ( 20.01 )
        VsDr: Change at Monotherapy V19 (n=36)
    -2.6 ( 14.21 )
        VsDr: Change at Monotherapy V20 (n=31)
    -3.8 ( 13.10 )
        VsDr: Change at Monotherapy V21 (n=28)
    -3.8 ( 11.52 )
        VsDr: Change at Monotherapy V22 (n=29)
    -4.0 ( 12.14 )
        VsDr: Change at Monotherapy V23 (n=27)
    -6.0 ( 14.69 )
        VsDr: Change at Monotherapy V24 (n=22)
    -3.8 ( 14.49 )
        VsDr: Change at Monotherapy V25 (n=22)
    -6.3 ( 11.41 )
        VsDr: Change at Monotherapy V26 (n=20)
    -4.4 ( 12.17 )
        VsDr: Change at Monotherapy V27 (n=20)
    -4.2 ( 13.35 )
        VsDr: Change at Monotherapy V28 (n=25)
    -2.6 ( 12.40 )
        VsDr: Change at Monotherapy V29 (n=16)
    -1.0 ( 12.87 )
        VsDr: Change at Monotherapy V30 (n=13)
    -3.0 ( 13.34 )
        VsDr: Change at Monotherapy V31 (n=13)
    -1.3 ( 12.03 )
        VsDr: Change at Monotherapy V32 (n=9)
    -0.6 ( 7.05 )
        VsDr: Change at Monotherapy V33 (n=6)
    1.9 ( 4.54 )
        VsDr: Change at Monotherapy V34 (n=6)
    1.9 ( 4.54 )
        VsDr: Change at Monotherapy V35 (n=4)
    0 ( 0 )
        VsDr: Change at Monotherapy V36 (n=5)
    0 ( 0 )
        VsDr: Change at Monotherapy V37 (n=4)
    0 ( 0 )
        VsDr: Change at Monotherapy V38 (n=2)
    0 ( 0 )
        VsDr: Change at Monotherapy V39 (n=2)
    0 ( 0 )
        VsDr: Change at Monotherapy V40 (n=3)
    0 ( 0 )
        VsDr: Change at Monotherapy V41 (n=3)
    0 ( 0 )
        VsDr: Change at Monotherapy V42 (n=2)
    0 ( 0 )
        VsDr: Change at Monotherapy V43 (n=3)
    0 ( 0 )
        VsDr: Change at Monotherapy V44 (n=2)
    0 ( 0 )
        VsDr: Change at Safety FU (n=51)
    -1.2 ( 21.27 )
        VsDr: Change at PD FU1 (n=40)
    1.5 ( 20.94 )
        VsDr: Change at PD FU2 (n=17)
    0 ( 17.12 )
        VsDr: Change at PD FU3 (n=10)
    1.1 ( 19.21 )
        VsDr: Change at PD FU4 (n=9)
    0 ( 22.91 )
        VsDr: Change at PD FU5 (n=4)
    -11.1 ( 22.22 )
        VsDr: Change at PD FU6 (n=3)
    0 ( 40.06 )
        VsDr: Change at PD FU7 (n=2)
    -16.7 ( 39.28 )
        VsDr: Change at PD FU8 (n=1)
    -44.4 ( 99999 )
        MtDf: Baseline (n=256)
    15.4 ( 22.75 )
        MtDf: Change at Beginning of Wk 3 (n=228)
    -1.2 ( 15.75 )
        MtDf: Change at Beginning of Wk 5 (n=233)
    -2.0 ( 19.50 )
        MtDf: Change at end of Wk 6 (n=227)
    -1.3 ( 17.99 )
        MtDf: Change at Maintenance C1V1 (n=187)
    -2.3 ( 20.89 )
        MtDf: Change at Maintenance C1V2 (n=201)
    -0.3 ( 20.02 )
        MtDf: Change at Maintenance C2V1 (n=204)
    -2.4 ( 20.42 )
        MtDf: Change at Maintenance C2V2 (n=197)
    -1.6 ( 19.22 )
        MtDf: Change at Maintenance C3V1 (n=185)
    -3.2 ( 19.11 )
        MtDf: Change at Maintenance C3V2 (n=189)
    -2.9 ( 18.23 )
        MtDf: Change at Maintenance C4V1 (n=190)
    -2.9 ( 19.34 )
        MtDf: Change at Maintenance C4V2 (n=184)
    -1.4 ( 19.65 )
        MtDf: Change at Maintenance C5V1 (n=174)
    -1.0 ( 17.96 )
        MtDf: Change at Maintenance C5V2 (n=162)
    -1.6 ( 20.14 )
        MtDf: Change at Maintenance C6V1 (n=164)
    -2.6 ( 19.53 )
        MtDf: Change at Maintenance C6V2 (n=161)
    -1.9 ( 19.08 )
        MtDf: Change at Monotherapy V1 (n=153)
    -0.9 ( 19.81 )
        MtDf: Change at Monotherapy V2 (n=140)
    -1.2 ( 19.42 )
        MtDf: Change at Monotherapy V3 (n=131)
    -0.4 ( 21.19 )
        MtDf: Change at Monotherapy V4 (n=111)
    -1.2 ( 20.54 )
        MtDf: Change at Monotherapy V5 (n=99)
    1.3 ( 22.52 )
        MtDf: Change at Monotherapy V6 (n=95)
    -0.2 ( 23.52 )
        MtDf: Change at Monotherapy V7 (n=85)
    -0.2 ( 24.16 )
        MtDf: Change at Monotherapy V8 (n=71)
    -3.0 ( 21.76 )
        MtDf: Change at Monotherapy V9 (n=70)
    -4.2 ( 20.51 )
        MtDf: Change at Monotherapy V10 (n=68)
    -4.4 ( 22.34 )
        MtDf: Change at Monotherapy V11 (n=66)
    -1.5 ( 18.99 )
        MtDf: Change at Monotherapy V12 (n=59)
    -3.4 ( 20.45 )
        MtDf: Change at Monotherapy V13 (n=53)
    -2.9 ( 25.73 )
        MtDf: Change at Monotherapy V14 (n=53)
    -2.4 ( 22.69 )
        MtDf: Change at Monotherapy V15 (n=56)
    -5.4 ( 22.82 )
        MtDf: Change at Monotherapy V16 (n=47)
    -4.3 ( 21.30 )
        MtDf: Change at Monotherapy V17 (n=43)
    -2.1 ( 23.66 )
        MtDf: Change at Monotherapy V18 (n=39)
    1.9 ( 24.86 )
        MtDf: Change at Monotherapy V19 (n=36)
    -4.0 ( 20.60 )
        MtDf: Change at Monotherapy V20 (n=31)
    -2.2 ( 23.38 )
        MtDf: Change at Monotherapy V21 (n=28)
    -3.2 ( 20.48 )
        MtDf: Change at Monotherapy V22 (n=29)
    -6.5 ( 24.94 )
        MtDf: Change at Monotherapy V23 (n=27)
    -0.6 ( 22.98 )
        MtDf: Change at Monotherapy V24 (n=22)
    -4.0 ( 26.46 )
        MtDf: Change at Monotherapy V25 (n=22)
    -4.0 ( 26.46 )
        MtDf: Change at Monotherapy V26 (n=20)
    -5.6 ( 24.58 )
        MtDf: Change at Monotherapy V27 (n=20)
    -5.0 ( 25.10 )
        MtDf: Change at Monotherapy V28 (n=15)
    -5.2 ( 30.82 )
        MtDf: Change at Monotherapy V29 (n=16)
    -6.9 ( 27.78 )
        MtDf: Change at Monotherapy V30 (n=13)
    0 ( 25.26 )
        MtDf: Change at Monotherapy V31 (n=13)
    -3.4 ( 28.10 )
        MtDf: Change at Monotherapy V32 (n=9)
    -4.9 ( 28.39 )
        MtDf: Change at Monotherapy V33 (n=6)
    -7.4 ( 35.60 )
        MtDf: Change at Monotherapy V34 (n=6)
    -9.3 ( 28.47 )
        MtDf: Change at Monotherapy V35 (n=4)
    0 ( 0 )
        MtDf: Change at Monotherapy V36 (n=5)
    -15.6 ( 34.78 )
        MtDf: Change at Monotherapy V37 (n=4)
    0 ( 0 )
        MtDf: Change at Monotherapy V38 (n=2)
    0 ( 0 )
        MtDf: Change at Monotherapy V39 (n=2)
    0 ( 0 )
        MtDf: Change at Monotherapy V40 (n=3)
    0 ( 0 )
        MtDf: Change at Monotherapy V41 (n=3)
    0 ( 0 )
        MtDf: Change at Monotherapy V42 (n=2)
    0 ( 0 )
        MtDf: Change at Monotherapy V43 (n=3)
    0 ( 0 )
        MtDf: Change at Monotherapy V44 (n=2)
    0 ( 0 )
        MtDf: Change at Safety FU (n=49)
    -2.4 ( 23.30 )
        MtDf: Change at PD FU1 (n=40)
    5.8 ( 28.99 )
        MtDf: Change at PD FU2 (n=17)
    12.7 ( 15.44 )
        MtDf: Change at PD FU3 (n=10)
    -3.3 ( 20.32 )
        MtDf: Change at PD FU4 (n=9)
    1.2 ( 35.33 )
        MtDf: Change at PD FU5 (n=4)
    2.8 ( 40.95 )
        MtDf: Change at PD FU6 (n=3)
    3.7 ( 16.97 )
        MtDf: Change at PD FU7 (n=2)
    11.1 ( 15.71 )
        MtDf: Change at PD FU8 (n=1)
    0 ( 99999 )
        CmDf: Baseline (n=255)
    17.2 ( 24.37 )
        CmDf: Change at Beginning of Wk 3 (n=228)
    -4.0 ( 21.50 )
        CmDf: Change at Beginning of Wk 5 (n=233)
    -4.6 ( 21.86 )
        CmDf: Change at end of Wk 6 (n=227)
    -2.8 ( 20.43 )
        CmDf: Change at Maintenance C1V1 (n=186)
    -2.0 ( 22.83 )
        CmDf: Change at Maintenance C1V2 (n=200)
    -2.9 ( 22.04 )
        CmDf: Change at Maintenance C2V1 (n=203)
    -4.2 ( 19.14 )
        CmDf: Change at Maintenance C2V2 (n=196)
    -2.7 ( 21.17 )
        CmDf: Change at Maintenance C3V1 (n=183)
    -2.9 ( 19.87 )
        CmDf: Change at Maintenance C3V2 (n=187)
    -3.4 ( 19.48 )
        CmDf: Change at Maintenance C4V1 (n=189)
    -3.0 ( 20.70 )
        CmDf: Change at Maintenance C4V2 (n=184)
    -3.6 ( 20.23 )
        CmDf: Change at Maintenance C5V1 (n=173)
    -3.5 ( 20.27 )
        CmDf: Change at Maintenance C5V2 (n=162)
    -3.2 ( 21.11 )
        CmDf: Change at Maintenance C6V1 (n=163)
    -3.1 ( 20.56 )
        CmDf: Change at Maintenance C6V2 (n=158)
    -3.9 ( 20.39 )
        CmDf: Change at Monotherapy V1 (n=153)
    -1.3 ( 21.70 )
        CmDf: Change at Monotherapy V2 (n=139)
    -1.0 ( 19.82 )
        CmDf: Change at Monotherapy V3 (n=131)
    -3.3 ( 19.42 )
        CmDf: Change at Monotherapy V4 (n=111)
    -2.8 ( 20.53 )
        CmDf: Change at Monotherapy V5 (n=99)
    -2.2 ( 20.69 )
        CmDf: Change at Monotherapy V6 (n=95)
    0.1 ( 23.57 )
        CmDf: Change at Monotherapy V7 (n=85)
    0.1 ( 24.70 )
        CmDf: Change at Monotherapy V8 (n=71)
    0.4 ( 26.47 )
        CmDf: Change at Monotherapy V9 (n=70)
    -3.1 ( 21.23 )
        CmDf: Change at Monotherapy V10 (n=68)
    -4.1 ( 23.97 )
        CmDf: Change at Monotherapy V11 (n=66)
    -3.0 ( 22.52 )
        CmDf: Change at Monotherapy V12 (n=59)
    -1.0 ( 22.64 )
        CmDf: Change at Monotherapy V13 (n=52)
    -1.6 ( 26.14 )
        CmDf: Change at Monotherapy V14 (n=53)
    -2.5 ( 22.92 )
        CmDf: Change at Monotherapy V15 (n=56)
    -0.6 ( 26.33 )
        CmDf: Change at Monotherapy V16 (n=47)
    0.2 ( 27.26 )
        CmDf: Change at Monotherapy V17 (n=42)
    -0.5 ( 26.76 )
        CmDf: Change at Monotherapy V18 (n=39)
    2.6 ( 31.16 )
        CmDf: Change at Monotherapy V19 (n=36)
    -2.2 ( 28.09 )
        CmDf: Change at Monotherapy V20 (n=31)
    -1.1 ( 29.73 )
        CmDf: Change at Monotherapy V21 (n=28)
    -4.0 ( 17.69 )
        CmDf: Change at Monotherapy V22 (n=28)
    -4.4 ( 28.90 )
        CmDf: Change at Monotherapy V23 (n=27)
    -6.6 ( 31.16 )
        CmDf: Change at Monotherapy V24 (n=21)
    -11.1 ( 28.97 )
        CmDf: Change at Monotherapy V25 (n=21)
    -3.2 ( 36.20 )
        CmDf: Change at Monotherapy V26 (n=20)
    -4.4 ( 33.70 )
        CmDf: Change at Monotherapy V27 (n=20)
    -8.6 ( 29.86 )
        CmDf: Change at Monotherapy V28 (n=15)
    -5.9 ( 38.00 )
        CmDf: Change at Monotherapy V29 (n=15)
    -14.8 ( 30.19 )
        CmDf: Change at Monotherapy V30 (n=13)
    -17.1 ( 31.95 )
        CmDf: Change at Monotherapy V31 (n=13)
    -5.1 ( 40.98 )
        CmDf: Change at Monotherapy V32 (n=9)
    -6.2 ( 21.60 )
        CmDf: Change at Monotherapy V33 (n=6)
    -7.4 ( 16.73 )
        CmDf: Change at Monotherapy V34 (n=6)
    -6.5 ( 18.06 )
        CmDf: Change at Monotherapy V35 (n=4)
    -13.9 ( 16.67 )
        CmDf: Change at Monotherapy V36 (n=5)
    -6.7 ( 21.66 )
        CmDf: Change at Monotherapy V37 (n=4)
    -13.9 ( 16.67 )
        CmDf: Change at Monotherapy V38 (n=2)
    -27.8 ( 7.86 )
        CmDf: Change at Monotherapy V39 (n=2)
    -11.1 ( 15.71 )
        CmDf: Change at Monotherapy V40 (n=3)
    -18.5 ( 16.97 )
        CmDf: Change at Monotherapy V41 (n=3)
    -18.5 ( 16.97 )
        CmDf: Change at Monotherapy V42 (n=2)
    -11.1 ( 15.71 )
        CmDf: Change at Monotherapy V43 (n=3)
    -18.5 ( 16.97 )
        CmDf: Change at Monotherapy V44 (n=2)
    -27.8 ( 7.86 )
        CmDf: Change at Safety FU (n=50)
    -2.9 ( 25.67 )
        CmDf: Change at PD FU1 (n=40)
    2.4 ( 28.10 )
        CmDf: Change at PD FU2 (n=17)
    0.3 ( 21.02 )
        CmDf: Change at PD FU3 (n=10)
    0 ( 14.81 )
        CmDf: Change at PD FU4 (n=9)
    8.6 ( 15.49 )
        CmDf: Change at PD FU5 (n=4)
    11.1 ( 15.71 )
        CmDf: Change at PD FU6 (n=3)
    14.8 ( 16.97 )
        CmDf: Change at PD FU7 (n=2)
    5.6 ( 7.86 )
        CmDf: Change at PD FU8 (n=1)
    0 ( 99999 )
    No statistical analyses for this end point

