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    Clinical Trial Results:
    A Phase II Open-Label, Randomized, Multi-Centre Comparative Study of Bevacizumab-Based Therapy in Paediatric Patients with Newly Diagnosed Supratentorial, Infratentorial Cerebellar, or Peduncular High-Grade Glioma

    Summary
    EudraCT number
    		 2010-022189-28
    Trial protocol
    		 BE   AT   CZ   DE   GB   SE   HU   FR   ES   DK   FI   NL   IT   PL   Outside EU/EEA  
    Global end of trial date
    29 Jan 2020

    Results information
    Results version number
    		 v3(current)
    This version publication date
    08 Aug 2020
    First version publication date
    17 Sep 2016
    Other versions
    		 v1 , v2
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    bo25041
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01390948
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F., F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F., F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000056-PIP03-10
    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
    29 Jan 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jan 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the benefit in terms of event-free survival (EFS) of the addition of bevacizumab to postoperative radiotherapy with concomitant and adjuvant temozolomide (TMZ).
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Oct 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    Sweden: 4
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    United Kingdom: 29
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Czech Republic: 4
    Country: Number of subjects enrolled
    Denmark: 3
    Country: Number of subjects enrolled
    France: 29
    Country: Number of subjects enrolled
    Hungary: 4
    Country: Number of subjects enrolled
    Italy: 21
    Country: Number of subjects enrolled
    Canada: 8
    Country: Number of subjects enrolled
    Australia: 5
    Worldwide total number of subjects
    124
    EEA total number of subjects
    111
    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)
    2
    Children (2-11 years)
    71
    Adolescents (12-17 years)
    51
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Chemoradiation + temozolomide (TMZ) and Chemoradiation + Bevacizumab + TMZ arms: 174 subjects were screened; 121 were randomised; 116 received study treatment. Young Patient Cohort: 4 subjects were screened; 3 were enrolled and received study treatment (these subjects were not randomised and are not included in efficacy analyses).

    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
    		 Main Cohort: Chemoradiation + TMZ
    Arm description
    		 Subjects received a total dose of 54 Grey (Gy) units delivered in 30 daily fractions of 1.8 Gy over 6 weeks with 75 milligrams per meter squared (mg/m^2) TMZ daily for up to 49 days followed by a treatment break of approximately 4 weeks. The treatment break was followed by an adjuvant treatment phase where subjects received 150 to 200 mg/m^2 of TMZ daily on Days 1-5 of each cycle. TMZ was given at a dose of 150 mg/m^2 on Days 1-5 of cycle 1 and then escalated to 200 mg/m^2 on days 1-5 from cycle 2 onwards depending on the tolerance during the 1st cycle.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Temozolomide (TMZ)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    75 milligrams per square meter (mg/m^2) daily continuous starting concomitantly with the first radiation fraction and ending with the last radiation fraction for a maximum number of treatment days = 49 days. During the TMZ adjuvant treatment phase: TMZ (150 to 200 mg/m^2/day) x 12 cycles, 1st cycle 150 mg/m^2 on Days 1-5, escalated to 200 mg/m^2 on Days 1-5 from the 2nd cycle onwards depending on the tolerance during the 1st cycle. Cycle length = 28 days.

    Arm title
    		 Main Cohort: Chemoradiation + Bevacizumab + TMZ
    Arm description
    		 Subjects received a total dose of 54 Gy units delivered in 30 daily fractions of 1.8 Gy over 6 weeks with 75 mg/m^2 TMZ daily for up to 49 days followed by a treatment break of approximately 4 weeks. The treatment break was followed by an adjuvant treatment phase where subjects received 150 to 200 mg/m^2 of TMZ daily on Days 1-5 of each cycle. TMZ was given at a dose of 150 mg/m^2 on Days 1-5 of cycle 1 and then escalated to 200 mg/m^2 on days 1-5 from cycle 2 onwards depending on the tolerance during the 1st cycle. Bevacizumab was given concomitantly at a dose of 10 milligrams per kilogram (mg/kg) every 2 weeks throughout the entire treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Temozolomide (TMZ)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    75 milligrams per square meter (mg/m^2) daily continuous starting concomitantly with the first radiation fraction and ending with the last radiation fraction for a maximum number of treatment days = 49 days. During the TMZ adjuvant treatment phase: TMZ (150 to 200 mg/m^2/day) x 12 cycles, 1st cycle 150 mg/m^2 on Days 1-5, escalated to 200 mg/m^2 on Days 1-5 from the 2nd cycle onwards depending on the tolerance during the 1st cycle. Cycle length = 28 days.

