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    Clinical Trial Results:
    Randomized Non Comparative Phase II Trial With Bevacizumab and Fotemustine in the Treatment of Recurrent Glioblastoma

    Summary
    EudraCT number
    		 2011-001363-46
    Trial protocol
    		 IT  
    Global end of trial date
    12 Dec 2013

    Results information
    Results version number
    		 v3(current)
    This version publication date
    19 Jun 2016
    First version publication date
    07 Aug 2015
    Other versions
    		 v1 (removed from public view) , v2
    Version creation reason
    • Correction of full data set
    We have identified data errors in the EudraCT record of ML25739 whilst undergoing QC due to system bug.

    Trial information

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    Trial identification
    Sponsor protocol code
    ML25739
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01474239
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, 41 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
    12 Dec 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Dec 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to assess the efficacy of bevacizumab in terms of the 6-month overall survival rate (OS-6), measured from the beginning of study drug administration to the death of the participant from any cause.
    Protection of trial subjects
    The study was conducted in accordance with the principles of the “Declaration of Helsinki” and Good Clinical Practice (GCP) and investigators were trained according to applicable Sponsor standard operating procedures (SOPs).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Nov 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 14 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 91
    Worldwide total number of subjects
    91
    EEA total number of subjects
    91
    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)
    71
    From 65 to 84 years
    20
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Study included 28-day screening period. Participants were randomized according to a 2:1 ratio to one of the 2 treatment groups. A total of 99 participants were screened, of which 91 were randomized.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Bevacizumab
    Arm description
    		 Participants received bevacizumab 10 milligrams per kilogram (mg/kg) via intravenous (IV) infusion every 14 days until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin®
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab was supplied in 4 milliliter (mL) ampoules of injectable 25 milligram per milliliter (mg/mL) solution to be given by infusion. The bevacizumab solution was not to be mixed with glucose solutions or any other products except saline solution (0.9 percent [%]). The final concentration had to be maintained within 1.4-16.5 mg/mL.

    Arm title
    		 Fotemustine
    Arm description
    		 Participants received fotemustine 75 milligrams per square meter (mg/m^2) via IV infusion on Days 1, 8, and 15 (induction phase), followed by a 35-day drug-free interval, and then fotemustine 100 mg/m^2 every 21 days (maintenance phase) until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.
    Arm type
    		 Calibration Arm

    Investigational medicinal product name
    Fotemustine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Fotemustine was supplied in 4 mL ampoules containing 200 mg in a sterile alcohol solution. Fotemustine solution was diluted in 250-400 mL 5% glucose solution and administered by infusion.

    Number of subjects in period 1
    		Bevacizumab Fotemustine
    Started
    59
    32
    Completed
    0
    0
    Not completed
    59
    32
         Adverse Event
    12
    3
         Death
    1
    1
         Withdrawal for Economic Reason
    1
    -
         Clinical Disease Progression
    7
    1
         Consent Withdrawn by Subject
    1
    2
         Disease Progression
    37
    25

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Bevacizumab
    Reporting group description
    		 Participants received bevacizumab 10 milligrams per kilogram (mg/kg) via intravenous (IV) infusion every 14 days until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.

    Reporting group title
    Fotemustine
    Reporting group description
    		 Participants received fotemustine 75 milligrams per square meter (mg/m^2) via IV infusion on Days 1, 8, and 15 (induction phase), followed by a 35-day drug-free interval, and then fotemustine 100 mg/m^2 every 21 days (maintenance phase) until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.

    Reporting group values
    		 Bevacizumab Fotemustine Total
    Number of subjects
    		 59 32 91
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 56.86 ± 9.4 55.63 ± 10.64 -
    Gender categorical
    Units: Subjects
        Female
    		 20 9 29
        Male
    		 39 23 62

    End points

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    End points reporting groups
    Reporting group title
    Bevacizumab
    Reporting group description
    		 Participants received bevacizumab 10 milligrams per kilogram (mg/kg) via intravenous (IV) infusion every 14 days until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.

    Reporting group title
    Fotemustine
    Reporting group description
    		 Participants received fotemustine 75 milligrams per square meter (mg/m^2) via IV infusion on Days 1, 8, and 15 (induction phase), followed by a 35-day drug-free interval, and then fotemustine 100 mg/m^2 every 21 days (maintenance phase) until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.

    Primary: Percentage of Participants Alive 6 Months After Start of Treatment

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    End point title
    		 Percentage of Participants Alive 6 Months After Start of Treatment [1]
    End point description
    Overall survival (OS) was defined as the time in months from the start of treatment to death due to any cause. If a participant was not known to have died, time was censored at the last date the participant was known to be alive, which was defined as the latest among date of last visit, date of last sample collected for laboratory exam, date of magnetic resonance imaging (MRI) assessment, date of last treatment, date of discontinuation, and date of last available follow-up visit. Participants with no information after baseline were censored at Day 1. OS was estimated by the Kaplan-Meier method. Analysis was performed on intent-to-treat (ITT) population defined as all randomized participants with at least one administration of the study drug.
    End point type
    Primary
    End point timeframe
    6 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: The performed statistical analysis was single arm analysis and in EudraCT it is not possible to report single arm statistical analysis.
    End point values
    		 Bevacizumab Fotemustine
    Number of subjects analysed
    59
    32
    Units: percentage of participants
        number (confidence interval 95%)
    62.07 (48.37 to 74.49)
    73.33 (54.11 to 87.72)
    No statistical analyses for this end point