    Secondary: 2L and 3L Treatment: Change From 2L Baseline in EORTC QLQ BN20 Multiple Item Score

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    End point title
    		 2L and 3L Treatment: Change From 2L Baseline in EORTC QLQ BN20 Multiple Item Score
    End point description
    The BN20 consists of 4 multiple items scales (future uncertainty [FtUn], visual disorder [VsDr], motor dysfunction [MtDf], communication deficit [CmDf]) and 7 single items (headache, seizures, drowsiness, hair loss, itching, difficulty with bladder control, and weakness of both legs). All questions used 4-point scale (1='Not at all' to 4='Very much'). Multiple item scores were transformed to a 0-100 scale, where higher score=more severe symptoms/poor QoL. The change from baseline in multiple items scales score at different time points is reported. Analysis was performed on ITT population. 'Number of Subject Analysed'=participants evaluable for this outcome measure; 'n'=participants evaluable at specified time point for different arms, respectively; ‘99999’=either data were not available because no participant was evaluable or SD was not available because only 1 participant was evaluable at indicated time point.
    End point type
    Secondary
    End point timeframe
    2L Baseline (2L treatment V1); 2L treatment: V2-V41 (Q2W) until PD2; 3L treatment: V1-V61 (Q2W) until PD3; Safety FU (30 days after last 3L dose); PD FU1 (8 Wk after Safety FU); end of study (up to 41 months overall)
    End point values
    		 Placebo + Lomustine/SOC (ITT) Bevacizumab + Lomustine/SOC (ITT)
    Number of subjects analysed
    57
    59
    Units: units on a scale
    arithmetic mean (standard deviation)
        FtUn: 2L Baseline (n=57,59)
    28.9 ( 25.90 )
    37.2 ( 26.69 )
        FtUn: Change at 2L V2 (n=44,38)
    0.7 ( 19.32 )
    -0.9 ( 16.19 )
        FtUn: Change at 2L V3 (n=39,37)
    3.8 ( 17.08 )
    -3.9 ( 22.89 )
        FtUn: Change at 2L V4 (n=28,31)
    3.3 ( 12.49 )
    -2.4 ( 20.66 )
        FtUn: Change at 2L V5 (n=21,19)
    0.8 ( 11.76 )
    -12.3 ( 18.50 )
        FtUn: Change at 2L V6 (n=17,14)
    14.1 ( 19.78 )
    -8.3 ( 17.60 )
        FtUn: Change at 2L V7 (n=7,10)
    -4.8 ( 13.49 )
    -5.0 ( 17.21 )
        FtUn: Change at 2L V8 (n=4,7)
    -2.1 ( 4.17 )
    -4.4 ( 18.69 )
        FtUn: Change at 2L V9 (n=5,8)
    1.7 ( 12.36 )
    -4.9 ( 22.80 )
        FtUn: Change at 2L V10 (n=4,6)
    -6.3 ( 12.50 )
    -15.3 ( 18.57 )
        FtUn: Change at 2L V11 (n=4,6)
    4.2 ( 4.81 )
    -8.8 ( 24.18 )
        FtUn: Change at 2L V12 (n=2,4)
    12.5 ( 17.68 )
    -16.7 ( 20.41 )
        FtUn: Change at 2L V13 (n=3,3)
    8.3 ( 16.67 )
    -22.2 ( 17.35 )
        FtUn: Change at 2L V14 (n=2,1)
    8.3 ( 11.79 )
    -8.3 ( 99999 )
        FtUn: Change at 2L V15 (n=1,1)
    8.3 ( 99999 )
    -8.3 ( 99999 )
        FtUn: Change at 2L V16 (n=1,0)
    25.0 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 2L V17 (n=1,1)
    8.3 ( 99999 )
    -8.3 ( 99999 )
        FtUn: Change at 2L V18 (n=0,1)
    99999 ( 99999 )
    0 ( 99999 )
        FtUn: Change at 2L V19 (n=1,0)
    16.7 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 2L V20 (n=1,0)
    25.0 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 2L V21 (n=1,0)
    25.0 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 2L V22 (n=1,0)
    25.0 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 2L V24 (n=1,0)
    8.3 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 2L V25 (n=1,0)
    8.3 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 2L V26 (n=1,0)
    25.0 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 2L V27 (n=1,0)
    25.0 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 2L V28 (n=1,0)
    25.0 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 2L V29 (n=1,0)
    25.0 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 2L V30 (n=1,0)
    16.7 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 2L V31 (n=1,0)
    25.0 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 2L V32 (n=1,0)
    33.3 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 2L V33 (n=1,0)
    33.3 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 2L V34 (n=1,0)
    33.3 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 2L V35 (n=1,0)
    41.7 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 2L V36 (n=1,0)
    50.0 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 2L V38 (n=1,0)
    16.7 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 2L V39 (n=1,0)
    25.0 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 2L V40 (n=1,0)
    41.7 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 2L V41 (n=1,0)
    33.3 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 3L V1 (n=17,17)
    10.3 ( 19.66 )
    7.2 ( 19.89 )
        FtUn: Change at 3L V2 (n=13,14)
    7.1 ( 14.77 )
    6.9 ( 19.48 )
        FtUn: Change at 3L V3 (n=11,13)
    4.5 ( 15.53 )
    7.1 ( 19.50 )
        FtUn: Change at 3L V4 (n=12,13)
    12.5 ( 22.33 )
    4.5 ( 21.41 )
        FtUn: Change at 3L V5 (n=9,8)
    2.8 ( 17.18 )
    -2.1 ( 15.27 )
        FtUn: Change at 3L V6 (n=6,3)
    7.4 ( 19.38 )
    2.8 ( 17.35 )
        FtUn: Change at 3L V7 (n=3,4)
    13.9 ( 24.06 )
    8.3 ( 28.87 )
        FtUn: Change at 3L V8 (n=3,3)
    0 ( 0 )
    -11.1 ( 19.25 )
        FtUn: Change at 3L V9 (n=3,3)
    0 ( 14.43 )
    -11.1 ( 19.25 )
        FtUn: Change at 3L V10 (n=3,1)
    16.7 ( 25.00 )
    8.3 ( 99999 )
        FtUn: Change at 3L V11 (n=2,1)
    -8.3 ( 23.57 )
    -33.3 ( 99999 )
        FtUn: Change at 3L V12 (n=2,2)
    4.2 ( 17.68 )
    -16.7 ( 23.57 )
        FtUn: Change at 3L V13 (n=2,0)
    0 ( 23.57 )
    99999 ( 99999 )
        FtUn: Change at 3L V14 (n=2,0)
    0 ( 11.79 )
    99999 ( 99999 )
        FtUn: Change at 3L V15 (n=2,0)
    8.3 ( 23.57 )
    99999 ( 99999 )
        FtUn: Change at 3L V16 (n=2,0)
    0 ( 11.79 )
    99999 ( 99999 )
        FtUn: Change at 3L V17 (n=2,0)
    8.3 ( 23.57 )
    99999 ( 99999 )
        FtUn: Change at 3L V18 (n=2,0)
    0 ( 11.79 )
    99999 ( 99999 )
        FtUn: Change at 3L V19 (n=1,0)
    -8.3 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 3L V20 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 3L V21 (n=1,0)
    -8.3 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 3L V22 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 3L V23 (n=1,0)
    -8.3 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 3L V25 (n=1,0)
    -16.7 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 3L V26 (n=1,0)
    -16.7 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 3L V27 (n=1,0)
    -16.7 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 3L V28 (n=1,0)
    -8.3 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 3L V30 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 3L V31 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 3L V32 (n=1,0)
    -8.3 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 3L V33 (n=1,0)
    8.3 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 3L V34 (n=1,0)
    -8.3 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 3L V35 (n=1,0)
    8.3 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 3L V36 (n=1,0)
    8.3 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 3L V37 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 3L V38 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 3L V39 (n=1,0)
    8.3 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 3L V41 (n=1,0)
    -8.3 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 3L V42 (n=1,0)
    8.3 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 3L V43 (n=1,0)
    8.3 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 3L V44 (n=1,0)
    8.3 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 3L V45 (n=1,0)
    -8.3 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 3L V46 (n=1,0)
    -8.3 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 3L V47 (n=1,0)
    -8.3 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 3L V48 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 3L V49 (n=1,0)
    8.3 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 3L V51 (n=1,0)
    8.3 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 3L V52 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 3L V53 (n=1,0)
    8.3 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 3L V54 (n=1,0)
    8.3 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 3L V55 (n=1,0)
    -8.3 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 3L V56 (n=1,0)
    8.3 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 3L V57 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 3L V58 (n=1,0)
    -8.3 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 3L V59 (n=1,0)
    -16.7 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 3L V60 (n=1,0)
    -8.3 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at 3L V61 (n=1,0)
    8.3 ( 99999 )
    99999 ( 99999 )
        FtUn: Change at Safety FU (n=6,12)
    23.6 ( 14.35 )
    0.7 ( 17.93 )
        FtUn: Change at PD FU1 (n=1,3)
    0 ( 99999 )
    11.1 ( 4.81 )
        FtUn: Change at end of study (n=3,2)
    22.2 ( 9.62 )
    -8.3 ( 11.79 )
        VsDr: 2L Baseline (n=57,59)
    11.8 ( 17.63 )
    18.6 ( 25.72 )
        VsDr: Change at 2L V2 (n=44,38)
    0.8 ( 10.55 )
    -0.7 ( 12.53 )
        VsDr: Change at 2L V3 (n=39,37)
    1.7 ( 10.05 )
    -6.3 ( 20.54 )
        VsDr: Change at 2L V4 (n=28,31)
    1.2 ( 7.76 )
    0.7 ( 21.07 )
        VsDr: Change at 2L V5 (n=21,19)
    2.6 ( 9.88 )
    -8.8 ( 18.36 )
        VsDr: Change at 2L V6 (n=17,14)
    4.6 ( 17.15 )
    -11.9 ( 27.72 )
        VsDr: Change at 2L V7 (n=7,10)
    0 ( 6.42 )
    -11.1 ( 24.57 )
        VsDr: Change at 2L V8 (n=4,7)
    -2.8 ( 5.56 )
    -9.5 ( 26.00 )
        VsDr: Change at 2L V9 (n=5,7)
    6.7 ( 9.94 )
    -11.1 ( 24.85 )
        VsDr: Change at 2L V10 (n=4,6)
    2.8 ( 5.56 )
    -11.1 ( 27.22 )
        VsDr: Change at 2L V11 (n=4,6)
    2.8 ( 5.56 )
    -8.3 ( 20.41 )
        VsDr: Change at 2L V12 (n=2,4)
    5.6 ( 7.86 )
    -16.7 ( 33.33 )
        VsDr: Change at 2L V13 (n=3,3)
    11.1 ( 11.11 )
    -16.7 ( 28.87 )
        VsDr: Change at 2L V14 (n=2,1)
    11.1 ( 15.71 )
    0 ( 99999 )
        VsDr: Change at 2L V15 (n=1,1)
    0 ( 99999 )
    0 ( 99999 )
        VsDr: Change at 2L V16 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 2L V17 (n=1,1)
    0 ( 99999 )
    0 ( 99999 )
        VsDr: Change at 2L V18 (n=0,1)
    99999 ( 99999 )
    0 ( 99999 )
        VsDr: Change at 2L V19 (n=1,0)
    11.1 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 2L V20 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 2L V21 (n=1,0)
    11.1 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 2L V22 (n=1,0)
    11.1 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 2L V24 (n=1,0)
    11.1 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 2L V25 (n=1,0)
    5.6 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 2L V26 (n=1,0)
    11.1 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 2L V27 (n=1,0)
    11.1 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 2L V28 (n=1,0)
    -11.1 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 2L V29 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 2L V30 (n=1,0)
    11.1 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 2L V31 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 2L V32 (n=1,0)
    11.1 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 2L V33 (n=1,0)
    11.1 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 2L V34 (n=1,0)
    11.1 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 2L V35 (n=1,0)
    11.1 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 2L V36 (n=1,0)
    11.1 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 2L V38 (n=1,0)
    11.1 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 2L V39 (n=1,0)
    11.1 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 2L V40 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 2L V41 (n=1,0)
    -11.1 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 3L V1 (n=17,16)
    7.8 ( 25.39 )
    5.6 ( 21.47 )
        VsDr: Change at 3L V2 (n=13,14)
    5.6 ( 14.34 )
    14.3 ( 17.12 )
        VsDr: Change at 3L V3 (n=11,14)
    -1.0 ( 3.35 )
    9.5 ( 17.89 )
        VsDr: Change at 3L V4 (n=12,13)
    1.9 ( 13.26 )
    12.8 ( 16.88 )
        VsDr: Change at 3L V5 (n=9,8)
    0 ( 5.56 )
    6.9 ( 15.64 )
        VsDr: Change at 3L V6 (n=6,3)
    0 ( 7.03 )
    18.5 ( 23.13 )
        VsDr: Change at 3L V7 (n=3,4)
    0 ( 11.11 )
    2.8 ( 5.56 )
        VsDr: Change at 3L V8 (n=3,3)
    -3.7 ( 6.42 )
    0 ( 0 )
        VsDr: Change at 3L V9 (n=3,3)
    0 ( 11.11 )
    0 ( 0 )
        VsDr: Change at 3L V10 (n=3,1)
    0 ( 11.11 )
    0 ( 99999 )
        VsDr: Change at 3L V11 (n=2,1)
    0 ( 0 )
    0 ( 99999 )
        VsDr: Change at 3L V12 (n=2,2)
    0 ( 0 )
    0 ( 0 )
        VsDr: Change at 3L V13 (n=2,0)
    5.6 ( 7.86 )
    99999 ( 99999 )
        VsDr: Change at 3L V14 (n=2,0)
    0 ( 0 )
    99999 ( 99999 )
        VsDr: Change at 3L V15 (n=2,0)
    0 ( 0 )
    99999 ( 99999 )
        VsDr: Change at 3L V16 (n=2,0)
    5.6 ( 7.86 )
    99999 ( 99999 )
        VsDr: Change at 3L V17 (n=2,0)
    5.6 ( 7.86 )
    99999 ( 99999 )
        VsDr: Change at 3L V18 (n=2,0)
    5.6 ( 7.86 )
    99999 ( 99999 )
        VsDr: Change at 3L V19 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 3L V20 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 3L V21 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 3L V22 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 3L V23 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 3L V25 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 3L V26 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 3L V27 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 3L V28 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 3L V30 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 3L V31 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 3L V32 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 3L V33 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 3L V34 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 3L V35 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 3L V36 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 3L V37 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 3L V38 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 3L V39 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 3L V41 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 3L V42 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 3L V43 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 3L V44 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 3L V45 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 3L V46 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 3L V47 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 3L V48 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 3L V49 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 3L V51 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 3L V52 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 3L V53 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 3L V54 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 3L V55 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 3L V56 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 3L V57 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 3L V58 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 3L V59 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 3L V60 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at 3L V61 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        VsDr: Change at Safety FU (n=6,12)