    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
    10 milligrams per kilogram every 2 weeks during the study for up to 12 cycles, each cycle length of 28 days

    Arm title
    		 Bevacizumab + TMZ Young Patient Cohort (YPC)
    Arm description
    		 Subjects aged >/= 6 months and < 3 years received 10 mg/kg Bevacizumab every 2 weeks and 150 to 200 mg/m^2 of TMZ daily on Days 1-5 of each cycle. TMZ was given at a dose of 150 mg/m^2 on Days 1-5 of cycle 1 and then escalated to 200 mg/m^2 on days 1-5 from cycle 2 onwards depending on the tolerance during the 1st cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Temozolomide (TMZ)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    150 to 200 mg/m2/day from Days 1 to 5 every 28 days for a total of 12 cycles. Cycle length = 28 days.

    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
    10 milligrams per kilogram every 2 weeks during the study for up to 12 cycles, each cycle length of 28 days

    Number of subjects in period 1
    		Main Cohort: Chemoradiation + TMZ Main Cohort: Chemoradiation + Bevacizumab + TMZ Bevacizumab + TMZ Young Patient Cohort (YPC)
    Started
    59
    62
    3
    Treated
    56
    60
    3
    Completed
    44
    44
    2
    Not completed
    15
    18
    1
         Consent withdrawn by subject
    2
    2
    -
         Disease progression
    2
    5
    -
         End of Study
    1
    -
    -
         Death during follow-up
    10
    11
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Main Cohort: Chemoradiation + TMZ
    Reporting group description
    		 Subjects received a total dose of 54 Grey (Gy) units delivered in 30 daily fractions of 1.8 Gy over 6 weeks with 75 milligrams per meter squared (mg/m^2) TMZ daily for up to 49 days followed by a treatment break of approximately 4 weeks. The treatment break was followed by an adjuvant treatment phase where subjects received 150 to 200 mg/m^2 of TMZ daily on Days 1-5 of each cycle. TMZ was given at a dose of 150 mg/m^2 on Days 1-5 of cycle 1 and then escalated to 200 mg/m^2 on days 1-5 from cycle 2 onwards depending on the tolerance during the 1st cycle.

    Reporting group title
    Main Cohort: Chemoradiation + Bevacizumab + TMZ
    Reporting group description
    		 Subjects received a total dose of 54 Gy units delivered in 30 daily fractions of 1.8 Gy over 6 weeks with 75 mg/m^2 TMZ daily for up to 49 days followed by a treatment break of approximately 4 weeks. The treatment break was followed by an adjuvant treatment phase where subjects received 150 to 200 mg/m^2 of TMZ daily on Days 1-5 of each cycle. TMZ was given at a dose of 150 mg/m^2 on Days 1-5 of cycle 1 and then escalated to 200 mg/m^2 on days 1-5 from cycle 2 onwards depending on the tolerance during the 1st cycle. Bevacizumab was given concomitantly at a dose of 10 milligrams per kilogram (mg/kg) every 2 weeks throughout the entire treatment period.

    Reporting group title
    Bevacizumab + TMZ Young Patient Cohort (YPC)
    Reporting group description
    		 Subjects aged >/= 6 months and < 3 years received 10 mg/kg Bevacizumab every 2 weeks and 150 to 200 mg/m^2 of TMZ daily on Days 1-5 of each cycle. TMZ was given at a dose of 150 mg/m^2 on Days 1-5 of cycle 1 and then escalated to 200 mg/m^2 on days 1-5 from cycle 2 onwards depending on the tolerance during the 1st cycle.