    Primary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS) [2]
    End point description
    OS was defined as the time in months from the start of treatment to death due to any cause. If a participant was not known to have died, time was censored at the last date the participant was known to be alive, which was defined as the latest among date of last visit, date of last sample collected for laboratory exam, date of MRI assessment, date of last treatment, date of discontinuation, and date of last available follow-up visit. Participants with no information after baseline were censored at Day 1. OS was estimated by the Kaplan-Meier method. Analysis was performed on ITT population.
    End point type
    Primary
    End point timeframe
    Baseline until death (up to 691 days)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The performed statistical analysis was single arm analysis and in EudraCT it is not possible to report single arm statistical analysis.
    End point values
    		 Bevacizumab Fotemustine
    Number of subjects analysed
    59
    32
    Units: months
        median (confidence interval 95%)
    7.26 (5.82 to 9.2)
    8.66 (6.34 to 15.38)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Were Alive and Progression Free 6 Months After Start of Treatment

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    End point title
    		 Percentage of Participants Who Were Alive and Progression Free 6 Months After Start of Treatment
    End point description
    Progression-free survival (PFS) was defined as the time in months from the start of treatment to the date of the first occurrence of disease progression or death from any cause, whichever occurred first. PFS was estimated by the Kaplan-Meier method. Progression was assessed using Response Assessment in Neuro-Oncology (RANO) or the Macdonald Response Criteria, whichever occurred first. As per the RANO criteria, progression was defined as 25 percent (%) or more increase in enhancing lesions despite stable or increasing steroid dose; increase (significant) in non-enhancing T2/FLAIR lesions, not attributable to other non-tumor causes; any new lesions; and clinical deterioration (not attributable to other non-tumor causes and not due to steroid decrease). As per the Macdonald criteria, progression was defined as 25% or more increase in enhancing lesions; any new lesions; and clinical deterioration. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 Bevacizumab Fotemustine
    Number of subjects analysed
    59
    32
    Units: percentage of participants
        number (confidence interval 95%)
    26.32 (15.54 to 39.66)
    10.71 (2.27 to 28.23)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS)

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    End point title
    		 Progression-Free Survival (PFS)
    End point description
    PFS was defined as the time in months from the start of treatment to the date of the first occurrence of disease progression or death from any cause, whichever occurred first. PFS was estimated by Kaplan-Meier method. Progression was assessed using the RANO or the Macdonald Response Criteria, whichever occurred first. As per the RANO criteria, progression was defined as 25% or more increase in enhancing lesions despite stable or increasing steroid dose; increase (significant) in non-enhancing T2/FLAIR lesions, not attributable to other non-tumor causes; any new lesions; and clinical deterioration (not attributable to other non-tumor causes and not due to steroid decrease). As per the Macdonald criteria, progression was defined as 25% or more increase in enhancing lesions; any new lesions; and clinical deterioration. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline until disease progression or death (baseline, 46 days after first administration of study drug, and thereafter every 56 days up to 691 days)
    End point values
    		 Bevacizumab Fotemustine
    Number of subjects analysed
    59
    32
    Units: months
        median (confidence interval 95%)
    3.38 (3.15 to 4.37)
    3.45 (1.87 to 3.84)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Alive 9 Months After Start of Treatment

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    End point title
    		 Percentage of Participants Alive 9 Months After Start of Treatment
    End point description
    OS was defined as the time in months from the start of treatment to death due to any cause. If a participant was not known to have died, time was censored at the last date the participant was known to be alive, which was defined as the latest among date of last visit, date of last sample collected for laboratory exam, date of MRI assessment, date of last treatment, date of discontinuation and date of last available follow-up visit. Participants with no information after baseline were censored at Day 1. OS was estimated by the Kaplan-Meier method. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    9 months
    End point values
    		 Bevacizumab Fotemustine
    Number of subjects analysed
    59
    32
    Units: percentage of participants
        number (confidence interval 95%)
    37.93 (25.51 to 51.63)
    46.67 (28.34 to 65.67)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Alive 12 Months After Start of Treatment

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    End point title
    		 Percentage of Participants Alive 12 Months After Start of Treatment
    End point description
    OS was defined as the time in months from the start of treatment to death due to any cause. If a participant was not known to have died, time was censored at the last date the participant was known to be alive, which was defined as the latest among date of last visit, date of last sample collected for laboratory exam, date of MRI assessment, date of last treatment, date of discontinuation and date of last available follow-up visit. Participants with no information after baseline were censored at Day 1. OS was estimated by the Kaplan-Meier method. Analysis was performed on ITT population and included only participants with evaluable data.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Bevacizumab Fotemustine
    Number of subjects analysed
    58
    30
    Units: percentage of participants
        number (confidence interval 95%)
    25.86 (15.26 to 39.04)
    40 (22.66 to 59.4)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Alive 30 Days After Last Dose of Study Drug

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    End point title
    		 Percentage of Participants Alive 30 Days After Last Dose of Study Drug
    End point description
    OS was defined as the time in months from the start of treatment to death due to any cause. If a participant was not known to have died, time was censored at the last date the participant was known to be alive, which was defined as the latest among date of last visit, date of last sample collected for laboratory exam, date of MRI assessment, date of last treatment, date of discontinuation and date of last available follow-up visit. Participants with no information after baseline were censored at Day 1. OS was estimated by the Kaplan-Meier method. Analysis was performed on ITT population and included only participants with evaluable data.
    End point type
    Secondary
    End point timeframe
    30 days after last dose of study drug (up to Day 600)
    End point values
    		 Bevacizumab Fotemustine
    Number of subjects analysed
    58
    30
    Units: percentage of participants
        number (confidence interval 95%)
    93.1 (83.27 to 98.09)
    90 (73.47 to 97.89)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With a Best Overall Response of Complete Response (CR) or Partial Response (PR)