    11.1 ( 24.34 )
    -2.8 ( 26.85 )
        VsDr: Change at PD FU1 (n=1,3)
    0 ( 99999 )
    -7.4 ( 6.42 )
        VsDr: Change at end of study (n=3,2)
    27.8 ( 25.46 )
    0 ( 0 )
        MtDf: 2L Baseline (n=57,59)
    17.5 ( 23.75 )
    19.3 ( 25.49 )
        MtDf: Change at 2L V2 (n=44,38)
    3.3 ( 14.49 )
    3.4 ( 15.04 )
        MtDf: Change at 2L V3 (n=39,37)
    3.7 ( 12.83 )
    3.0 ( 21.97 )
        MtDf: Change at 2L V4 (n=27,30)
    7.2 ( 15.39 )
    11.9 ( 19.78 )
        MtDf: Change at 2L V5 (n=20,19)
    10.0 ( 17.99 )
    8.2 ( 14.27 )
        MtDf: Change at 2L V6 (n=17,14)
    13.7 ( 20.98 )
    10.3 ( 15.39 )
        MtDf: Change at 2L V7 (n=7,10)
    12.7 ( 22.62 )
    8.9 ( 20.15 )
        MtDf: Change at 2L V8 (n=4,7)
    11.1 ( 20.29 )
    11.1 ( 25.66 )
        MtDf: Change at 2L V9 (n=5,8)
    6.7 ( 14.91 )
    8.3 ( 33.99 )
        MtDf: Change at 2L V10 (n=4,6)
    0 ( 0 )
    0 ( 7.03 )
        MtDf: Change at 2L V11 (n=4,6)
    0 ( 0 )
    0.9 ( 7.38 )
        MtDf: Change at 2L V12 (n=2,4)
    0 ( 0 )
    0 ( 0 )
        MtDf: Change at 2L V13 (n=3,3)
    0 ( 0 )
    11.1 ( 11.11 )
        MtDf: Change at 2L V14 (n=2,1)
    0 ( 0 )
    0 ( 99999 )
        MtDf: Change at 2L V15 (n=1,1)
    0 ( 99999 )
    -11.1 ( 99999 )
        MtDf: Change at 2L V16 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 2L V17 (n=1,1)
    0 ( 99999 )
    0 ( 99999 )
        MtDf: Change at 2L V18 (n=0,1)
    99999 ( 99999 )
    0 ( 99999 )
        MtDf: Change at 2L V19 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 2L V20 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 2L V21 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 2L V22 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 2L V24 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 2L V25 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 2L V26 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 2L V27 (n=1,0)
    11.1 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 2L V28 (n=1,0)
    -22.2 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 2L V29 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 2L V30 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 2L V31 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 2L V32 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 2L V33 (n=1,0)
    11.1 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 2L V34 (n=1,0)
    22.2 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 2L V35 (n=1,0)
    22.2 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 2L V36 (n=1,0)
    22.2 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 2L V38 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 2L V39 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 2L V40 (n=1,0)
    11.1 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 2L V41 (n=1,0)
    11.1 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 3L V1 (n=17,16)
    5.2 ( 20.83 )
    27.1 ( 37.18 )
        MtDf: Change at 3L V2 (n=13,14)
    6.8 ( 16.69 )
    15.9 ( 27.81 )
        MtDf: Change at 3L V3 (n=11,14)
    1.0 ( 3.35 )
    20.6 ( 30.46 )
        MtDf: Change at 3L V4 (n=12,13)
    3.7 ( 13.68 )
    29.1 ( 35.00 )
        MtDf: Change at 3L V5 (n=9,8)
    2.5 ( 9.26 )
    21.5 ( 29.46 )
        MtDf: Change at 3L V6 (n=6,3)
    3.7 ( 9.07 )
    22.2 ( 19.25 )
        MtDf: Change at 3L V7 (n=3,4)
    7.4 ( 12.83 )
    19.4 ( 38.89 )
        MtDf: Change at 3L V8 (n=3,3)
    0 ( 0 )
    0 ( 0 )
        MtDf: Change at 3L V9 (n=3,3)
    7.4 ( 12.83 )
    0 ( 0 )
        MtDf: Change at 3L V10 (n=3,1)
    0 ( 0 )
    11.1 ( 99999 )
        MtDf: Change at 3L V11 (n=2,1)
    0 ( 0 )
    0 ( 99999 )
        MtDf: Change at 3L V12 (n=2,2)
    0 ( 0 )
    0 ( 0 )
        MtDf: Change at 3L V13 (n=2,0)
    0 ( 0 )
    99999 ( 99999 )
        MtDf: Change at 3L V14 (n=2,0)
    0 ( 0 )
    99999 ( 99999 )
        MtDf: Change at 3L V15 (n=2,0)
    -11.1 ( 15.71 )
    99999 ( 99999 )
        MtDf: Change at 3L V16 (n=2,0)
    0 ( 0 )
    99999 ( 99999 )
        MtDf: Change at 3L V17 (n=2,0)
    -11.1 ( 15.71 )
    99999 ( 99999 )
        MtDf: Change at 3L V18 (n=2,0)
    0 ( 0 )
    99999 ( 99999 )
        MtDf: Change at 3L V19 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 3L V20 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 3L V21 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 3L V22 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 3L V23 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 3L V25 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 3L V26 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 3L V27 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 3L V28 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 3L V30 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 3L V31 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 3L V32 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 3L V33 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 3L V34 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 3L V35 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 3L V36 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 3L V37 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 3L V38 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 3L V39 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 3L V41 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 3L V42 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 3L V43 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 3L V44 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 3L V45 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 3L V46 (n=1,0)
    -11.1 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 3L V47 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 3L V48 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 3L V49 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 3L V51 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 3L V52 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 3L V53 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 3L V54 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 3L V55 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 3L V56 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 3L V57 (n=1,0)
    -11.1 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 3L V58 (n=1,0)
    -11.1 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 3L V59 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 3L V60 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at 3L V61 (n=1,0)
    -11.1 ( 99999 )
    99999 ( 99999 )
        MtDf: Change at Safety FU (n=6,12)
    7.4 ( 19.46 )
    11.6 ( 12.19 )
        MtDf: Change at PD FU1 (n=1,3)
    0 ( 99999 )
    22.2 ( 11.11 )
        MtDf: Change at end of study (n=3,2)
    29.6 ( 33.95 )
    11.1 ( 15.71 )
        CmDf: 2L Baseline (n=57,59)
    17.3 ( 22.62 )
    24.1 ( 25.45 )
        CmDf: Change at 2L V2 (n=44,38)
    1.0 ( 14.54 )
    -1.5 ( 12.43 )
        CmDf: Change at 2L V3 (n=39,38)
    2.8 ( 12.67 )
    2.6 ( 18.53 )
        CmDf: Change at 2L V4 (n=27,30)
    -0.4 ( 13.60 )
    1.1 ( 13.79 )
        CmDf: Change at 2L V5 (n=21,19)
    -3.2 ( 15.37 )
    -0.3 ( 11.78 )
        CmDf: Change at 2L V6 (n=17,14)
    4.6 ( 18.03 )
    -1.6 ( 15.63 )
        CmDf: Change at 2L V7 (n=7,10)
    -1.6 ( 10.00 )
    2.2 ( 12.61 )
        CmDf: Change at 2L V8 (n=4,7)
    0 ( 0 )
    0.8 ( 15.85 )
        CmDf: Change at 2L V9 (n=5,8)
    -2.2 ( 4.97 )
    6.9 ( 17.76 )
        CmDf: Change at 2L V10 (n=4,6)
    2.8 ( 5.56 )
    7.4 ( 21.85 )
        CmDf: Change at 2L V11 (n=4,6)
    -2.8 ( 5.56 )
    -1.9 ( 8.36 )
        CmDf: Change at 2L V12 (n=2,4)
    0 ( 0 )
    8.3 ( 18.98 )
        CmDf: Change at 2L V13 (n=3,3)
    0 ( 0 )
    3.7 ( 25.66 )
        CmDf: Change at 2L V14 (n=2,1)
    5.6 ( 7.86 )
    -16.7 ( 99999 )
        CmDf: Change at 2L V15 (n=1,1)
    11.1 ( 99999 )
    -11.1 ( 99999 )
        CmDf: Change at 2L V16 (n=1,0)
    11.1 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 2L V17 (n=1,1)
    11.1 ( 99999 )
    -11.1 ( 99999 )
        CmDf: Change at 2L V18 (n=0,1)
    99999 ( 99999 )
    -11.1 ( 99999 )
        CmDf: Change at 2L V19 (n=1,0)
    11.1 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 2L V20 (n=1,0)
    11.1 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 2L V21 (n=1,0)
    11.1 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 2L V22 (n=1,0)
    11.1 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 2L V24 (n=1,0)
    11.1 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 2L V25 (n=1,0)
    5.6 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 2L V26 (n=1,0)
    11.1 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 2L V27 (n=1,0)
    11.1 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 2L V28 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 2L V29 (n=1,0)
    22.2 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 2L V30 (n=1,0)
    11.1 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 2L V31 (n=1,0)
    11.1 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 2L V32 (n=1,0)
    11.1 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 2L V33 (n=1,0)
    11.1 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 2L V34 (n=1,0)
    33.3 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 2L V35 (n=1,0)
    22.2 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 2L V36 (n=1,0)
    22.2 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 2L V38 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 2L V39 (n=1,0)
    22.2 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 2L V40 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 2L V41 (n=1,0)
    22.2 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 3L V1 (n=17,16)
    3.9 ( 19.62 )
    9.0 ( 19.55 )
        CmDf: Change at 3L V2 (n=13,13)
    0.9 ( 15.36 )
    3.4 ( 16.60 )
        CmDf: Change at 3L V3 (n=11,14)
    -2.0 ( 10.91 )
    5.6 ( 19.85 )
        CmDf: Change at 3L V4 (n=12,13)
    2.8 ( 10.73 )
    8.5 ( 24.91 )
        CmDf: Change at 3L V5 (n=9,8)
    1.2 ( 15.16 )
    5.6 ( 26.56 )
        CmDf: Change at 3L V6 (n=6,3)
    -1.9 ( 24.76 )
    0 ( 11.11 )
        CmDf: Change at 3L V7 (n=3,4)
    -11.1 ( 19.25 )
    -2.8 ( 13.98 )
        CmDf: Change at 3L V8 (n=3,3)
    -14.8 ( 16.97 )
    -7.4 ( 12.83 )
        CmDf: Change at 3L V9 (n=3,3)
    -22.2 ( 29.40 )
    -7.4 ( 12.83 )
        CmDf: Change at 3L V10 (n=3,1)
    -7.4 ( 12.83 )
    0 ( 99999 )
        CmDf: Change at 3L V11 (n=2,1)
    -5.6 ( 7.86 )
    -22.2 ( 99999 )
        CmDf: Change at 3L V12 (n=2,2)
    5.6 ( 7.86 )
    -11.1 ( 15.71 )
        CmDf: Change at 3L V13 (n=2,0)
    5.6 ( 7.86 )
    99999 ( 99999 )
        CmDf: Change at 3L V14 (n=2,0)
    -5.6 ( 7.86 )
    99999 ( 99999 )
        CmDf: Change at 3L V15 (n=2,0)
    5.6 ( 7.86 )
    99999 ( 99999 )
        CmDf: Change at 3L V16 (n=2,0)
    -5.6 ( 7.86 )
    99999 ( 99999 )
        CmDf: Change at 3L V17 (n=2,0)
    5.6 ( 7.86 )
    99999 ( 99999 )
        CmDf: Change at 3L V18 (n=2,0)
    11.1 ( 15.71 )
    99999 ( 99999 )
        CmDf: Change at 3L V19 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 3L V20 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 3L V21 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 3L V22 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 3L V23 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 3L V25 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 3L V26 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 3L V27 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 3L V28 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 3L V30 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 3L V31 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 3L V32 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 3L V33 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 3L V34 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 3L V35 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 3L V36 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 3L V37 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 3L V38 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 3L V39 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 3L V41 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 3L V42 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 3L V43 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 3L V44 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 3L V45 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 3L V46 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 3L V47 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 3L V48 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 3L V49 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 3L V51 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 3L V52 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 3L V53 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 3L V54 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 3L V55 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 3L V56 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 3L V57 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 3L V58 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 3L V59 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 3L V60 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at 3L V61 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        CmDf: Change at Safety FU (n=6,12)
    1.9 ( 4.54 )
    8.3 ( 16.50 )
        CmDf: Change at PD FU1 (n=1,3)
    22.2 ( 99999 )
    44.4 ( 11.11 )
        CmDf: Change at end of study (n=3,2)
    7.4 ( 6.42 )
    0 ( 0 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Mini Mental Status Examination (MMSE) Score <27 or >/=27