    Reporting group values
    		 Main Cohort: Chemoradiation + TMZ Main Cohort: Chemoradiation + Bevacizumab + TMZ Bevacizumab + TMZ Young Patient Cohort (YPC) Total
    Number of subjects
    		 59 62 3 124
    Age categorical
    Units: Subjects
        < 3 years
    		 0 0 3 3
        >/= 3 years and < 6 years
    		 6 10 0 16
        >/= 6 years and < 13 years
    		 30 35 0 65
        >/= 13 years and < 18 years
    		 23 17 0 40
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 11.1 ± 3.8 10.1 ± 3.8 1.3 ± 0.6 -
    Gender categorical
    Units: Subjects
        Female
    		 23 28 0 51
        Male
    		 36 34 3 73

    End points

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    End points reporting groups
    Reporting group title
    Main Cohort: Chemoradiation + TMZ
    Reporting group description
    		 Subjects received a total dose of 54 Grey (Gy) units delivered in 30 daily fractions of 1.8 Gy over 6 weeks with 75 milligrams per meter squared (mg/m^2) TMZ daily for up to 49 days followed by a treatment break of approximately 4 weeks. The treatment break was followed by an adjuvant treatment phase where subjects received 150 to 200 mg/m^2 of TMZ daily on Days 1-5 of each cycle. TMZ was given at a dose of 150 mg/m^2 on Days 1-5 of cycle 1 and then escalated to 200 mg/m^2 on days 1-5 from cycle 2 onwards depending on the tolerance during the 1st cycle.

    Reporting group title
    Main Cohort: Chemoradiation + Bevacizumab + TMZ
    Reporting group description
    		 Subjects received a total dose of 54 Gy units delivered in 30 daily fractions of 1.8 Gy over 6 weeks with 75 mg/m^2 TMZ daily for up to 49 days followed by a treatment break of approximately 4 weeks. The treatment break was followed by an adjuvant treatment phase where subjects received 150 to 200 mg/m^2 of TMZ daily on Days 1-5 of each cycle. TMZ was given at a dose of 150 mg/m^2 on Days 1-5 of cycle 1 and then escalated to 200 mg/m^2 on days 1-5 from cycle 2 onwards depending on the tolerance during the 1st cycle. Bevacizumab was given concomitantly at a dose of 10 milligrams per kilogram (mg/kg) every 2 weeks throughout the entire treatment period.

    Reporting group title
    Bevacizumab + TMZ Young Patient Cohort (YPC)
    Reporting group description
    		 Subjects aged >/= 6 months and < 3 years received 10 mg/kg Bevacizumab every 2 weeks and 150 to 200 mg/m^2 of TMZ daily on Days 1-5 of each cycle. TMZ was given at a dose of 150 mg/m^2 on Days 1-5 of cycle 1 and then escalated to 200 mg/m^2 on days 1-5 from cycle 2 onwards depending on the tolerance during the 1st cycle.

    Primary: Event-Free Survival (EFS) as Assessed by the Central Radiology Review Committee (CRRC)

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    End point title
    		 Event-Free Survival (EFS) as Assessed by the Central Radiology Review Committee (CRRC) [1]
    End point description
    EFS was defined as the time from diagnosis to the earliest occurrence of any of the following: tumor progression, tumor recurrence, second primary non-high-grade glioma (HGG) malignancy or death attributable to any cause. Tumor assessments were conducted using magnetic resonance imaging (MRI) and reviewed by the site-independent CRRC using RANO criteria. Tumor progression was defined as clear clinical progression or >/= 25% increase in the sum of the products of perpendicular diameters of the contrast enhancing lesions compared with the smallest tumor measurement obtained either at baseline (if no decrease was observed) or best response and with the subject on stable or increasing doses of corticosteroids. Tumor recurrence was defined as recurrence after tumor was completely resected (no disease present at baseline). EFS was estimated using the Kaplan-Meier method. Randomised subject population: all randomised subjects regardless of whether they received study treatment.
    End point type
    Primary
    End point timeframe
    From the time of randomisation to the date of clinical cutoff (up to 1 year)
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Analysis was planned to be performed between arm "Chemoradiation + TMZ" and arm "Chemoradiation + Bevacizumab + TMZ" only
    End point values
    		 Main Cohort: Chemoradiation + TMZ Main Cohort: Chemoradiation + Bevacizumab + TMZ
    Number of subjects analysed
    59
    62
    Units: months
        median (confidence interval 95%)
    11.79 (7.85 to 16.39)
    8.21 (7.75 to 12.68)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Main Cohort: Chemoradiation + Bevacizumab + TMZ v Main Cohort: Chemoradiation + TMZ
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1292
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9
         upper limit
    		 2.3