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    End point title
    		 Percentage of Participants With a Best Overall Response of Complete Response (CR) or Partial Response (PR)
    End point description
    Percentage of participants achieving CR or PR as overall response between first drug administration and documented disease progression were calculated. Tumor response was evaluated according to both, the RANO and the Macdonald response criteria. As per Macdonald criteria, CR was defined as the disappearance of all enhancing disease, sustained for at least 4 weeks, and no new lesions along with clinical features of clinically stable or improved, with no corticosteroid; PR was defined as a 50% or more decrease of all measurable enhancing lesions, sustained for at least 4 weeks, and no new lesion along with clinical features of clinically stable or improved, with stable or reduced corticosteroids. RANO criteria defined CR and PR the same as Macdonald criteria with the following additions: CR - improved non enhancing T2/FLAIR lesions; PR - no progression of non-measurable disease, stable or improved non enhancing FLAIR/T2 lesions. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline until disease progression or death (baseline, 46 days after first administration of study drug, and thereafter every 56 days up to 691 days)
    End point values
    		 Bevacizumab Fotemustine
    Number of subjects analysed
    59
    32
    Units: percentage of participants
    number (not applicable)
        RANO Evaluation
    28.81
    9.38
        MacDonald Evaluation
    28.81
    6.25
    No statistical analyses for this end point

    Secondary: Change From Screening in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Scores at Weeks 8, 16, 24, 32, 40, 48, 56, 64, and 72