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    End point title
    		 Percentage of Participants with Mini Mental Status Examination (MMSE) Score <27 or >/=27
    End point description
    The MMSE score measures general cognitive functioning (via following subscales: orientation, memory, attention, concentration, naming, repetition, comprehension, and ability to create a sentence and to copy two intersecting polygons). It was used to screen for cognitive impairment at a given point in time. Total score is derived from sub-scores; total score ranged from 0 to 30, with higher score = better cognitive state. Percentage of participants with MMSE total score <27 or >/=27 is reported at Baseline and 2L-Baseline. Analysis was performed on enrolled analysis set for Baseline and on ITT population for 2L Baseline. 'Number of Subject Analysed'=participants evaluable for this outcome measure at Baseline/2L Baseline.
    End point type
    Secondary
    End point timeframe
    Baseline [for 1L Bevacizumab] and 2L Baseline [for Placebo + Lomustine/SOC (ITT) and Bevacizumab + Lomustine/SOC (ITT)]
    End point values
    		 1L Bevacizumab Placebo + Lomustine/SOC (ITT) Bevacizumab + Lomustine/SOC (ITT)
    Number of subjects analysed
    225
    55
    58
    Units: percentage of participants
    number (not applicable)
        MMSE total score <27
    26.7
    29.1
    37.9
        MMSE total score >/=27
    71.1
    70.9
    62.1
        Missing
    2.2
    0.0
    0.0
    No statistical analyses for this end point

    Secondary: 1L Treatment: Change From Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Part A (Immediate Recall) z-score

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    End point title
    		 1L Treatment: Change From Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Part A (Immediate Recall) z-score
    End point description
    The HVLT-R is a test of learning and memory consisting of 3 parts (Part A, B, and C). In Part A (immediate recall), the participant was asked to learn and recall a list of 12 words over three trials. The Part A score ranges from 0 to 36, with higher scores = better memory. The raw scores were normalized into standardized z-scores for each time point using participant’s age at enrollment. The change from Baseline in z-scores was then calculated for each time point and is reported here. Analysis was performed on enrolled analysis set. 'Number of Subject Analysed'=participants evaluable for this outcome measure; 'n'=participants evaluable at specified time point; ‘99999’=SD could not be calculated as only 1 participant was evaluable at indicated time point.
    End point type
    Secondary
    End point timeframe
    Baseline; Maintenance: D1(V1) Cycles 1, 3, 5 (Q4W); Monotherapy: every 3rd visit starting from V1 to V43 (Q3W); Safety FU (30 days after last 1L dose); PD FUs (8 Wk after Safety FU [PD FU1], then every 12 Wk until PD1) (up to 41 months overall)
    End point values
    		 1L Bevacizumab
    Number of subjects analysed
    220
    Units: z-score
    arithmetic mean (standard deviation)
        Baseline (n=220)
    -1.60 ( 1.625 )
        Change at Maintenance C1V1 (n=198)
    0.03 ( 1.204 )
        Change at Maintenance C3V1 (n=176)
    -0.13 ( 1.416 )
        Change at Maintenance C5V1 (n=154)
    0.08 ( 1.400 )
        Change at Monotherapy V1 (n=134)
    0.01 ( 1.319 )
        Change at Monotherapy V4 (n=96)
    0.14 ( 1.489 )
        Change at Monotherapy V7 (n=76)
    0.33 ( 1.295 )
        Change at Monotherapy V10 (n=66)
    0.49 ( 1.316 )
        Change at Monotherapy V13 (n=54)
    0.53 ( 1.516 )
        Change at Monotherapy V16 (n=42)
    0.34 ( 1.379 )
        Change at Monotherapy V19 (n=34)
    0.23 ( 1.202 )
        Change at Monotherapy V22 (n=21)
    0.26 ( 0.969 )
        Change at Monotherapy V25 (n=21)
    0.20 ( 1.219 )
        Change at Monotherapy V28 (n=14)
    0.43 ( 1.404 )
        Change at Monotherapy V31 (n=10)
    0.79 ( 0.983 )
        Change at Monotherapy V34 (n=6)
    0.35 ( 1.086 )
        Change at Monotherapy V37 (n=2)
    -1.88 ( 0.688 )
        Change at Monotherapy V40 (n=3)
    -0.24 ( 1.200 )
        Change at Monotherapy V43 (n=2)
    -2.01 ( 0.874 )
        Change at Safety FU (n=18)
    0.44 ( 2.128 )
        Change at PD FU1 (n=26)
    0.30 ( 1.770 )
        Change at PD FU2 (n=15)
    -0.28 ( 1.355 )
        Change at PD FU3 (n=7)
    1.19 ( 2.203 )
        Change at PD FU4 (n=4)
    0.78 ( 0.506 )
        Change at PD FU5 (n=2)
    0.54 ( 0.764 )
        Change at PD FU6 (n=2)
    -0.47 ( 1.316 )
        Change at PD FU7 (n=1)
    1.35 ( 99999 )
        Change at PD FU8 (n=1)
    1.35 ( 99999 )
    No statistical analyses for this end point

    Secondary: 2L and 3L Treatment: Change From 2L Baseline in HVLT-R Part A (Immediate Recall) z-score

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    End point title
    		 2L and 3L Treatment: Change From 2L Baseline in HVLT-R Part A (Immediate Recall) z-score
    End point description
    The HVLT-R is a test of learning and memory consisting of 3 parts (Part A, B, and C). In Part A (immediate recall), the participant was asked to learn and recall a list of 12 words over three trials. The Part A score ranges from 0 to 36, with higher scores = better memory. The raw scores were normalized into standardized z-scores for each time point using participant’s age at enrollment. The change from 2L Baseline in z-scores was then calculated for each time point and is reported here. Analysis was performed on ITT population. 'Number of Subject Analysed'=participants evaluable for this outcome measure; 'n'=participants evaluable at specified time point for different arms, respectively; ‘99999’=either data were not available because no participant was evaluable or SD was not available because only 1 participant was evaluable at indicated time point.
    End point type
    Secondary
    End point timeframe
    2L Baseline; 2L treatment: every 6th visit starting from V7 to V43 (Q2W); 3L treatment: every 6th visit starting from V1 to V37, V49, V61 (Q2W); Safety FU (30 days after last 3L dose); PD FU1 (8 Wk after Safety FU); end of study (up to 41 months overall)
    End point values
    		 Placebo + Lomustine/SOC (ITT) Bevacizumab + Lomustine/SOC (ITT)
    Number of subjects analysed
    54
    58
    Units: z-scores
    arithmetic mean (standard deviation)
        2L Baseline (n=54,58)
    -1.62 ( 1.871 )
    -2.03 ( 1.969 )
        Change at 2L V7 (n=22,28)
    -0.79 ( 1.513 )
    -0.41 ( 1.561 )
        Change at 2L V13 (n=4,2)
    -0.23 ( 0.327 )
    0.02 ( 0.351 )
        Change at 2L V19 (n=1,0)
    -0.47 ( 99999 )
    99999 ( 99999 )
        Change at 2L V25 (n=1,0)
    -0.70 ( 99999 )
    99999 ( 99999 )
        Change at 2L V31 (n=1,0)
    -1.86 ( 99999 )
    99999 ( 99999 )
        Change at 2L V37 (n=1,0)
    -0.93 ( 99999 )
    99999 ( 99999 )
        Change at 2L V43 (n=1,0)
    -1.63 ( 99999 )
    99999 ( 99999 )
        Change at 3L V1 (n=6,11)
    -0.48 ( 1.141 )
    -0.48 ( 2.062 )
        Change at 3L V7 (n=7,8)
    0.20 ( 0.478 )
    0.18 ( 1.660 )
        Change at 3L V13 (n=2,2)
    -0.95 ( 0.965 )
    1.45 ( 0.186 )
        Change at 3L V19 (n=2,0)
    -0.33 ( 0.844 )
    99999 ( 99999 )
        Change at 3L V25 (n=1,0)
    0.26 ( 99999 )
    99999 ( 99999 )
        Change at 3L V31 (n=1,0)
    1.32 ( 99999 )
    99999 ( 99999 )
        Change at 3L V37 (n=1,0)
    1.32 ( 99999 )
    99999 ( 99999 )
        Change at 3L V49 (n=1,0)
    1.05 ( 99999 )
    99999 ( 99999 )
        Change at 3L V61 (n=1,0)
    1.58 ( 99999 )
    99999 ( 99999 )
        Change at Safety FU (n=0,2)
    99999 ( 99999 )
    0.28 ( 0.723 )
        Change at PD FU1 (n=0,2)
    99999 ( 99999 )
    -2.76 ( 1.303 )
        Change at end of study (n=1,0)
    -0.93 ( 99999 )
    99999 ( 99999 )
    No statistical analyses for this end point

    Secondary: 1L Treatment: Change From Baseline in HVLT-R Part B (Delayed Recall) z-score

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    End point title
    		 1L Treatment: Change From Baseline in HVLT-R Part B (Delayed Recall) z-score
    End point description
    The HVLT-R is a test of learning and memory consisting of 3 parts (Part A, B, C). In Part B (delayed recall), the participant was asked to recall the words learned in Part A after a delay of 20 minutes. The Part B score ranged from 0 to 12, with higher scores = better memory. The raw scores were normalized into standardized z-scores for each time point using participant’s age at enrollment. The change from Baseline in z-score was then calculated for each time point and is reported here. Analysis was performed on enrolled analysis set. 'Number of Subject Analysed'=participants evaluable for this outcome measure; 'n'=participants evaluable at specified time point; ‘99999’=SD could not be calculated as only 1 participant was evaluable at indicated time point.
    End point type
    Secondary
    End point timeframe
    Baseline; Maintenance: D1(V1) Cycles 1, 3, 5 (Q4W); Monotherapy: every 3rd visit starting from V1 to V43 (Q3W); Safety FU (30 days after last 1L dose); PD FUs (8 Wk after Safety FU [PD FU1], then every 12 Wk until PD1) (up to 41 months overall)
    End point values
    		 1L Bevacizumab
    Number of subjects analysed
    215
    Units: z-scores
    arithmetic mean (standard deviation)
        Baseline (n=215)
    -1.85 ( 1.894 )
        Change at Maintenance C1V1 (n=190)
    0 ( 1.559 )
        Change at Maintenance C3V1 (n=170)
    -0.30 ( 1.611 )
        Change at Maintenance C5V1 (n=150)
    -0.08 ( 1.517 )
        Change at Monotherapy V1 (n=131)
    -0.11 ( 1.451 )
        Change at Monotherapy V4 (n=94)
    -0.07 ( 1.608 )
        Change at Monotherapy V7 (n=74)
    0.15 ( 1.419 )
        Change at Monotherapy V10 (n=64)
    0.21 ( 1.358 )
        Change at Monotherapy V13 (n=51)
    0.30 ( 1.247 )
        Change at Monotherapy V16 (n=39)
    0.02 ( 1.200 )
        Change at Monotherapy V19 (n=31)
    0.02 ( 1.254 )
        Change at Monotherapy V22 (n=20)
    -0.25 ( 1.350 )
        Change at Monotherapy V25 (n=20)
    -0.03 ( 1.210 )
        Change at Monotherapy V28 (n=13)
    -0.26 ( 1.604 )
        Change at Monotherapy V31 (n=9)
    0.44 ( 0.836 )
        Change at Monotherapy V34 (n=6)
    -0.10 ( 1.009 )
        Change at Monotherapy V37 (n=2)
    -1.19 ( 2.473 )
        Change at Monotherapy V40 (n=3)
    -0.57 ( 1.001 )
        Change at Monotherapy V43 (n=2)
    -2.60 ( 1.317 )
        Change at Safety FU (n=17)
    -0.18 ( 1.980 )
        Change at PD FU1 (n=25)
    -0.16 ( 1.529 )
        Change at PD FU2 (n=15)
    -0.63 ( 1.696 )
        Change at PD FU3 (n=6)
    0.95 ( 1.615 )
        Change at PD FU4 (n=3)
    0.20 ( 0.340 )
        Change at PD FU5 (n=2)
    -0.28 ( 0.393 )
        Change at PD FU6 (n=2)
    -1.11 ( 0 )
        Change at PD FU7 (n=1)
    0 ( 99999 )
        Change at PD FU8 (n=1)
    0 ( 99999 )
    No statistical analyses for this end point