    Secondary: Overall Survival

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    End point title
    		 Overall Survival [2]
    End point description
    Overall Survival was defined as the time of diagnosis to the date of death due to any cause. Overall Survival was estimated using the Kaplan-Meier method. Randomised subject population included all randomised subjects regardless of whether they received study treatment.
    End point type
    Secondary
    End point timeframe
    From the time of randomisation to the date of clinical cutoff (up to approximately 60 months)
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Analysis was planned to be performed between arm "Chemoradiation + TMZ" and arm "Chemoradiation + Bevacizumab + TMZ" only
    End point values
    		 Main Cohort: Chemoradiation + TMZ Main Cohort: Chemoradiation + Bevacizumab + TMZ
    Number of subjects analysed
    59
    62
    Units: months
        median (confidence interval 95%)
    20.27 (14.75 to 33.77)
    18.30 (16.20 to 25.69)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With 1-Year Survival

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    End point title
    		 Percentage of Subjects With 1-Year Survival [3]
    End point description
    1-year survival was estimated using the Kaplan-Meier method. Randomised subject population included all randomised subjects regardless of whether they received study treatment. Here, number of subjects analyzed signifies the subjects who were evaluable for the outcome measure.
    End point type
    Secondary
    End point timeframe
    1 year after end of treatment
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Analysis was planned to be performed between arm "Chemoradiation + TMZ" and arm "Chemoradiation + Bevacizumab + TMZ" only
    End point values
    		 Main Cohort: Chemoradiation + TMZ Main Cohort: Chemoradiation + Bevacizumab + TMZ
    Number of subjects analysed
    59
    62
    Units: percentage of subjects
        number (confidence interval 95%)
    67.69 (55.39 to 79.99)
    74.83 (63.79 to 85.87)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With EFS as Determined by the CRRC at 6 Months

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    End point title
    		 Percentage of Subjects With EFS as Determined by the CRRC at 6 Months [4]
    End point description
    EFS was defined as the time from randomisation to the earliest occurrence of any of the following: tumor progression, tumor recurrence, second primary non- HGG malignancy or death attributable to any cause. Tumor assessments were conducted using MRI and reviewed by the site-independent CRRC using RANO criteria. Tumor progression was defined as clear clinical progression or >/= 25% increase in the sum of the products of perpendicular diameters of the contrast enhancing lesions compared with the smallest tumor measurement obtained either at baseline (if no decrease was observed) or best response and with the subject on stable or increasing doses of corticosteroids. Tumor recurrence was defined as recurrence after tumor was completely resected (no disease present at baseline). EFS was estimated using the Kaplan-Meier method. Randomised subject population included all randomised subjects regardless of whether they received study treatment.
    End point type
    Secondary
    End point timeframe
    6 months
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Analysis was planned to be performed between arm "Chemoradiation + TMZ" and arm "Chemoradiation + Bevacizumab + TMZ" only
    End point values
    		 Main Cohort: Chemoradiation + TMZ Main Cohort: Chemoradiation + Bevacizumab + TMZ
    Number of subjects analysed
    59
    62
    Units: percentage of participants
        number (confidence interval 95%)
    66.46 (52.58 to 77.13)
    68.43 (55.06 to 78.58)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With EFS as Determined by the CRRC at 1 Year

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    End point title
    		 Percentage of Subjects With EFS as Determined by the CRRC at 1 Year [5]
    End point description
    EFS was defined as the time from randomisation to the earliest occurrence of any of the following: tumor progression, tumor recurrence, second primary non- HGG malignancy or death attributable to any cause. Tumor assessments were conducted using MRI and reviewed by the site-independent CRRC using RANO criteria. Tumor progression was defined as clear clinical progression or >/= 25% increase in the sum of the products of perpendicular diameters of the contrast enhancing lesions compared with the smallest tumor measurement obtained either at baseline (if no decrease was observed) or best response and with the subject on stable or increasing doses of corticosteroids. Tumor recurrence was defined as recurrence after tumor was completely resected (no disease present at baseline). EFS was estimated using the Kaplan-Meier method. Randomised subject population included all randomised subjects regardless of whether they received study treatment.
    End point type
    Secondary
    End point timeframe
    1 year
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Analysis was planned to be performed between arm "Chemoradiation + TMZ" and arm "Chemoradiation + Bevacizumab + TMZ" only
    End point values
    		 Main Cohort: Chemoradiation + TMZ Main Cohort: Chemoradiation + Bevacizumab + TMZ
    Number of subjects analysed
    59
    62
    Units: percentage of subjects
        number (confidence interval 95%)
    48.37 (34.82 to 60.65)
    38.28 (25.79 to 50.64)
    No statistical analyses for this end point