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    End point title
    		 Change From Screening in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Scores at Weeks 8, 16, 24, 32, 40, 48, 56, 64, and 72
    End point description
    EORTC QLQ-C30: included global health status/quality of life (QOL), functional scales (physical, role, cognitive, emotional, and social), symptom scales (fatigue, pain, nausea/vomiting), and single items (dyspnea, appetite loss, insomnia, constipation, diarrhea, and financial difficulties). Most questions used a 4- point scale (1 ‘Not at All’ to 4 ‘Very Much’); 2 questions used a 7-point scale (1 ‘Very Poor’ to 7 ‘Excellent’). Scores were averaged and transformed to a 0-100 scale; a higher score for Global Qol/functional scales indicates better level of QoL/functioning, or a higher score for symptom scale indicates greater degree of symptoms. Analysis was performed on ITT population and included only participants with evaluable data. The number 99999 signifies data not available either because no participant was evaluable (when 99999 is reported for both mean and standard deviation) or only one participant was evaluable (when 99999 is reported only for standard deviation).
    End point type
    Secondary
    End point timeframe
    Screening, Weeks 8, 16, 24, 32, 40, 48, 56, 64, and 72
    End point values
    		 Bevacizumab Fotemustine
    Number of subjects analysed
    58 [3]
    31 [4]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Physical Functioning (Fn): Screening (n=58,31)
    71.95 ± 25.65
    78.92 ± 25.07
        Physical Fn: Change at Week 8 (n=27,16)
    10.37 ± 19.07
    7.08 ± 12.76
        Physical Fn: Change at Week 16 (n=15,7)
    7.56 ± 19.17
    8.57 ± 13.72
        Physical Fn: Change at Week 24 (n=14,1)
    13.81 ± 24.17
    0 ± 99999
        Physical Fn: Change at Week 32 (n=7,2)
    18.1 ± 28.21
    13.33 ± 9.43
        Physical Fn: Change at Week 40 (n=9,1)
    4.44 ± 19.72
    6.67 ± 99999
        Physical Fn: Change at Week 48 (n=4,1)
    3.33 ± 16.78
    6.67 ± 99999
        Physical Fn: Change at Week 56 (n=4,0)
    6.67 ± 9.43
    99999 ± 99999
        Physical Fn: Change at Week 64 (n=1,0)
    0 ± 99999
    99999 ± 99999
        Physical Fn: Change at Week 72 (n=1,0)
    0 ± 99999
    99999 ± 99999
        Role Fn: Screening (n=58,31)
    67.82 ± 31.04
    73.66 ± 32.14
        Role Fn: Change at Week 8 (n=27,16)
    6.17 ± 34.01
    4.17 ± 21.52
        Role Fn: Change at Week 16 (n=15,7)
    2.22 ± 25.87
    2.38 ± 26.23
        Role Fn: Change at Week 24 (n=14,1)
    14.29 ± 33.88
    0 ± 99999
        Role Fn: Change at Week 32 (n=7,2)
    16.67 ± 28.87
    0 ± 0
        Role Fn: Change at Week 40 (n=9,1)
    0 ± 22.05
    0 ± 99999
        Role Fn: Change at Week 48 (n=4,1)
    0 ± 36
    0 ± 99999
        Role Fn: Change at Week 56 (n=4,0)
    -12.5 ± 36.96
    99999 ± 99999
        Role Fn: Change at Week 64 (n=1,0)
    -50 ± 99999
    99999 ± 99999
        Role Fn: Change at Week 72 (n=1,0)
    -50 ± 99999
    99999 ± 99999
        Emotional Fn: Screening (n=58,31)
    73.56 ± 23.47
    74.19 ± 23.41
        Emotional Fn: Change at Week 8 (n=27,16)
    -8.02 ± 23.62
    8.33 ± 24.91
        Emotional Fn: Change at Week 16 (n=15,7)
    -0.56 ± 14.25
    -2.38 ± 27.52
        Emotional Fn: Change at Week 24 (n=14,1)
    10.12 ± 29.63
    -33.33 ± 99999
        Emotional Fn: Change at Week 32 (n=7,2)
    -2.38 ± 15
    16.67 ± 0
        Emotional Fn: Change at Week 40 (n=9,1)
    -5.56 ± 24.65
    8.33 ± 99999
        Emotional Fn: Change at Week 48 (n=4,1)
    14.58 ± 27.53
    8.33 ± 99999
        Emotional Fn: Change at Week 56 (n=4,0)
    -4.17 ± 27.64
    99999 ± 99999
        Emotional Fn: Change at Week 64 (n=1,0)
    8.33 ± 99999
    99999 ± 99999
        Emotional Fn: Change at Week 72 (n=1,0)
    8.33 ± 99999
    99999 ± 99999
        Cognitive Fn: Screening (n=58,31)
    70.4 ± 25.18
    79.03 ± 24.33
        Cognitive Fn: Change at Week 8 (n=27,16)
    4.94 ± 23.49
    7.29 ± 23.55
        Cognitive Fn: Change at Week 16 (n=15,7)
    2.22 ± 17.67
    -4.76 ± 34.31
        Cognitive Fn: Change at Week 24 (n=14,1)
    10.71 ± 24.11
    0 ± 99999
        Cognitive Fn: Change at Week 32 (n=7,2)
    0 ± 16.67
    8.33 ± 11.79
        Cognitive Fn: Change at Week 40 (n=9,1)
    -1.85 ± 19.44
    0 ± 99999
        Cognitive Fn: Change at Week 48 (n=4,1)
    0 ± 0
    0 ± 99999
        Cognitive Fn: Change at Week 56 (n=4,0)
    -4.17 ± 20.97
    99999 ± 99999
        Cognitive Fn: Change at Week 64 (n=1,0)
    16.67 ± 99999
    99999 ± 99999
        Cognitive Fn: Change at Week 72 (n=1,0)
    16.67 ± 99999
    99999 ± 99999
        Social Fn: Screening (n=58,31)
    72.99 ± 28.07
    81.18 ± 24.24
        Social Fn: Change at Week 8 (n=27,16)
    1.85 ± 31.12
    4.17 ± 23.96
        Social Fn: Change at Week 16 (n=15,7)
    1.11 ± 27.07
    -2.38 ± 26.23
        Social Fn: Change at Week 24 (n=14,1)
    13.1 ± 39.32
    0 ± 99999
        Social Fn: Change at Week 32 (n=7,2)
    -7.14 ± 38.32
    8.33 ± 11.79
        Social Fn: Change at Week 40 (n=9,1)
    -5.56 ± 22.05
    16.67 ± 99999
        Social Fn: Change at Week 48 (n=4,1)
    -4.17 ± 36.96
    16.67 ± 99999
        Social Fn: Change at Week 56 (n=4,0)
    -12.5 ± 28.46
    99999 ± 99999
        Social Fn: Change at Week 64 (n=1,0)
    -66.67 ± 99999
    99999 ± 99999
        Social Fn: Change at Week 72 (n=1,0)
    -66.67 ± 99999
    99999 ± 99999
        QOL: Screening (n=58,31)
    58.05 ± 26.4
    66.13 ± 24.9
        QOL: Change at Week 8 (n=27,16)
    -3.09 ± 20.17
    6.25 ± 22.87
        QOL: Change at Week 16 (n=15,7)
    -4.44 ± 14.39
    7.14 ± 23.78
        QOL: Change at Week 24 (n=14,1)
    4.76 ± 21.11
    0 ± 99999
        QOL: Change at Week 32 (n=7,2)
    3.57 ± 17.91
    -12.5 ± 17.68
        QOL: Change at Week 40 (n=9,1)
    -2.78 ± 25.34
    0 ± 99999
        QOL: Change at Week 48 (n=4,1)
    10.42 ± 14.23
    0 ± 99999
        QOL: Change at Week 56 (n=4,0)
    2.08 ± 34.94
    99999 ± 99999
        QOL: Change at Week 64 (n=1,0)
    0 ± 99999
    99999 ± 99999
        QOL: Change at Week 72 (n=1,0)
    0 ± 99999
    99999 ± 99999
        Fatigue: Screening (n=58,31)
    31.99 ± 25.5
    24.01 ± 22.05
        Fatigue: Change at Week 8 (n=27,16)
    -3.29 ± 32.59
    -13.19 ± 25.73
        Fatigue: Change at Week 16 (n=15,7)
    2.22 ± 21.5
    -9.52 ± 17.48
        Fatigue: Change at Week 24 (n=14,1)
    -6.35 ± 29.79
    -11.11 ± 99999
        Fatigue: Change at Week 32 (n=7,2)
    3.17 ± 17.82
    -5.56 ± 7.86
        Fatigue: Change at Week 40 (n=9,1)
    9.88 ± 23.2
    -11.11 ± 99999
        Fatigue: Change at Week 48 (n=4,1)