    Secondary: 2L and 3L Treatment: Change From 2L Baseline in HVLT-R Part B (Delayed Recall) z-score

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    End point title
    		 2L and 3L Treatment: Change From 2L Baseline in HVLT-R Part B (Delayed Recall) z-score
    End point description
    The HVLT-R is a test of learning and memory consisting of 3 parts (Part A, B, C). In Part B (delayed recall), the participant was asked to recall the words learned in Part A after a delay of 20 minutes. The Part B score ranged from 0 to 12, with higher scores = better memory. The raw scores were normalized into standardized z-scores for each time point using participant’s age at enrollment. The change from Baseline in z-score was then calculated for each time point and is reported here. Analysis was performed on ITT population. 'Number of Subject Analysed'=participants evaluable for this outcome measure; 'n'=participants evaluable at specified time point for different arms, respectively; ‘99999’=either data were not available because no participant was evaluable or SD was not available because only 1 participant was evaluable at indicated time point.
    End point type
    Secondary
    End point timeframe
    2L Baseline; 2L treatment: every 6th visit starting from V7 to V43 (Q2W); 3L treatment: every 6th visit starting from V1 to V37, V49, V61 (Q2W); Safety FU (30 days after last 3L dose); PD FU1 (8 Wk after Safety FU); end of study (up to 41 months overall)
    End point values
    		 Placebo + Lomustine/SOC (ITT) Bevacizumab + Lomustine/SOC (ITT)
    Number of subjects analysed
    53
    58
    Units: z-scores
    arithmetic mean (standard deviation)
        2L Baseline (n=53,58)
    -1.96 ( 1.778 )
    -2.52 ( 2.033 )
        Change at 2L V7 (n=22,28)
    -0.51 ( 1.866 )
    -0.49 ( 1.646 )
        Change at 2L V13 (n=4,2)
    -0.50 ( 1.646 )
    0.0 ( 0.0 )
        Change at 2L V19 (n=1,0)
    -1.11 ( 99999 )
    99999 ( 99999 )
        Change at 2L V25 (n=1,0)
    -1.67 ( 99999 )
    99999 ( 99999 )
        Change at 2L V31 (n=1,0)
    -2.22 ( 99999 )
    99999 ( 99999 )
        Change at 2L V37 (n=1,0)
    -1.11 ( 99999 )
    99999 ( 99999 )
        Change at 2L V43 (n=1,0)
    -2.78 ( 99999 )
    99999 ( 99999 )
        Change at 3L V1 (n=6,11)
    0.30 ( 1.303 )
    -0.44 ( 1.432 )
        Change at 3L V7 (n=7,7)
    -0.15 ( 1.549 )
    -0.71 ( 2.172 )
        Change at 3L V13 (n=2,2)
    -2.48 ( 4.344 )
    0.29 ( 1.248 )
        Change at 3L V19 (n=2,0)
    -1.41 ( 1.155 )
    99999 ( 99999 )
        Change at 3L V25 (n=1,0)
    -1.18 ( 99999 )
    99999 ( 99999 )
        Change at 3L V31 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        Change at 3L V37 (n=1,0)
    0.59 ( 99999 )
    99999 ( 99999 )
        Change at 3L V49 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        Change at 3L V61 (n=1,0)
    0.59 ( 99999 )
    99999 ( 99999 )
        Change at Safety FU (n=0,3)
    99999 ( 99999 )
    -1.15 ( 1.520 )
        Change at PD FU1 (n=0,2)
    99999 ( 99999 )
    -1.76 ( 0 )
        Change at end of study (n=1,0)
    -1.11 ( 99999 )
    99999 ( 99999 )
    No statistical analyses for this end point

    Secondary: 1L Treatment: Change From Baseline in HVLT-R Part C (Delayed Recognition) z-score

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    End point title
    		 1L Treatment: Change From Baseline in HVLT-R Part C (Delayed Recognition) z-score
    End point description
    The HVLT-R is a test of learning and memory consisting of 3 parts (Part A, B, C). In Part C (delayed recognition), the participant was asked to identify the list of 12 words learned in Part A from distractors. The Part C score ranged from -12 to 12, with higher scores = better memory. The raw scores were normalized into standardized z-scores for each time point using participant’s age at enrollment. The change from Baseline in z-score was then calculated for each time point and is reported here. Analysis was performed on enrolled analysis set. 'Number of Subject Analysed'=participants evaluable for this outcome measure; 'n'=participants evaluable at specified time point; ‘99999’=SD could not be calculated as only 1 participant was evaluable at indicated time point.
    End point type
    Secondary
    End point timeframe
    Baseline; Maintenance: D1(V1) Cycles 1, 3, 5 (Q4W); Monotherapy: every 3rd visit starting from V1 to V43 (Q3W); Safety FU (30 days after last 1L dose); PD FUs (8 Wk after Safety FU [PD FU1], then every 12 Wk until PD1) (up to 41 months overall)
    End point values
    		 1L Bevacizumab
    Number of subjects analysed
    222
    Units: z-score
    arithmetic mean (standard deviation)
        Baseline (n=222)
    -1.06 ( 1.952 )
        Change at Maintenance C1V1 (n=198)
    -0.05 ( 1.972 )
        Change at Maintenance C3V1 (n=177)
    0.44 ( 2.093 )
        Change at Maintenance C5V1 (n=155)
    0.04 ( 1.911 )
        Change at Monotherapy V1 (n=135)
    0.04 ( 1.932 )
        Change at Monotherapy V4 (n=96)
    0.01 ( 2.101 )
        Change at Monotherapy V7 (n=76)
    0.20 ( 1.793 )
        Change at Monotherapy V10 (n=66)
    0.23 ( 2.064 )
        Change at Monotherapy V13 (n=53)
    0.38 ( 2.089 )
        Change at Monotherapy V16 (n=41)
    0.21 ( 1.756 )
        Change at Monotherapy V19 (n=33)
    -0.05 ( 1.515 )
        Change at Monotherapy V22 (n=21)
    0.43 ( 1.059 )
        Change at Monotherapy V25 (n=20)
    0.13 ( 1.389 )
        Change at Monotherapy V28 (n=14)
    -0.29 ( 2.085 )
        Change at Monotherapy V31 (n=10)
    -0.32 ( 0.904 )
        Change at Monotherapy V34 (n=6)
    0.63 ( 0.844 )
        Change at Monotherapy V37 (n=2)
    0.36 ( 0.505 )
        Change at Monotherapy V40 (n=3)
    1.08 ( 0.957 )
        Change at Monotherapy V43 (n=2)
    0.26 ( 1.653 )
        Change at Safety FU (n=17)
    0.40 ( 2.692 )
        Change at PD FU1 (n=25)
    0.33 ( 2.817 )
        Change at PD FU2 (n=15)
    -0.85 ( 2.100 )
        Change at PD FU3 (n=6)
    1.64 ( 3.950 )
        Change at PD FU4 (n=4)
    -0.21 ( 2.979 )
        Change at PD FU5 (n=2)
    0.36 ( 0.505 )
        Change at PD FU6 (n=2)
    -0.71 ( 2.020 )
        Change at PD FU7 (n=1)
    0 ( 99999 )
        Change at PD FU8 (n=1)
    0 ( 99999 )
    No statistical analyses for this end point

    Secondary: 2L and 3L Treatment: Change From 2L Baseline in HVLT-R Part C (Delayed Recognition) z-score

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    End point title
    		 2L and 3L Treatment: Change From 2L Baseline in HVLT-R Part C (Delayed Recognition) z-score
    End point description
    The HVLT-R is a test of learning and memory consisting of 3 parts (Part A, B, C). In Part C (delayed recognition), the participant was asked to identify the list of 12 words learned in Part A from distractors. The Part C score ranged from -12 to 12, with higher scores = better memory. The raw scores were normalized into standardized z-scores for each time point using participant’s age at enrollment. The change from Baseline in z-score was then calculated for each time point and is reported here. Analysis was performed on ITT population. 'Number of Subject Analysed'=participants evaluable for this outcome measure; 'n'=participants evaluable at specified time point for different arms, respectively; ‘99999’=either data were not available because no participant was evaluable or SD was not available because only 1 participant was evaluable at indicated time point.
    End point type
    Secondary
    End point timeframe
    2L Baseline; 2L treatment: every 6th visit starting from V7 to V43 (Q2W); 3L treatment: every 6th visit starting from V1 to V37, V49, V61 (Q2W); Safety FU (30 days after last 3L dose); PD FU1 (8 Wk after Safety FU); end of study (up to 41 months overall)
    End point values
    		 Placebo + Lomustine/SOC (ITT) Bevacizumab + Lomustine/SOC (ITT)
    Number of subjects analysed
    53
    58
    Units: z-scores
    arithmetic mean (standard deviation)
        2L Baseline (n=53,58)
    -1.27 ( 2.071 )
    -1.25 ( 2.261 )
        Change at 2L V7 (n=22,28)
    0.08 ( 1.621 )
    -0.74 ( 1.837 )
        Change at 2L V13 (n=4,2)
    -0.63 ( 0.859 )
    0.36 ( 0.505 )
        Change at 2L V19 (n=1,0)
    -2.14 ( 99999 )
    99999 ( 99999 )
        Change at 2L V25 (n=1,0)
    0.71 ( 99999 )
    99999 ( 99999 )
        Change at 2L V31 (n=1,0)
    -0.71 ( 99999 )
    99999 ( 99999 )
        Change at 2L V37 (n=1,0)
    -0.71 ( 99999 )
    99999 ( 99999 )
        Change at 2L V43 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        Change at 3L V1 (n=7,11)
    0.24 ( 2.066 )
    -0.43 ( 2.125 )
        Change at 3L V7 (n=7,7)
    0.66 ( 3.076 )
    -0.41 ( 1.128 )
        Change at 3L V13 (n=2,2)
    -1.27 ( 0.781 )
    0.91 ( 1.286 )
        Change at 3L V19 (n=2,0)
    -1.07 ( 1.515 )
    99999 ( 99999 )
        Change at 3L V25 (n=1,0)
    -5.45 ( 99999 )
    99999 ( 99999 )
        Change at 3L V31 (n=1,0)
    -0.91 ( 99999 )
    99999 ( 99999 )
        Change at 3L V37 (n=1,0)
    -0.91 ( 99999 )
    99999 ( 99999 )
        Change at 3L V49 (n=1,0)
    -1.82 ( 99999 )
    99999 ( 99999 )
        Change at 3L V61 (n=1,0)
    0.91 ( 99999 )
    99999 ( 99999 )
        Change at Safety FU (n=0,3)
    99999 ( 99999 )
    -3.31 ( 2.852 )
        Change at PD FU1 (n=0,2)
    99999 ( 99999 )
    0 ( 0 )
        Change at end of study (n=1,0)
    2.14 ( 99999 )
    99999 ( 99999 )
    No statistical analyses for this end point

    Secondary: 1L Treatment: Change From Baseline in Controlled Oral Word Association (COWA) z-score