    Secondary: EFS as Assessed by the Investigator

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    End point title
    		 EFS as Assessed by the Investigator [6]
    End point description
    EFS was defined as the time from randomisation to the earliest occurrence of any of the following: tumor progression, tumor recurrence, second primary non-HGG malignancy or death attributable to any cause. Tumor assessments were conducted using MRI and reviewed by the investigator using RANO criteria. Tumor progression was defined as clear clinical progression or >/= 25% increase in the sum of the products of perpendicular diameters of the contrast enhancing lesions compared with the smallest tumor measurement obtained either at baseline (if no decrease was observed) or best response and with the subject on stable or increasing doses of corticosteroids. Tumor recurrence was defined as recurrence after tumor was completely resected (no disease present at baseline). EFS was estimated using the Kaplan-Meier method. Randomised subject population included all randomised subjects regardless of whether they received study treatment.
    End point type
    Secondary
    End point timeframe
    From the time of randomisation to the date of clinical cutoff (up to 1 year)
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Analysis was planned to be performed between arm "Chemoradiation + TMZ" and arm "Chemoradiation + Bevacizumab + TMZ" only
    End point values
    		 Main Cohort: Chemoradiation + TMZ Main Cohort: Chemoradiation + Bevacizumab + TMZ
    Number of subjects analysed
    59
    62
    Units: months
        median (confidence interval 95%)
    11.79 (8.51 to 20.53)
    11.27 (8.11 to 14.49)
    No statistical analyses for this end point

    Secondary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR) [7]
    End point description
    ORR was defined as the percentage of subjects with a complete response (CR) or partial response (PR) determined on two consecutive occasions >/= 4 weeks apart. Tumor assessments were conducted using MRI and reviewed by the site-independent CRRC using RANO criteria. The following were needed to qualify as CR: complete disappearance of all measurable enhancing lesions sustained for at least 4 weeks by MRI, no steroids above physiological levels, clinical status stable or improved compared to baseline. The following were needed to qualify as PR: ≥ 50% decrease from baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks by MRI, steroid dose not increased compared to baseline, clinical status stable or improved compared to baseline. Randomised subject population with a measurable lesion at baseline.
    End point type
    Secondary
    End point timeframe
    From the time of randomisation to the date of clinical cutoff (up to 1 year)
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Analysis was planned to be performed between arm "Chemoradiation + TMZ" and arm "Chemoradiation + Bevacizumab + TMZ" only
    End point values
    		 Main Cohort: Chemoradiation + TMZ Main Cohort: Chemoradiation + Bevacizumab + TMZ
    Number of subjects analysed
    15
    12
    Units: percentage of subjects
        number (confidence interval 95%)
    40 (19.09 to 66.77)
    41.7 (18.1 to 70.6)
    No statistical analyses for this end point

    Secondary: Concordance between Structural Versus Multimodal Imaging for CRRC-Assessed Event-Free Survival

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    End point title
    		 Concordance between Structural Versus Multimodal Imaging for CRRC-Assessed Event-Free Survival [8]
    End point description
    Concordance is presented as the percentage of subjects with concordance between assessments. EFS concordance was defined as event Structural assessment and Diffusion Perfusion assessment occurs within 28 days or no event Structural and no Diffusion Perfusion. Randomised subject population included all randomised subjects regardless of whether they received study treatment.
    End point type
    Secondary
    End point timeframe
    From the time of randomisation to the date of clinical cutoff (up to 1 year)
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Analysis was planned to be performed between arm "Chemoradiation + TMZ" and arm "Chemoradiation + Bevacizumab + TMZ" only
    End point values
    		 Main Cohort: Chemoradiation + TMZ Main Cohort: Chemoradiation + Bevacizumab + TMZ
    Number of subjects analysed
    59
    62
    Units: percentage of subjects
    number (not applicable)
        EFS concordance
    96.6
    87.1
    No statistical analyses for this end point