    -8.33 ± 18.98
    -11.11 ± 99999
        Fatigue: Change at Week 56 (n=4,0)
    2.78 ± 30.6
    99999 ± 99999
        Fatigue: Change at Week 64 (n=1,0)
    0 ± 99999
    99999 ± 99999
        Fatigue: Change at Week 72 (n=1,0)
    0 ± 99999
    99999 ± 99999
        Nausea: Screening (n=58,31)
    2.01 ± 7.7
    1.08 ± 4.16
        Nausea: Change at Week 8 (n=27,16)
    1.85 ± 10.68
    -8.33 ± 14.91
        Nausea: Change at Week 16 (n=15,7)
    0 ± 6.3
    -14.29 ± 20.25
        Nausea: Change at Week 24 (n=14,1)
    -5.95 ± 10.56
    0 ± 99999
        Nausea: Change at Week 32 (n=7,2)
    -2.38 ± 6.3
    0 ± 0
        Nausea: Change at Week 40 (n=9,1)
    -9.26 ± 8.78
    0 ± 99999
        Nausea: Change at Week 48 (n=4,1)
    0 ± 0
    -16.67 ± 99999
        Nausea: Change at Week 56 (n=4,0)
    -4.17 ± 8.33
    99999 ± 99999
        Nausea: Change at Week 64 (n=1,0)
    -16.67 ± 99999
    99999 ± 99999
        Nausea: Change at Week 72 (n=1,0)
    -16.67 ± 99999
    99999 ± 99999
        Pain: Screening (n=58,31)
    6.9 ± 16.82
    14.52 ± 23.47
        Pain: Change at Week 8 (n=27,16)
    -1.85 ± 24.61
    -6.25 ± 26.44
        Pain: Change at Week 16 (n=15,7)
    -10 ± 19.72
    -2.38 ± 20.25
        Pain: Change at Week 24 (n=14,1)
    -8.33 ± 28.31
    0 ± 99999
        Pain: Change at Week 32 (n=7,2)
    0 ± 16.67
    -8.33 ± 11.79
        Pain: Change at Week 40 (n=9,1)
    -7.41 ± 18.84
    0 ± 99999
        Pain: Change at Week 48 (n=4,1)
    -29.17 ± 28.46
    0 ± 99999
        Pain: Change at Week 56 (n=4,0)
    0 ± 19.25
    99999 ± 99999
        Pain: Change at Week 64 (n=1,0)
    -16.67 ± 99999
    99999 ± 99999
        Pain: Change at Week 72 (n=1,0)
    -16.67 ± 99999
    99999 ± 99999
        Dyspnea: Screening (n=58,31)
    11.49 ± 22.12
    3.23 ± 10.02
        Dyspnea: Change at Week 8 (n=27,16)
    4.94 ± 28.8
    -6.25 ± 21.84
        Dyspnea: Change at Week 16 (n=15,7)
    0 ± 25.2
    4.76 ± 12.6
        Dyspnea: Change at Week 24 (n=14,1)
    -9.52 ± 27.51
    0 ± 99999
        Dyspnea: Change at Week 32 (n=7,2)
    0 ± 27.22
    0 ± 0
        Dyspnea: Change at Week 40 (n=9,1)
    3.7 ± 20.03
    0 ± 99999
        Dyspnea: Change at Week 48 (n=4,1)
    -8.33 ± 16.67
    0 ± 99999
        Dyspnea: Change at Week 56 (n=4,0)
    0 ± 27.22
    99999 ± 99999
        Dyspnea: Change at Week 64 (n=1,0)
    0 ± 99999
    99999 ± 99999
        Dyspnea: Change at Week 72 (n=1,0)
    0 ± 99999
    99999 ± 99999
        Insomnia: Screening (n=58,31)
    18.39 ± 28.73
    18.28 ± 22.51
        Insomnia: Change at Week 8 (n=27,16)
    1.23 ± 25.29
    -8.33 ± 33.33
        Insomnia: Change at Week 16 (n=15,7)
    2.22 ± 32.04
    -4.76 ± 29.99
        Insomnia: Change at Week 24 (n=14,1)
    -9.52 ± 46.09
    -33.33 ± 99999
        Insomnia: Change at Week 32 (n=7,2)
    28.57 ± 23
    16.67 ± 23.57
        Insomnia: Change at Week 40 (n=9,1)
    14.81 ± 24.22
    33.33 ± 99999
        Insomnia: Change at Week 48 (n=4,1)
    25 ± 31.91
    33.33 ± 99999
        Insomnia: Change at Week 56 (n=4,0)
    33.33 ± 27.22
    99999 ± 99999
        Insomnia: Change at Week 64 (n=1,0)
    0 ± 99999
    99999 ± 99999
        Insomnia: Change at Week 72 (n=1,0)
    0 ± 99999
    99999 ± 99999
        Appetite loss: Screening (n=58,31)
    7.47 ± 19.79
    5.38 ± 12.46
        Appetite loss: Change at Week 8 (n=27,16)
    0 ± 22.65
    -10.42 ± 23.47
        Appetite loss: Change at Week 16 (n=15,7)
    -2.22 ± 8.61
    -14.29 ± 26.23
        Appetite loss: Change at Week 24 (n=14,1)
    -7.14 ± 19.3
    0 ± 99999
        Appetite loss: Change at Week 32 (n=7,2)
    -4.76 ± 12.6
    0 ± 0
        Appetite loss: Change at Week 40 (n=9,1)
    -7.41 ± 14.7
    0 ± 99999
        Appetite loss: Change at Week 48 (n=4,1)
    -16.67 ± 19.25
    0 ± 99999
        Appetite loss: Change at Week 56 (n=4,0)
    -16.67 ± 19.25
    99999 ± 99999
        Appetite loss: Change at Week 64 (n=1,0)
    0 ± 99999
    99999 ± 99999
        Appetite loss: Change at Week 72 (n=1,0)
    0 ± 99999
    99999 ± 99999
        Constipation: Screening (n=58,31)
    17.82 ± 24.36
    17.2 ± 25.63
        Constipation: Change at Week 8 (n=26,16)
    3.85 ± 25.52
    -4.17 ± 26.87
        Constipation: Change at Week 16 (n=15,7)
    4.44 ± 17.21
    -9.52 ± 25.2
        Constipation: Change at Week 24 (n=14,1)
    2.38 ± 20.52
    0 ± 99999
        Constipation: Change at Week 32 (n=7,2)
    0 ± 38.49
    16.67 ± 23.57
        Constipation: Change at Week 40 (n=9,1)
    3.7 ± 26.06
    0 ± 99999
        Constipation: Change at Week 48 (n=4,1)
    -16.67 ± 19.25
    0 ± 99999
        Constipation: Change at Week 56 (n=4,0)
    0 ± 27.22
    99999 ± 99999
        Constipation: Change at Week 64 (n=1,0)
    -33.33 ± 99999
    99999 ± 99999
        Constipation: Change at Week 72 (n=1,0)
    -33.33 ± 99999
    99999 ± 99999
        Diarrhea: Screening (n=58,31)
    1.15 ± 6.14
    2.15 ± 8.32
        Diarrhea: Change at Week 8 (n=27,16)
    0 ± 9.25
    0 ± 0
        Diarrhea: Change at Week 16 (n=15,7)
    -6.67 ± 18.69
    0 ± 0
        Diarrhea: Change at Week 24 (n=14,1)
    -7.14 ± 19.3
    0 ± 99999
        Diarrhea: Change at Week 32 (n=7,2)
    -4.76 ± 12.6
    0 ± 0
        Diarrhea: Change at Week 40 (n=9,1)
    0 ± 0
    0 ± 99999
        Diarrhea: Change at Week 48 (n=4,1)
    0 ± 0
    0 ± 99999
        Diarrhea: Change at Week 56 (n=4,0)
    0 ± 0
    99999 ± 99999
        Diarrhea: Change at Week 64 (n=1,0)
    0 ± 99999
    99999 ± 99999
        Diarrhea: Change at Week 72 (n=1,0)
    0 ± 99999
    99999 ± 99999
        Financial Fn: Screening (n=58,31)
    17.82 ± 25.91
    25.81 ± 34.11
        Financial Fn: Change at Week 8 (n=27,16)
    6.17 ± 26.21
    -4.17 ± 11.39
        Financial Fn: Change at Week 16 (n=15,7)
    2.22 ± 15.26
    9.52 ± 46
        Financial Fn: Change at Week 24 (n=14,1)
    -4.76 ± 22.1
    0 ± 99999
        Financial Fn: Change at Week 32 (n=7,2)
    0 ± 19.25
    -16.67 ± 23.57
        Financial Fn: Change at Week 40 (n=9,1)
    -3.7 ± 26.06
    0 ± 99999
        Financial Fn: Change at Week 48 (n=4,1)
    -16.67 ± 19.25
    0 ± 99999
        Financial Fn: Change at Week 56 (n=4,0)
    -8.33 ± 31.91
    99999 ± 99999
        Financial Fn: Change at Week 64 (n=1,0)
    0 ± 99999
    99999 ± 99999
        Financial Fn: Change at Week 72 (n=1,0)
    0 ± 99999
    99999 ± 99999
    Notes
    [3] - n (number of participants) = participants with evaluable data for specified category.
    [4] - n (number of participants) = participants with evaluable data for specified category.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Corticosteroid Initiation During the Study Period