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    End point title
    		 1L Treatment: Change From Baseline in Controlled Oral Word Association (COWA) z-score
    End point description
    COWA is a test of phonemic verbal fluency. The participant was asked to produce as many words as possible in 60 seconds beginning with a specified letter (for 3 pre-specified letters). The total COWA score was calculated as the sum of acceptable words generated for each letter tested, with higher score indicating lower cognitive impairment. The raw scores were normalized into standardized z-scores for each time point using participant’s gender. The change from Baseline in z-score was then calculated for each time point and is reported here. Analysis was performed on enrolled analysis set. 'Number of Subject Analysed'=participants evaluable for this outcome measure; 'n'=participants evaluable at specified time point; ‘99999’=SD could not be calculated as only 1 participant was evaluable at indicated time point.
    End point type
    Secondary
    End point timeframe
    Baseline; Maintenance: D1(V1) Cycles 1, 3, 5 (Q4W); Monotherapy: every 3rd visit starting from V1 to V43 (Q3W); Safety FU (30 days after last 1L dose); PD FUs (8 Wk after Safety FU [PD FU1], then every 12 Wk until PD1) (up to 41 months overall)
    End point values
    		 1L Bevacizumab
    Number of subjects analysed
    219
    Units: z-scores
    arithmetic mean (standard deviation)
        Baseline (n=219)
    -1.50 ( 1.214 )
        Change at Maintenance C1V1 (n=196)
    0.16 ( 0.763 )
        Change at Maintenance C3V1 (n=175)
    0.18 ( 0.840 )
        Change at Maintenance C5V1 (n=152)
    0.31 ( 0.925 )
        Change at Monotherapy V1 (n=134)
    0.45 ( 1.022 )
        Change at Monotherapy V4 (n=98)
    0.33 ( 1.187 )
        Change at Monotherapy V7 (n=77)
    0.47 ( 0.943 )
        Change at Monotherapy V10 (n=65)
    0.69 ( 0.840 )
        Change at Monotherapy V13 (n=54)
    0.61 ( 0.995 )
        Change at Monotherapy V16 (n=42)
    0.88 ( 1.029 )
        Change at Monotherapy V19 (n=34)
    1.19 ( 1.190 )
        Change at Monotherapy V22 (n=21)
    0.95 ( 1.066 )
        Change at Monotherapy V25 (n=21)
    0.98 ( 0.891 )
        Change at Monotherapy V28 (n=14)
    1.27 ( 0.838 )
        Change at Monotherapy V31 (n=10)
    1.23 ( 1.166 )
        Change at Monotherapy V34 (n=6)
    1.12 ( 0.688 )
        Change at Monotherapy V37 (n=2)
    0.71 ( 0.253 )
        Change at Monotherapy V40 (n=3)
    0.23 ( 0.294 )
        Change at Monotherapy V43 (n=2)
    0.58 ( 0.821 )
        Change at Safety FU (n=18)
    0.36 ( 1.236 )
        Change at PD FU1 (n=27)
    0.46 ( 1.125 )
        Change at PD FU2 (n=16)
    0.17 ( 1.374 )
        Change at PD FU3 (n=7)
    0.93 ( 0.610 )
        Change at PD FU4 (n=4)
    -0.09 ( 0.531 )
        Change at PD FU5 (n=2)
    0.36 ( 1.660 )
        Change at PD FU6 (n=2)
    -1.67 ( 0.090 )
        Change at PD FU7 (n=1)
    0.92 ( 99999 )
        Change at PD FU8 (n=1)
    2.04 ( 99999 )
    No statistical analyses for this end point

    Secondary: 2L and 3L Treatment: Change From 2L Baseline in COWA z-score

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    End point title
    		 2L and 3L Treatment: Change From 2L Baseline in COWA z-score
    End point description
    COWA is a test of phonemic verbal fluency. The participant was asked to produce as many words as possible in 60 seconds beginning with a specified letter (for 3 pre-specified letters). The total COWA score was calculated as the sum of acceptable words generated for each letter tested, with higher score indicating lower cognitive impairment. The raw scores were normalized into standardized z-scores for each time point using participant’s gender. The change from Baseline in z-score was then calculated for each time point and is reported here. Analysis was performed on ITT population. 'Number of Subject Analysed'=participants evaluable for this outcome measure; 'n'=participants evaluable at specified time point for different arms, respectively; ‘99999’=either data were not available because no participant was evaluable or SD was not available because only 1 participant was evaluable at indicated time point.
    End point type
    Secondary
    End point timeframe
    2L Baseline; 2L treatment: every 6th visit starting from V7 to V43 (Q2W); 3L treatment: every 6th visit starting from V1 to V37, V49, V61 (Q2W); Safety FU (30 days after last 3L dose); PD FU1 (8 Wk after Safety FU); end of study (up to 41 months overall)
    End point values
    		 Placebo + Lomustine/SOC (ITT) Bevacizumab + Lomustine/SOC (ITT)
    Number of subjects analysed
    53
    58
    Units: z-scores
    arithmetic mean (standard deviation)
        2L Baseline (n=53,58)
    -1.17 ( 1.425 )
    -1.35 ( 1.657 )
        Change at 2L V7 (n=22,29)
    -0.27 ( 0.824 )
    -0.28 ( 0.775 )
        Change at 2L V13 (n=4,2)
    0.26 ( 0.395 )
    -0.26 ( 0.361 )
        Change at 2L V19 (n=1,0)
    0.10 ( 99999 )
    99999 ( 99999 )
        Change at 2L V25 (n=1,0)
    0.10 ( 99999 )
    99999 ( 99999 )
        Change at 2L V31 (n=1,0)
    0.71 ( 99999 )
    99999 ( 99999 )
        Change at 2L V37 (n=1,0)
    0.31 ( 99999 )
    99999 ( 99999 )
        Change at 2L V43 (n=1,0)
    0.31 ( 99999 )
    99999 ( 99999 )
        Change at 3L V1 (n=6,11)
    -0.13 ( 0.701 )
    -0.63 ( 0.896 )
        Change at 3L V7 (n=7,8)
    -0.19 ( 0.673 )
    -0.59 ( 0.923 )
        Change at 3L V13 (n=2,2)
    0.51 ( 0.433 )
    -0.46 ( 1.371 )
        Change at 3L V19 (n=2,0)
    0.46 ( 0.216 )
    99999 ( 99999 )
        Change at 3L V25 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        Change at 3L V31 (n=1,0)
    0.10 ( 99999 )
    99999 ( 99999 )
        Change at 3L V37 (n=1,0)
    0.92 ( 99999 )
    99999 ( 99999 )
        Change at 3L V49 (n=1,0)
    0.41 ( 99999 )
    99999 ( 99999 )
        Change at 3L V61 (n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        Change at Safety FU (n=0,2)
    99999 ( 99999 )
    -0.51 ( 1.010 )
        Change at PD FU1 (n=0,2)
    99999 ( 99999 )
    -0.19 ( 0.018 )
        Change at end of study (n=1,0)
    -0.82 ( 99999 )
    99999 ( 99999 )
    No statistical analyses for this end point

    Secondary: 1L Treatment: Change From Baseline in Trail-Making Test (TMT) Part A z-score

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    End point title
    		 1L Treatment: Change From Baseline in Trail-Making Test (TMT) Part A z-score
    End point description
    TMT Part A test required the participant to connect circles numbered 1 - 25 in numerical order from 1 to 25, as fast as possible. The Part A score was the total time-to-completion, in seconds (higher scores reveal greater impairment), if the test was completed. If the test was not completed, the Part A score was adjusted based on the last number correctly reached on the test, as follows: Part A score = 25*(total time-to-completion/last number correctly reached). The raw scores were normalized into standardized z-scores for each time point using participant’s age and education at enrollment. The z-scores were multiplied by -1 (negative values=performance below the mean). Analysis was performed on enrolled analysis set. 'Number of Subject Analysed'=participants evaluable for this outcome measure; 'n'=participants evaluable at specified time point; ‘99999’=SD could not be calculated as only 1 participant was evaluable at indicated time point.
    End point type
    Secondary
    End point timeframe
    Baseline; Maintenance: D1(V1) Cycles 1, 3, 5 (Q4W); Monotherapy: every 3rd visit starting from V1 to V43 (Q3W); Safety FU (30 days after last 1L dose); PD FUs (8 Wk after Safety FU [PD FU1], then every 12 Wk until PD1) (up to 41 months overall)
    End point values
    		 1L Bevacizumab
    Number of subjects analysed
    216
    Units: z-scores
    arithmetic mean (standard deviation)
        Baseline (n=216)
    -6.40 ( 32.420 )
        Change at Maintenance C1V1 (n=191)
    2.37 ( 34.329 )
        Change at Maintenance C3V1 (n=171)
    2.73 ( 33.993 )
        Change at Maintenance C5V1 (n=151)
    3.17 ( 35.703 )
        Change at Monotherapy V1 (n=131)
    1.52 ( 12.429 )
        Change at Monotherapy V4 (n=92)
    -0.76 ( 9.295 )
        Change at Monotherapy V7 (n=73)
    1.86 ( 12.680 )
        Change at Monotherapy V10 (n=64)
    2.82 ( 17.302 )
        Change at Monotherapy V13 (n=52)
    3.16 ( 19.286 )
        Change at Monotherapy V16 (n=42)
    1.06 ( 3.666 )
        Change at Monotherapy V19 (n=34)
    1.35 ( 3.943 )
        Change at Monotherapy V22 (n=21)
    1.67 ( 4.715 )
        Change at Monotherapy V25 (n=21)
    1.77 ( 4.470 )
        Change at Monotherapy V28 (n=14)
    2.66 ( 5.365 )
        Change at Monotherapy V31 (n=10)
    2.82 ( 4.920 )
        Change at Monotherapy V34 (n=6)
    1.60 ( 1.874 )
        Change at Monotherapy V37 (n=2)
    0.69 ( 2.257 )
        Change at Monotherapy V40 (n=3)
    1.09 ( 2.155 )
        Change at Monotherapy V43 (n=2)
    1.07 ( 2.230 )
        Change at Safety FU (n=17)
    -0.75 ( 8.737 )
        Change at PD FU1 (n=24)
    -0.73 ( 3.243 )
        Change at PD FU2 (n=15)
    0.56 ( 2.636 )
        Change at PD FU3 (n=7)
    1.03 ( 3.541 )
        Change at PD FU4 (n=4)
    2.20 ( 4.336 )
        Change at PD FU5 (n=2)
    3.38 ( 4.639 )
        Change at PD FU6 (n=1)
    -6.11 ( 99999 )
        Change at PD FU7 (n=1)
    7.00 ( 99999 )
        Change at PD FU8 (n=1)
    6.77 ( 99999 )
    No statistical analyses for this end point

    Secondary: 2L and 3L Treatment: Change From 2L Baseline in TMT Part A z-score

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    End point title
    		 2L and 3L Treatment: Change From 2L Baseline in TMT Part A z-score
    End point description
    TMT Part A test required the participant to connect circles numbered 1-25 in numerical order from 1 to 25, as fast as possible. The Part A score = total time-to-completion, in seconds (higher scores reveal greater impairment), if the test was completed. Otherwise, the Part A score was adjusted based on the last number correctly reached, as follows: Part A score = 25*(total time-to-completion/last number correctly reached). The raw scores were normalized into standardized z-scores for each time point using participant’s age and education. The z-scores were multiplied by -1 (negative values=performance below the mean). Analysis was performed on ITT population. 'Number of Subject Analysed'=participants evaluable for this outcome measure; 'n'=participants evaluable at specified time point for different arms, respectively; ‘99999’=either data were not available because no participant was evaluable or SD was not available because only 1 participant was evaluable at indicated time point.
    End point type
    Secondary
    End point timeframe
    2L Baseline; 2L treatment: every 6th visit starting from V7 to V43 (Q2W); 3L treatment: every 6th visit starting from V1 to V37, V49, V61 (Q2W); Safety FU (30 days after last 3L dose); PD FU1 (8 Wk after Safety FU); end of study (up to 41 months overall)
    End point values
    		 Placebo + Lomustine/SOC (ITT) Bevacizumab + Lomustine/SOC (ITT)
    Number of subjects analysed
    54
    58
    Units: z-scores
    arithmetic mean (standard deviation)
        2L Baseline (n=54,58)
    -5.94 ( 14.103 )
    -4.62 ( 8.563 )
        Change at 2L V7 (n=22,28)
    -2.04 ( 4.304 )
    -2.48 ( 7.091 )
        Change at 2L V13 (n=4,2)
    0.39 ( 1.599 )
    0.92 ( 1.867 )
        Change at 2L V19 (n=1,0)
    -9.72 ( 99999 )
    99999 ( 99999 )
        Change at 2L V25 (n=1,0)
    1.49 ( 99999 )
    99999 ( 99999 )
        Change at 2L V31 (n=1,0)
    0.15 ( 99999 )
    99999 ( 99999 )
        Change at 2L V37 (n=1,0)
    -4.63 ( 99999 )
    99999 ( 99999 )
        Change at 2L V43 (n=1,0)
    -1.35 ( 99999 )
    99999 ( 99999 )
        Change at 3L V1 (n=6,11)
    -6.32 ( 10.342 )
    -3.78 ( 4.640 )
        Change at 3L V7 (n=7,7)
    -1.02 ( 3.064 )
    -19.57 ( 32.309 )
        Change at 3L V13 (n=2,2)
    -1.91 ( 5.121 )
    -0.40 ( 0.419 )
        Change at 3L V19 (n=2,0)
    -2.36 ( 5.755 )
    99999 ( 99999 )
        Change at 3L V25 (n=1,0)
    0.91 ( 99999 )
    99999 ( 99999 )
        Change at 3L V31 (n=1,0)
    0.91 ( 99999 )
    99999 ( 99999 )
        Change at 3L V37 (n=1,0)
    1.31 ( 99999 )
    99999 ( 99999 )
        Change at 3L V49 (n=1,0)
    1.51 ( 99999 )
    99999 ( 99999 )
        Change at 3L V61 (n=1,0)
    0.60 ( 99999 )
    99999 ( 99999 )
        Change at Safety FU (n=0,2)
    99999 ( 99999 )
    -0.18 ( 0.822 )
        Change at PD FU1 (n=0,2)
    99999 ( 99999 )
    -1.70 ( 0.122 )
        Change at end of study (n=1,0)
    -52.64 ( 99999 )
    99999 ( 99999 )
    No statistical analyses for this end point