    Secondary: Health Status as Measured by the Health Utility Index (HUI)

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    End point title
    		 Health Status as Measured by the Health Utility Index (HUI) [9]
    End point description
    HUI is a preference-based, multi-attitude, health-related instrument specifically developed for use with children. HUI consists of eight attributes of health status: vision, hearing, speech, ambulation, dexterity, emotion, cognition and pain. Each attribute had 5 or 6 levels varying from highly impaired to normal. Each of the eight health dimensions was tested separately and a composite score ranging between 1 (perfect health) and 0 (death) was obtained for subjects aged 5 years or older. Randomised subject population aged 5 years or older with a measure at the specified time point. Here, 'n' represents the number of subjects with a measure at the specified time point. Here, '99999' represents that the confidence interval is not applicable because a single subject was analyzed; and '999999' represents data that is not available because no subjects were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, Cycle 6 of the adjuvant phase, end of treatment (approximately 58 weeks post-baseline), and yearly during the follow-up period (maximum 5 years in follow-up)
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Analysis was planned to be performed between arm "Chemoradiation + TMZ" and arm "Chemoradiation + Bevacizumab + TMZ" only
    End point values
    		 Main Cohort: Chemoradiation + TMZ Main Cohort: Chemoradiation + Bevacizumab + TMZ
    Number of subjects analysed
    36
    45
    Units: unit on a scale
    arithmetic mean (standard deviation)
        Baseline (n=36,45)
    0.713 ± 0.317
    0.73 ± 0.274
        Cycle 6, Day 1 (n=30,39)
    0.785 ± 0.239
    0.779 ± 0.232
        End of Treatment (n=21,21)
    0.832 ± 0.216
    0.820 ± 0.209
        Yearly Follow-Up 1 (n=9,7)
    0.906 ± 0.110
    0.926 ± 0.109
        Yearly Follow-up 2 (n=9,8)
    0.737 ± 0.326
    0.793 ± 0.219
        Additional Safety Follow-Up (Visit 2) (n=8,10)
    0.784 ± 0.287
    0.901 ± 0.147
        Additional Safety Follow-Up (Visit 4) (n=7,6)
    0.814 ± 0.304
    0.830 ± 0.143
        Additional Safety Follow-Up (Visit 6) (n=2,2)
    1.000 ± 0.000
    0.490 ± 0.537
        Additional Safety Follow-Up (Visit 8) (n=0,1)
    999999 ± 999999
    0.930 ± 99999
        End of Study (n=3,6)
    0.647 ± 0.496
    0.79 ± 0.234
    No statistical analyses for this end point

    Secondary: Neurological Psychological Function as Measured by the Wechsler Scale

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    End point title
    		 Neurological Psychological Function as Measured by the Wechsler Scale [10]
    End point description
    The Wechsler Intelligence Scale for Children version IV (WISC-IV) was used to generate a full scale IQ which represents a child's general intellectual ability. The average IQ score is 100, with lower scores representing lower intellectual ability. Randomised subject population included all randomised subjects regardless of whether they received study treatment.
    End point type
    Secondary
    End point timeframe
    End of treatment (approximately 58 weeks post-baseline)
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Analysis was planned to be performed between arm "Chemoradiation + TMZ" and arm "Chemoradiation + Bevacizumab + TMZ" only
    End point values
    		 Main Cohort: Chemoradiation + TMZ Main Cohort: Chemoradiation + Bevacizumab + TMZ
    Number of subjects analysed
    59
    62
    Units: units on a scale
        geometric mean (standard deviation)
    92 ± 9.8
    97 ± 18.4
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Who Completed >/= 90% of Planned Radiotherapy and TMZ Administrations

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    End point title
    		 Percentage of Subjects Who Completed >/= 90% of Planned Radiotherapy and TMZ Administrations [11]
    End point description
    Safety population included all subjects that received study treatment.
    End point type
    Secondary
    End point timeframe
    From the time of randomisation of the first subject to the date of clinical cutoff (approximately 52 months)
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Analysis was planned to be performed between arm "Chemoradiation + TMZ" and arm "Chemoradiation + Bevacizumab + TMZ" only
    End point values
    		 Main Cohort: Chemoradiation + TMZ Main Cohort: Chemoradiation + Bevacizumab + TMZ
    Number of subjects analysed
    56
    60
    Units: percentage of subjects
    number (not applicable)
        Radiotherapy
    94.6
    98.3
        TMZ
    85.7
    88.3
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With a Treatment Delay or Discontinuation