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    End point title
    		 Percentage of Participants With Corticosteroid Initiation During the Study Period
    End point description
    Corticosteroid initiation was assessed in participants not receiving corticosteroids at screening. The participant had the event if he/she started on corticosteroids with a dosage greater than equal to (>/=) 2 mg dexamethasone equivalent. Analysis was performed on ITT population and included only participants who were not receiving corticosteroids at screening.
    End point type
    Secondary
    End point timeframe
    Baseline until recurrence (up to 691 days)
    End point values
    		 Bevacizumab Fotemustine
    Number of subjects analysed
    17
    12
    Units: percentage of participants
        number (not applicable)
    58.82
    41.67
    No statistical analyses for this end point

    Secondary: Time to Corticosteroid Initiation

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    End point title
    		 Time to Corticosteroid Initiation
    End point description
    Time to corticosteroid initiation was defined as the time from screening to the start date of the first corticosteroid administration in participants not receiving corticosteroids at screening. The participant had the event if he/she started on corticosteroids with a dosage ≥2 mg dexamethasone equivalent. Instead, if the participant was not known to have the event, time was censored at the last available visit date. Time to corticosteroid initiation was estimated using the Kaplan Meier method. Analysis was performed on ITT population and included only participants who were not receiving corticosteroids at screening. The number 99999 signifies data not available due to higher number (>40%) of censored participants.
    End point type
    Secondary
    End point timeframe
    Baseline until recurrence (up to 691 days)
    End point values
    		 Bevacizumab Fotemustine
    Number of subjects analysed
    17
    12
    Units: months
        median (confidence interval 95%)
    4.49 (1.87 to 99999)
    5.93 (0.3 to 99999)
    No statistical analyses for this end point