    Secondary: 1L Treatment: Change From Baseline in TMT Part B z-score

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    End point title
    		 1L Treatment: Change From Baseline in TMT Part B z-score
    End point description
    TMT Part B required the participant to connect 25 circles numbered 1-13 and A-L in order (1-A-2-B...) as fast as possible. The Part B score was the total time-to-completion, in seconds (higher scores=greater impairment), if the test was completed. If the test was not completed, the Part B score was adjusted based on the number of circles correctly connected on the test, as follows: Part B score = 25*(total time-to-completion/last number of correctly connected circle). The raw scores were normalized into standardized z-scores for each time point using participant’s age and education. The z-scores were multiplied by -1 (negative values=performance below the mean). Analysis was performed on enrolled analysis set. 'Number of Subject Analysed'=participants evaluable for this outcome measure; 'n'=participants evaluable at specified time point; ‘99999’=SD could not be calculated as only 1 participant was evaluable at indicated time point.
    End point type
    Secondary
    End point timeframe
    Baseline; Maintenance: D1(V1) Cycles 1, 3, 5 (Q4W); Monotherapy: every 3rd visit starting from V1 to V43 (Q3W); Safety FU (30 days after last 1L dose); PD FUs (8 Wk after Safety FU [PD FU1], then every 12 Wk until PD1) (up to 41 months overall)
    End point values
    		 1L Bevacizumab
    Number of subjects analysed
    203
    Units: z-scores
    arithmetic mean (standard deviation)
        Baseline (n=203)
    -9.38 ( 23.115 )
        Change at Maintenance C1V1 (n=173)
    1.18 ( 22.407 )
        Change at Maintenance C3V1 (n=154)
    1.44 ( 24.412 )
        Change at Maintenance C5V1 (n=140)
    -2.58 ( 55.685 )
        Change at Monotherapy V1 (n=121)
    1.74 ( 26.685 )
        Change at Monotherapy V4 (n=82)
    -1.14 ( 17.561 )
        Change at Monotherapy V7 (n=66)
    3.10 ( 20.006 )
        Change at Monotherapy V10 (n=57)
    4.69 ( 27.281 )
        Change at Monotherapy V13 (n=46)
    4.83 ( 21.081 )
        Change at Monotherapy V16 (n=37)
    2.42 ( 6.649 )
        Change at Monotherapy V19 (n=31)
    3.28 ( 7.420 )
        Change at Monotherapy V22 (n=19)
    3.76 ( 8.984 )
        Change at Monotherapy V25 (n=18)
    2.40 ( 3.161 )
        Change at Monotherapy V28 (n=12)
    2.37 ( 3.522 )
        Change at Monotherapy V31 (n=8)
    3.36 ( 3.053 )
        Change at Monotherapy V34 (n=5)
    2.77 ( 1.211 )
        Change at Monotherapy V37 (n=1)
    1.60 ( 99999 )
        Change at Monotherapy V40 (n=2)
    1.88 ( 0.792 )
        Change at Monotherapy V43 (n=1)
    1.73 ( 99999 )
        Change at Safety FU (n=14)
    -0.42 ( 6.000 )
        Change at PD FU1 (n=22)
    -1.65 ( 8.005 )
        Change at PD FU2 (n=15)
    0.79 ( 4.900 )
        Change at PD FU3 (n=6)
    -15.15 ( 39.732 )
        Change at PD FU4 (n=3)
    4.36 ( 3.270 )
        Change at PD FU5 (n=1)
    7.12 ( 99999 )
        Change at PD FU6 (n=0)
    99999 ( 99999 )
        Change at PD FU7 (n=1)
    7.04 ( 99999 )
        Change at PD FU8 (n=1)
    6.80 ( 99999 )
    No statistical analyses for this end point

    Secondary: 2L and 3L Treatment: Change From 2L Baseline in TMT Part B z-score

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    End point title
    		 2L and 3L Treatment: Change From 2L Baseline in TMT Part B z-score
    End point description
    TMT Part B required the participant to connect 25 circles numbered 1-13 and A-L in order (1-A-2-B...) as fast as possible. The Part B score=total time-to-completion in seconds (higher scores=greater impairment), if the test was completed. Otherwise, Part B score was adjusted based on the number of circles correctly connected, as follows: Part B score=25*(total time-to-completion/last number of correctly connected circle). The raw scores were normalized into standardized z-scores for each time point using participant’s age and education. The z-scores were multiplied by -1 (negative values=performance below the mean). Analysis was performed on ITT population. 'Number of Subject Analysed'=participants evaluable for this outcome measure; 'n'=participants evaluable at specified time point for different arms, respectively; ‘99999’=either data were not available because no participant was evaluable or SD was not available because only 1 participant was evaluable at indicated time point.
    End point type
    Secondary
    End point timeframe
    2L Baseline; 2L treatment: every 6th visit starting from V7 to V43 (Q2W); 3L treatment: every 6th visit starting from V1 to V37, V49, V61 (Q2W); Safety FU (30 days after last 3L dose); PD FU1 (8 Wk after Safety FU); end of study (up to 41 months overall)
    End point values
    		 Placebo + Lomustine/SOC (ITT) Bevacizumab + Lomustine/SOC (ITT)
    Number of subjects analysed
    54
    57
    Units: z-scores
    arithmetic mean (standard deviation)
        2L Baseline (n=54,57)
    -12.51 ( 37.406 )
    -11.42 ( 20.524 )
        Change at 2L V7 (n=22,27)
    -3.33 ( 6.879 )
    -5.78 ( 14.211 )
        Change at 2L V13 (n=4,2)
    1.07 ( 5.508 )
    -0.09 ( 0.129 )
        Change at 2L V19 (n=1,0)
    4.40 ( 99999 )
    99999 ( 99999 )
        Change at 2L V25 (n=1,0)
    -2.15 ( 99999 )
    99999 ( 99999 )
        Change at 2L V31 (n=1,0)
    -7.62 ( 99999 )
    99999 ( 99999 )
        Change at 2L V37 (n=1,0)
    -0.43 ( 99999 )
    99999 ( 99999 )
        Change at 2L V43 (n=1,0)
    3.11 ( 99999 )
    99999 ( 99999 )
        Change at 3L V1 (n=6,11)
    -13.10 ( 21.948 )
    -59.93 ( 137.707 )
        Change at 3L V7 (n=7,7)
    -7.26 ( 8.449 )
    -14.44 ( 24.248 )
        Change at 3L V13 (n=2,2)
    -9.09 ( 13.148 )
    0.68 ( 1.392 )
        Change at 3L V19 (n=2,0)
    -26.24 ( 25.443 )
    99999 ( 99999 )
        Change at 3L V25 (n=1,0)
    -13.04 ( 99999 )
    99999 ( 99999 )
        Change at 3L V31 (n=1,0)
    -0.69 ( 99999 )
    99999 ( 99999 )
        Change at 3L V37 (n=1,0)
    -1.11 ( 99999 )
    99999 ( 99999 )
        Change at 3L V49 (n=1,0)
    -8.32 ( 99999 )
    99999 ( 99999 )
        Change at 3L V61 (n=1,0)
    -0.69 ( 99999 )
    99999 ( 99999 )
        Change at Safety FU (n=0,3)
    99999 ( 99999 )
    0.32 ( 6.517 )
        Change at PD FU1 (n=0,2)
    99999 ( 99999 )
    -8.21 ( 7.813 )
    No statistical analyses for this end point

    Secondary: Number of Participants with Hospitalizations According to Type of Hospitalizations

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    End point title
    		 Number of Participants with Hospitalizations According to Type of Hospitalizations
    End point description
    Number of participants with hospitalizations according to type of hospitalizations (emergency room, normal hospital room, intensive care unit [ICU]/critical care unit [CCU]) was reported. One participant could have more than one type of hospitalization. Analysis was performed on safety set, which included all participants who received at least one dose of any study treatment. 'Number of Subject Analysed'=Number of participants hospitalized.
    End point type
    Secondary
    End point timeframe
    From Baseline up to death or study withdrawal/study end (up to 41 months overall)
    End point values
    		 1L Bevacizumab Placebo + Lomustine/SOC (Safety 2L+) Bevacizumab + Lomustine/SOC (Safety 2L+) Placebo + Lomustine/SOC (Safety 4L+) Bevacizumab + Lomustine/SOC (Safety 4L+) Cross-over (Safety 4L+)
    Number of subjects analysed
    111
    13
    14
    1
    2
    0 [14]
    Units: participants
        Emergency room
    37
    2
    7
    1
    0
        normal hospital room
    102
    10
    13
    1
    2
        ICU/CCU
    8
    2
    0
    0
    0
    Notes
    [14] - No participant was hospitalized in this arm
    No statistical analyses for this end point

    Secondary: Duration of Hospitalizations According to Type of Hospitalizations

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    End point title
    		 Duration of Hospitalizations According to Type of Hospitalizations
    End point description
    Duration of hospitalization (in days) according to type of hospitalizations (emergency room, normal hospital room, ICU/CCU) was reported. Analysis was performed on safety set. 'Number of Subject Analysed'=Number of participants hospitalized; 'n'=participants evaluable for specified category for different arms, respectively.
    End point type
    Secondary
    End point timeframe
    From Baseline up to death or study withdrawal/study end (up to 41 months overall)
    End point values
    		 1L Bevacizumab Placebo + Lomustine/SOC (Safety 2L+) Bevacizumab + Lomustine/SOC (Safety 2L+) Placebo + Lomustine/SOC (Safety 4L+) Bevacizumab + Lomustine/SOC (Safety 4L+) Cross-over (Safety 4L+)
    Number of subjects analysed
    111
    13
    14
    1
    2
    0 [15]
    Units: days
    median (full range (min-max))
        Emergency room (n=36,2,7,1,0,0)
    1.0 (0 to 32)
    1.0 (1 to 1)
    1.0 (0 to 36)
    0 (0 to 0)
    99999 (99999 to 99999)
    ( to )
        Normal hospital room (n=100,10,12,1,2,0)
    10.0 (0 to 108)
    3.5 (1 to 22)
    6.5 (1 to 49)
    14.0 (14 to 14)
    6.5 (6 to 7)
    ( to )
        ICU/CCU (n=7,2,0,0,0,0)
    4.0 (1 to 30)
    12.0 (11 to 13)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    ( to )
    Notes
    [15] - No participant was hospitalized in this arm.
    No statistical analyses for this end point

    Secondary: EuroQol Five-Dimension Questionnaire (EQ-5D) Score

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    End point title
    		 EuroQol Five-Dimension Questionnaire (EQ-5D) Score
    End point description
    End point type
    Secondary
    End point timeframe
    From Baseline up to death or study withdrawal/study end (up to 41 months overall)
    End point values
    		 1L Bevacizumab
    Number of subjects analysed
    0 [16]
    Units: units on a scale
        arithmetic mean (standard deviation)
    ( )
    Notes
    [16] - Because the study was terminated early, data were not summarized and only reported in listings.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Baseline up to death or study withdrawal/study end (up to 41 months overall)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    1L Bevacizumab
    Reporting group description
    		 Participants received 1L treatment with radiotherapy, temozolomide, and bevacizumab. All three treatments were given concurrently for the first 6 weeks, followed by 6 cycles (of 28 days each) of temozolomide plus bevacizumab, followed by bevacizumab monotherapy until PD1 or unacceptable toxicity.

    Reporting group title
    Placebo + Lomustine/SOC (Safety 2L+)
    Reporting group description
    		 At PD1, eligible participants for 2L therapy were randomized and received bevacizumab-placebo plus lomustine until PD2. After PD2, eligible participants continued 3L treatment with bevacizumab-placebo plus the appropriate SOC treatment (generally used to treat recurrence) at the discretion of the investigator and the participant. Analysis set included all participants who received at least one dose of 2L study treatment. Participants were analyzed as treated during 2L and 3L.

    Reporting group title
    Bevacizumab + Lomustine/SOC (Safety 2L+)
    Reporting group description
    		 At PD1, eligible participants for 2L therapy were randomized and received bevacizumab plus lomustine until PD2. After PD2, eligible participants continued 3L treatment with bevacizumab plus the appropriate SOC treatment (generally used to treat recurrence) at the discretion of the investigator and the participant. Analysis set included all participants who received at least one dose of 2L study treatment. Participants were analyzed as treated during 2L and 3L.

    Reporting group title
    Placebo + Lomustine/SOC (Safety 4L+)
    Reporting group description
    		 After PD3, eligible participants continued 4L and later line of treatment with bevacizumab-placebo plus the appropriate SOC treatment (generally used to treat recurrence) at the discretion of the investigator and the participant. Analysis set included all participants who received at least one dose of 4L study treatment. Participants were analyzed as treated during 4L and later lines.

    Reporting group title
    Bevacizumab + Lomustine/SOC (Safety 4L+)
    Reporting group description
    		 After PD3, eligible participants continued 4L and later line of treatment with bevacizumab plus the appropriate SOC treatment (generally used to treat recurrence) at the discretion of the investigator and the participant. Analysis set included all participants who received at least one dose of 4L study treatment. Participants were analyzed as treated during 4L and later lines.

    Reporting group title
    Cross-over (Safety 4L+)
    Reporting group description
    		 After PD3, eligible participants cross-over from bevacizumab-placebo treatment and received 4L and later line of treatment with bevacizumab plus the appropriate SOC treatment (generally used to treat recurrence) at the discretion of the investigator and the participant. Analysis set included all participants who received at least one dose of 4L study treatment. Participants were analyzed as treated during 4L and later lines.