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    End point title
    		 Percentage of Subjects With a Treatment Delay or Discontinuation [12]
    End point description
    Randomised subject population included all randomised subjects regardless of whether they received study treatment.
    End point type
    Secondary
    End point timeframe
    From the time of randomisation of the first subject to the date of clinical cutoff (approximately 52 months)
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Analysis was planned to be performed between arm "Chemoradiation + TMZ" and arm "Chemoradiation + Bevacizumab + TMZ" only
    End point values
    		 Main Cohort: Chemoradiation + TMZ Main Cohort: Chemoradiation + Bevacizumab + TMZ
    Number of subjects analysed
    59
    62
    Units: percentage of subjects
    number (not applicable)
        AE leading to dose modification/interruption
    60.7
    71.7
        AE leading to withdrawal from treatment
    5.4
    21.7
    No statistical analyses for this end point

    Secondary: Number of Dose Administrations of Study Treatment in the Concurrent Phase

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    End point title
    		 Number of Dose Administrations of Study Treatment in the Concurrent Phase [13]
    End point description
    Number of doses were assessed for the concurrent phase, which is the treatment period after the initial treatment phase and including the subsequent treatment break of approximately 4 weeks. Safety population included all subjects that received study drug. Here, '99999' represents that the data is not applicable because Bevacizumab was not administered for the arm.
    End point type
    Secondary
    End point timeframe
    Beginning of the concurrent phase to end of treatment break (10 weeks)
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Analysis was planned to be performed between arm "Chemoradiation + TMZ" and arm "Chemoradiation + Bevacizumab + TMZ" only
    End point values
    		 Main Cohort: Chemoradiation + TMZ Main Cohort: Chemoradiation + Bevacizumab + TMZ
    Number of subjects analysed
    56
    60
    Units: Radio (Grays); TMV/Bev (number of doses)
    median (full range (min-max))
        Radiotherapy (n= 56, 60)
    54.0 (4 to 60)
    54.0 (2 to 56)
        TMZ (n= 56, 60)
    42 (1 to 50)
    42 (3 to 49)
        Bevacizumab (n= 0, 60)
    99999 (99999 to 99999)
    6.0 (1 to 10)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With an Adverse Event (AE)

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    End point title
    		 Percentage of Subjects With an Adverse Event (AE) [14]
    End point description
    An AE was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Safety population included all subjects that received study drug.
    End point type
    Secondary
    End point timeframe
    From the time of randomisation of the first subject to the date of clinical cutoff (approximately 60 months)
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Analysis was planned to be performed between arm "Chemoradiation + TMZ" and arm "Chemoradiation + Bevacizumab + TMZ" only
    End point values
    		 Main Cohort: Chemoradiation + TMZ Main Cohort: Chemoradiation + Bevacizumab + TMZ
    Number of subjects analysed
    56
    60
    Units: percentage of subjects
        number (not applicable)
    100
    98.3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From randomization/enrollment of the first participant to date of clinical cut off (approximately 52 months)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Chemoradiation + TMZ
    Reporting group description
    		 Subjects received a total dose of 54 Gy units delivered in 30 daily fractions of 1.8 Gy over 6 weeks with 75 mg/m^2 TMZ daily for up to 49 days followed by a treatment break of approximately 4 weeks. The treatment break was followed by an adjuvant treatment phase where subjects received 150 to 200 mg/m^2 of TMZ daily on Days 1-5 of each cycle. TMZ was given at a dose of 150 mg/m^2 on Days 1-5 of cycle 1 and then escalated to 200 mg/m^2 on days 1-5 from cycle 2 onwards depending on the tolerance during the 1st cycle.