    Secondary: Percentage of Participants in Each Class of Corticosteroid Use

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    End point title
    		 Percentage of Participants in Each Class of Corticosteroid Use
    End point description
    Corticosteroid use was classified as: 1. No Change (if corticosteroid dose at each assessment was equal to baseline); 2. Decreased (if corticosteroid dose at each assessment was lower than baseline); 3. Increased (corticosteroid dose at each assessment was greater than baseline). Analysis was performed on ITT population and included only participants with evaluable data.
    End point type
    Secondary
    End point timeframe
    Weeks 8, 16, 24, 32, 40, 48, 56, 64, 72, 80, 88, post-treatment follow-up (up to Day 691)
    End point values
    		 Bevacizumab Fotemustine
    Number of subjects analysed
    52 [5]
    28 [6]
    Units: percentage of participants
    number (not applicable)
        Week 8: Increased (n=52,28)
    17.31
    17.86
        Week 8: Decreased (n=52,28)
    23.08
    21.43
        Week 8: No Change (n=52,28)
    59.62
    60.71
        Week 16: Increased (n=33,18)
    21.21
    22.22
        Week 16: Decreased (n=33,18)
    36.36
    27.78
        Week 16: No Change (n=33,18)
    42.42
    50
        Week 24: Increased (n=21,5)
    28.57
    20
        Week 24: Decreased (n=21,5)
    33.33
    40
        Week 24: No Change (n=21,5)
    38.1
    40
        Week 32: Increased (n=14,3)
    14.29
    33.33
        Week 32: Decreased (n=14,3)
    42.86
    0
        Week 32: No Change (n=14,3)
    42.86
    66.67
        Week 40: Increased (n=10,2)
    0
    50
        Week 40: Decreased (n=10,2)
    60
    0
        Week 40: No Change (n=10,2)
    40
    50
        Week 48: Increased (n=8,1)
    0
    0
        Week 48: Decreased (n=8,1)
    50
    0
        Week 48: No Change (n=8,1)
    50
    100
        Week 56: Increased (n=6,1)
    0
    0
        Week 56: Decreased (n=6,1)
    33.33
    0
        Week 56: No Change (n=6,1)
    66.67
    100
        Week 64: Increased (n=3,1)
    0
    0
        Week 64: Decreased (n=3,1)
    0
    0
        Week 64: No Change (n=3,1)
    100
    100
        Week 72: Increased (n=3,0)
    0
    99999
        Week 72: Decreased (n=3,0)
    0
    99999
        Week 72: No Change (n=3,0)
    100
    99999
        Week 80: Increased (n=1,0)
    0
    99999
        Week 80: Decreased (n=1,0)
    0
    99999
        Week 80: No Change (n=1,0)
    100
    99999
        Week 88: Increased (n=1,0)
    100
    99999
        Week 88: Decreased (n=1,0)
    0
    99999
        Week 88: No Change (n=1,0)
    0
    99999
        Follow-up: Increased (n=9,3)
    33.33
    0
        Follow-up: Decreased (n=9,3)
    0
    33.33
        Follow-up: No Change (n=9,3)
    66.67
    66.67
    Notes
    [5] - n (number of participants) = participants with evaluable data for specified category.
    [6] - n (number of participants) = participants with evaluable data for specified category.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Karnofsky Performance Status (KPS) Deterioration

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    End point title
    		 Percentage of Participants With Karnofsky Performance Status (KPS) Deterioration
    End point description
    Deterioration of KPS was defined as a decrease of at least 20 percentage points with respect to the screening. KPS is an 11-level score which ranges between 0 (death) to 100 (complete healthy status); a higher score represents a higher ability to perform daily tasks. Analysis was performed on ITT population and included only participants with evaluable data.
    End point type
    Secondary
    End point timeframe
    Baseline until KPS deterioration (up to 691 days)
    End point values
    		 Bevacizumab Fotemustine
    Number of subjects analysed
    37
    14
    Units: percentage of participants
        number (not applicable)
    18.92
    14.29
    No statistical analyses for this end point

    Secondary: Time to Karnofsky Performance Status (KPS) Deterioration

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    End point title
    		 Time to Karnofsky Performance Status (KPS) Deterioration
    End point description
    Time to KPS deterioration was defined as the time from screening to the first date of deterioration of the KPS score. Deterioration of KPS was defined as a decrease of at least 20 percentage points with respect to the screening. KPS is an 11-level score which ranges between 0 (death) to 100 (complete healthy status); a higher score represents a higher ability to perform daily tasks. Time to KPS deterioration was estimated using Kaplan Meier method. If the participant was not known to have the event, time was censored at the last available visit date. Analysis was performed on ITT population and included only participants with evaluable data. The number 99999 signify data not available as <50% of participants had an event of interest.
    End point type
    Secondary
    End point timeframe
    Baseline until KPS deterioration (up to 691 days)
    End point values
    		 Bevacizumab Fotemustine
    Number of subjects analysed
    37
    14
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With World Health Organization (WHO) Performance Status (PS) Deterioration

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    End point title
    		 Percentage of Participants With World Health Organization (WHO) Performance Status (PS) Deterioration
    End point description
    WHO PS deterioration was defined as a decrease of at least 1 point with respect to the screening value. WHO PS is a 6-level score which ranges between 0 (fully active) to 5 (death); a lower score represents a higher ability to perform daily tasks. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline until WHO PS deterioration (up to 691 days)
    End point values
    		 Bevacizumab Fotemustine
    Number of subjects analysed
    59
    32
    Units: percentage of participants
        number (not applicable)
    47.46
    37.5
    No statistical analyses for this end point