    Serious adverse events
    		 1L Bevacizumab Placebo + Lomustine/SOC (Safety 2L+) Bevacizumab + Lomustine/SOC (Safety 2L+) Placebo + Lomustine/SOC (Safety 4L+) Bevacizumab + Lomustine/SOC (Safety 4L+) Cross-over (Safety 4L+)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    103 / 296 (34.80%)
    5 / 59 (8.47%)
    12 / 63 (19.05%)
    1 / 4 (25.00%)
    2 / 10 (20.00%)
    0 / 4 (0.00%)
         number of deaths (all causes)
    102
    41
    42
    3
    9
    2
         number of deaths resulting from adverse events
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 296 (0.68%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 296 (0.34%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 296 (0.34%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    1 / 296 (0.34%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 296 (1.01%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    2 / 296 (0.68%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 296 (0.34%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    1 / 296 (0.34%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    1 / 296 (0.34%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 296 (0.34%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatic obstruction
         subjects affected / exposed
    1 / 296 (0.34%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    9 / 296 (3.04%)
    0 / 59 (0.00%)
    2 / 63 (3.17%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    8 / 9
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 296 (0.34%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 296 (0.34%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 296 (0.34%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Platelet count decreased
         subjects affected / exposed
    14 / 296 (4.73%)
    1 / 59 (1.69%)
    1 / 63 (1.59%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 16
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    6 / 296 (2.03%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    3 / 296 (1.01%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphocyte count decreased
         subjects affected / exposed
    1 / 296 (0.34%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 296 (0.00%)
    0 / 59 (0.00%)
    1 / 63 (1.59%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    0 / 296 (0.00%)
    1 / 59 (1.69%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Wound dehiscence
         subjects affected / exposed
    2 / 296 (0.68%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Allergic transfusion reaction
         subjects affected / exposed
    1 / 296 (0.34%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 296 (0.34%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 296 (0.34%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin injury
         subjects affected / exposed
    1 / 296 (0.34%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 296 (0.34%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    0 / 296 (0.00%)
    0 / 59 (0.00%)
    1 / 63 (1.59%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    2 / 296 (0.68%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 296 (0.34%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    15 / 296 (5.07%)
    0 / 59 (0.00%)
    3 / 63 (4.76%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 18
    0 / 0
    0 / 4
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    7 / 296 (2.36%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    4 / 296 (1.35%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    2 / 296 (0.68%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    1 / 296 (0.34%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 296 (0.34%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paraplegia
         subjects affected / exposed
    1 / 296 (0.34%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    1 / 296 (0.34%)
    0 / 59 (0.00%)
    1 / 63 (1.59%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Senile dementia
         subjects affected / exposed
    1 / 296 (0.34%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 296 (0.34%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aphasia
         subjects affected / exposed
    0 / 296 (0.00%)
    0 / 59 (0.00%)
    1 / 63 (1.59%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myelitis transverse
         subjects affected / exposed
    0 / 296 (0.00%)
    0 / 59 (0.00%)
    1 / 63 (1.59%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural effusion
         subjects affected / exposed
    0 / 296 (0.00%)
    0 / 59 (0.00%)
    1 / 63 (1.59%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    14 / 296 (4.73%)
    1 / 59 (1.69%)
    1 / 63 (1.59%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    3 / 14
    1 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    4 / 296 (1.35%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    4 / 296 (1.35%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    1 / 296 (0.34%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 296 (0.34%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 296 (0.34%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    1 / 296 (0.34%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 296 (0.68%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    2 / 296 (0.68%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 296 (0.68%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 296 (0.34%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric perforation
         subjects affected / exposed
    1 / 296 (0.34%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 296 (0.34%)
    1 / 59 (1.69%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal perforation
         subjects affected / exposed
    1 / 296 (0.34%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 296 (0.34%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 296 (0.00%)
    0 / 59 (0.00%)
    1 / 63 (1.59%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulum
         subjects affected / exposed
    0 / 296 (0.00%)
    0 / 59 (0.00%)
    1 / 63 (1.59%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    0 / 296 (0.00%)
    1 / 59 (1.69%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 296 (0.34%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Secondary hypothyroidism
         subjects affected / exposed
    1 / 296 (0.34%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Lung infection
         subjects affected / exposed
    3 / 296 (1.01%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 296 (1.01%)
    0 / 59 (0.00%)
    1 / 63 (1.59%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 296 (0.68%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    1 / 296 (0.34%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes simplex encephalitis
         subjects affected / exposed
    1 / 296 (0.34%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 296 (0.34%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infected fistula
         subjects affected / exposed
    1 / 296 (0.34%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 296 (0.34%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 296 (0.34%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Salmonella sepsis
         subjects affected / exposed
    1 / 296 (0.34%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 296 (0.34%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 296 (0.34%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 296 (0.34%)
    1 / 59 (1.69%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 296 (0.00%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    1 / 296 (0.34%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 1L Bevacizumab Placebo + Lomustine/SOC (Safety 2L+) Bevacizumab + Lomustine/SOC (Safety 2L+) Placebo + Lomustine/SOC (Safety 4L+) Bevacizumab + Lomustine/SOC (Safety 4L+) Cross-over (Safety 4L+)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    266 / 296 (89.86%)
    47 / 59 (79.66%)
    54 / 63 (85.71%)
    4 / 4 (100.00%)
    7 / 10 (70.00%)
    4 / 4 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    112 / 296 (37.84%)
    13 / 59 (22.03%)
    17 / 63 (26.98%)
    0 / 4 (0.00%)
    2 / 10 (20.00%)
    2 / 4 (50.00%)
         occurrences all number
    196
    13
    21
    0
    2
    2
    Deep vein thrombosis
         subjects affected / exposed
    0 / 296 (0.00%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Venous thrombosis limb
         subjects affected / exposed
    0 / 296 (0.00%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    93 / 296 (31.42%)
    11 / 59 (18.64%)
    13 / 63 (20.63%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    2 / 4 (50.00%)
         occurrences all number
    126
    12
    13
    0
    1
    2
    Asthenia
         subjects affected / exposed
    69 / 296 (23.31%)
    12 / 59 (20.34%)
    14 / 63 (22.22%)
    1 / 4 (25.00%)
    5 / 10 (50.00%)
    1 / 4 (25.00%)
         occurrences all number
    113
    21
    18
    1
    5
    1
    Pyrexia
         subjects affected / exposed
    28 / 296 (9.46%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    31
    0
    0
    0
    0
    0
    Reproductive system and breast disorders
    Amenorrhoea
         subjects affected / exposed
    0 / 296 (0.00%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    30 / 296 (10.14%)
    3 / 59 (5.08%)
    4 / 63 (6.35%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    35
    3
    5
    0
    0
    1
    Cough
         subjects affected / exposed
    23 / 296 (7.77%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    25
    0
    0
    0
    0
    0
    Dysphonia
         subjects affected / exposed
    21 / 296 (7.09%)
    5 / 59 (8.47%)
    1 / 63 (1.59%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    24
    5
    1
    0
    0
    1
    Pulmonary embolism
         subjects affected / exposed
    0 / 296 (0.00%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    18 / 296 (6.08%)
    3 / 59 (5.08%)
    1 / 63 (1.59%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    21
    3
    1
    0
    0
    0
    Disorientation
         subjects affected / exposed
    0 / 296 (0.00%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Bradyphrenia
         subjects affected / exposed
    0 / 296 (0.00%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Investigations
    Platelet count decreased
         subjects affected / exposed
    44 / 296 (14.86%)
    7 / 59 (11.86%)
    9 / 63 (14.29%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    73
    10
    15
    0
    0
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    23 / 296 (7.77%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    28
    0
    0
    0
    0
    0
    Weight decreased
         subjects affected / exposed
    18 / 296 (6.08%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
         occurrences all number
    18
    0
    0
    0
    1
    0
    Neutrophil count decreased
         subjects affected / exposed
    16 / 296 (5.41%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    26
    0
    0
    0
    0
    0
    White blood cell count decreased
         subjects affected / exposed
    15 / 296 (5.07%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    28
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Hand fracture
         subjects affected / exposed
    0 / 296 (0.00%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    78 / 296 (26.35%)
    9 / 59 (15.25%)
    7 / 63 (11.11%)
    1 / 4 (25.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
         occurrences all number
    144
    9
    9
    1
    1
    0
    Seizure
         subjects affected / exposed
    21 / 296 (7.09%)
    4 / 59 (6.78%)
    3 / 63 (4.76%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    49
    5
    3
    0
    0
    0
    Dizziness
         subjects affected / exposed
    15 / 296 (5.07%)
    3 / 59 (5.08%)
    3 / 63 (4.76%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    19
    3
    3
    0
    0
    0
    Epilepsy
         subjects affected / exposed
    0 / 296 (0.00%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Dysarthria
         subjects affected / exposed
    0 / 296 (0.00%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Hemiparesis
         subjects affected / exposed
    0 / 296 (0.00%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Paraesthesia
         subjects affected / exposed
    0 / 296 (0.00%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Presyncope
         subjects affected / exposed
    0 / 296 (0.00%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    61 / 296 (20.61%)
    10 / 59 (16.95%)
    22 / 63 (34.92%)
    2 / 4 (50.00%)
    4 / 10 (40.00%)
    1 / 4 (25.00%)
         occurrences all number
    113
    18
    30
    2
    4
    1
    Leukopenia
         subjects affected / exposed
    30 / 296 (10.14%)
    9 / 59 (15.25%)
    8 / 63 (12.70%)
    2 / 4 (50.00%)
    2 / 10 (20.00%)
    0 / 4 (0.00%)
         occurrences all number
    48
    15
    12
    2
    2
    0
    Neutropenia
         subjects affected / exposed
    26 / 296 (8.78%)
    5 / 59 (8.47%)
    8 / 63 (12.70%)
    1 / 4 (25.00%)
    2 / 10 (20.00%)
    0 / 4 (0.00%)
         occurrences all number
    33
    7
    13
    1
    3
    0
    Lymphopenia
         subjects affected / exposed
    23 / 296 (7.77%)
    3 / 59 (5.08%)
    6 / 63 (9.52%)
    1 / 4 (25.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
         occurrences all number
    33
    3
    6
    1
    1
    0
    Anaemia
         subjects affected / exposed
    20 / 296 (6.76%)
    3 / 59 (5.08%)
    2 / 63 (3.17%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    25
    3
    2
    1
    0
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    0 / 296 (0.00%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    99 / 296 (33.45%)
    7 / 59 (11.86%)
    8 / 63 (12.70%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    154
    8
    11
    0
    0
    1
    Constipation
         subjects affected / exposed
    77 / 296 (26.01%)
    8 / 59 (13.56%)
    10 / 63 (15.87%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    1 / 4 (25.00%)
         occurrences all number
    111
    10
    14
    0
    1
    1
    Vomiting
         subjects affected / exposed
    49 / 296 (16.55%)
    2 / 59 (3.39%)
    5 / 63 (7.94%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    75
    2
    7
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    28 / 296 (9.46%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    39
    0
    0
    0
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    16 / 296 (5.41%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    18
    0
    0
    0
    0
    0
    Stomatitis
         subjects affected / exposed
    0 / 296 (0.00%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    25 / 296 (8.45%)
    0 / 59 (0.00%)
    4 / 63 (6.35%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    31
    0
    4
    0
    0
    0
    Alopecia
         subjects affected / exposed
    56 / 296 (18.92%)
    10 / 59 (16.95%)
    11 / 63 (17.46%)
    2 / 4 (50.00%)
    3 / 10 (30.00%)
    1 / 4 (25.00%)
         occurrences all number
    57
    10
    11
    2
    3
    1
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    71 / 296 (23.99%)
    10 / 59 (16.95%)
    13 / 63 (20.63%)
    1 / 4 (25.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
         occurrences all number
    113
    14
    18
    1
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    35 / 296 (11.82%)
    5 / 59 (8.47%)
    5 / 63 (7.94%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
         occurrences all number
    46
    5
    5
    0
    1
    0
    Pain in extremity
         subjects affected / exposed
    17 / 296 (5.74%)
    3 / 59 (5.08%)
    5 / 63 (7.94%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    21
    3
    6
    0
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    15 / 296 (5.07%)
    3 / 59 (5.08%)
    3 / 63 (4.76%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    15
    4
    3
    0
    0
    0
    Back pain
         subjects affected / exposed
    0 / 296 (0.00%)
    3 / 59 (5.08%)
    1 / 63 (1.59%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    3
    1
    0
    0
    0
    Muscular weakness
         subjects affected / exposed
    0 / 296 (0.00%)
    3 / 59 (5.08%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    0
    Neck pain
         subjects affected / exposed
    0 / 296 (0.00%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    19 / 296 (6.42%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    23
    0
    0
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    19 / 296 (6.42%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    21
    0
    0
    0
    0
    0
    Gingivitis
         subjects affected / exposed
    0 / 296 (0.00%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Rhinitis
         subjects affected / exposed
    0 / 296 (0.00%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    39 / 296 (13.18%)
    4 / 59 (6.78%)
    9 / 63 (14.29%)
    1 / 4 (25.00%)
    2 / 10 (20.00%)
    0 / 4 (0.00%)
         occurrences all number
    64
    7
    11
    1
    2
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 296 (0.00%)
    0 / 59 (0.00%)
    0 / 63 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Jul 2014
    Limited 2L treatment to be given in combination with bevacizumab or bevacizumab/placebo from SOC to lomustine only, now provided as investigational medicinal product; Removed fotemustine as an option in 3L treatment; Adapted statistical analysis following suppression of stratification by SOC regimen. Changed definition of PFS3 to: ‘from randomisation to PD3 or death; Permitted participants for whom operation or re-operation was clinically indicated at PD1 to enter the study as this reflected normal clinical practice; Amended sample size calculation based on more recent data showing median PFS had changed from 9.1 months to 10.6 months.
    16 Jan 2015
    Changed the study phase from IIIb to II; Reduced the number of participants enrolled from 510 to 300, the number of participants randomised from 300 to 200, and the number of study centres from 130 to 65; Reduced assumed drop-out rate prior to randomisation from 41% to 20% overall; Reduced the number of OS events required for final analysis from 250 to 130; Adjusted statistical analysis for the primary endpoint OS from one-sided alpha level = 5% with a power of 80% to one-side alpha = 10% with a power of 70%. This assumed a median survival time for participants randomised to receive bevacizumab of 9 months and of 6.57 months for participants randomised to receive non-bevacizumab treatment (corresponding to a HR of 0.73). Added that for HR, 80% CI would also be calculated, in addition to the 95% CI already stated; Removed interim analysis.
    27 Jun 2016
    Added details regarding participant management at the end of the study for ongoing participants still benefiting from bevacizumab and/or chemotherapy; Clarified 3L and later line treatment regarding the potential use of other investigational drugs to avoid confusion with the study investigational drugs.

    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.
    The study was terminated early because the primary endpoint (OS) could not be reached.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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