    Secondary: Time to WHO PS Deterioration

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    End point title
    		 Time to WHO PS Deterioration
    End point description
    Time to WHO PS deterioration was defined as the time from randomization to the first date of deterioration of the WHO performance status score. WHO PS score was defined as a decrease of at least 1 point with respect to the screening. WHO PS is a 6-level score which ranges between 0 (fully active) to 5 (death); a lower score represents a higher ability to perform daily tasks. Analysis was performed on ITT population. The number 99999 signify data not available as <50% of participants had an event of interest.
    End point type
    Secondary
    End point timeframe
    Baseline until WHO PS deterioration (up to 691 days)
    End point values
    		 Bevacizumab Fotemustine
    Number of subjects analysed
    59
    32
    Units: months
        median (confidence interval 95%)
    8.87 (4.17 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 691 days
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    Fotemustine
    Reporting group description
    		 Fotemustine 75 mg/m^2 IV infusion on Days 1, 8, and 15 (induction phase), followed by 35-day treatment free interval, and then fotemustine 100 mg/m^2 every 21 days (maintenance phase) until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.

    Reporting group title
    Bevacizumab
    Reporting group description
    		 Bevacizumab 10 mg/kg IV infusion every 14 days until disease progression was radiographically documented or the onset of toxicity prevented treatment continuation.

    Serious adverse events
    		 Fotemustine Bevacizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 32 (18.75%)
    17 / 59 (28.81%)
         number of deaths (all causes)
    23
    50
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour haemorrhage
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Road traffic accident
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vascular disorders
    Thrombophlebitis
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral ischaemia
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Partial seizures with secondary generalisation
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Condition aggravated
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pyrexia
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Fotemustine Bevacizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 32 (78.13%)
    35 / 59 (59.32%)
    Investigations
    Weight increased
         subjects affected / exposed
    1 / 32 (3.13%)
    4 / 59 (6.78%)
         occurrences all number
    1
    4
    Transaminases increased
         subjects affected / exposed
    4 / 32 (12.50%)
    3 / 59 (5.08%)
         occurrences all number
    6
    3
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 32 (3.13%)
    13 / 59 (22.03%)
         occurrences all number
    1
    29
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 32 (3.13%)
    5 / 59 (8.47%)
         occurrences all number
    1
    6
    Epilepsy
         subjects affected / exposed
    2 / 32 (6.25%)
    2 / 59 (3.39%)
         occurrences all number
    2
    2
    Convulsion
         subjects affected / exposed
    2 / 32 (6.25%)
    4 / 59 (6.78%)
         occurrences all number
    2
    7
    Partial seizures with secondary generalisation
         subjects affected / exposed
    0 / 32 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    7
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    3 / 32 (9.38%)
    1 / 59 (1.69%)
         occurrences all number
    3
    1
    Anaemia
         subjects affected / exposed
    5 / 32 (15.63%)
    1 / 59 (1.69%)
         occurrences all number
    5
    1
    Neutropenia
         subjects affected / exposed
    8 / 32 (25.00%)
    2 / 59 (3.39%)
         occurrences all number
    13
    2
    Thrombocytopenia
         subjects affected / exposed
    14 / 32 (43.75%)
    2 / 59 (3.39%)
         occurrences all number
    19
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 59 (1.69%)
         occurrences all number
    3
    1
    Asthenia
         subjects affected / exposed
    4 / 32 (12.50%)
    13 / 59 (22.03%)
         occurrences all number
    5
    13
    Oedema peripheral
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 59 (1.69%)
         occurrences all number
    2
    1
    Pyrexia
         subjects affected / exposed
    3 / 32 (9.38%)
    5 / 59 (8.47%)
         occurrences all number
    3
    6
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    2 / 32 (6.25%)
    3 / 59 (5.08%)
         occurrences all number
    2
    3
    Diarrhoea
         subjects affected / exposed
    0 / 32 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    4
    Nausea
         subjects affected / exposed
    4 / 32 (12.50%)
    2 / 59 (3.39%)
         occurrences all number
    4
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 32 (3.13%)
    3 / 59 (5.08%)
         occurrences all number
    1
    3
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 59 (1.69%)
         occurrences all number
    3
    1
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    1 / 32 (3.13%)
    3 / 59 (5.08%)
         occurrences all number
    1
    7
    Fungal infection
         subjects affected / exposed
    3 / 32 (9.38%)
    1 / 59 (1.69%)
         occurrences all number
    3
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Jan 2013
    Clarified the exclusion criteria; “previous treatment with bevacizumab or other anti-angiogenic drugs” was modified into “no prior treatment with bevacizumab or other vascular endothelial growth factor (VEGF) inhibitors or VEGF receptor signaling inhibitors here. Provided more time to perform magnetic resonance imaging (MRI) at baseline prior to randomization. Provided clear instructions about the determination of proteinuria by dipstick; this exam was required only for the participants treated with bevacizumab and not for those treated with fotemustine. Added an acronym to the study.
    01 Sep 2013
    Clarified the definition of database (DB) lock and end of study; the previous definition was modified into “follow up for survival will continue until 14 months after the randomization of the last participant or all participants have died whichever occurs first”. Amended the inclusion criteria; “Histologically confirmed recurrent glioblastoma multiforme (Grade IV)” was amended into “Histologically confirmed glioblastoma multiforme (Grade IV)”. The definition of follow-up period was changed to 14-months following randomization to provide additional information about the safety of Avastin not available at the time of first submission and first amendment. Adapted the time of serious adverse event (SAE) reporting in accordance with the latest safety directives.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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