    Reporting group title
    Chemoradiation + Bevacizumab + TMZ
    Reporting group description
    		 Subjects received a total dose of 54 Gy units delivered in 30 daily fractions of 1.8 Gy over 6 weeks with 75 mg/m^2 TMZ daily for up to 49 days followed by a treatment break of approximately 4 weeks. The treatment break was followed by an adjuvant treatment phase where subjects received 150 to 200 mg/m^2 of TMZ daily on Days 1-5 of each cycle. TMZ was given at a dose of 150 mg/m^2 on Days 1-5 of cycle 1 and then escalated to 200 mg/m^2 on days 1-5 from cycle 2 onwards depending on the tolerance during the 1st cycle. Bevacizumab was given concomitantly at a dose of 10 milligrams per kilogram (mg/kg) every 2 weeks throughout the entire treatment period.

    Reporting group title
    Bevacizumab + TMZ Young Patient Cohort (YPC)
    Reporting group description
    		 Subjects aged >/= 6 months and < 3 years received 10 mg/kg Bevacizumab every 2 weeks and 150 to 200 mg/m^2 of TMZ daily on Days 1-5 of each cycle. TMZ was given at a dose of 150 mg/m^2 on Days 1-5 of cycle 1 and then escalated to 200 mg/m^2 on days 1-5 from cycle 2 onwards depending on the tolerance during the 1st cycle.

    Serious adverse events
    		 Chemoradiation + TMZ Chemoradiation + Bevacizumab + TMZ Bevacizumab + TMZ Young Patient Cohort (YPC)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    27 / 56 (48.21%)
    35 / 60 (58.33%)
    0 / 3 (0.00%)
         number of deaths (all causes)
    41
    42
    2
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    B-CELL TYPE ACUTE LEUKAEMIA
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 60 (1.67%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Vascular disorders
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 60 (1.67%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    CATHETER SITE THROMBOSIS
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 60 (1.67%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CYST
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 60 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPOTHERMIA
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 60 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    IMPLANT SITE DEHISCENCE
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 60 (1.67%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    INFLUENZA LIKE ILLNESS
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 60 (1.67%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PYREXIA
         subjects affected / exposed
    5 / 56 (8.93%)
    12 / 60 (20.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    3 / 6
    6 / 17
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    DRUG HYPERSENSITIVITY
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 60 (1.67%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPERSENSITIVITY
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 60 (1.67%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 60 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    CONFUSIONAL STATE
         subjects affected / exposed
    0 / 56 (0.00%)
    2 / 60 (3.33%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    DEVICE OCCLUSION
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 60 (1.67%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    BODY TEMPERATURE INCREASED
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 60 (1.67%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LYMPHOCYTE COUNT DECREASED
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 60 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    NEUTROPHIL COUNT DECREASED
         subjects affected / exposed
    1 / 56 (1.79%)
    1 / 60 (1.67%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PLATELET COUNT DECREASED
         subjects affected / exposed
    0 / 56 (0.00%)
    2 / 60 (3.33%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    HAEMATURIA TRAUMATIC
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 60 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RADIUS FRACTURE
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 60 (1.67%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    CEREBRAL CYST
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 60 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CEREBRAL ISCHAEMIA
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 60 (1.67%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CEREBROSPINAL FLUID LEAKAGE
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 60 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DEPRESSED LEVEL OF CONSCIOUSNESS
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 60 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HEADACHE
         subjects affected / exposed
    2 / 56 (3.57%)
    4 / 60 (6.67%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HEMIPARESIS
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 60 (1.67%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYDROCEPHALUS
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 60 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MONOPLEGIA
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 60 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    NERVOUS SYSTEM DISORDER
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 60 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PARTIAL SEIZURES
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 60 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 60 (1.67%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PRESYNCOPE
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 60 (1.67%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SEIZURE
         subjects affected / exposed
    7 / 56 (12.50%)
    5 / 60 (8.33%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SOMNOLENCE
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 60 (1.67%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    STATUS EPILEPTICUS
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 60 (1.67%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    FEBRILE BONE MARROW APLASIA
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 60 (1.67%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    FEBRILE NEUTROPENIA
         subjects affected / exposed
    0 / 56 (0.00%)
    5 / 60 (8.33%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    THROMBOCYTOPENIA
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 60 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    EYELID OEDEMA
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 60 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    CONSTIPATION
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 60 (1.67%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GASTROOESOPHAGEAL REFLUX DISEASE
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 60 (1.67%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    NAUSEA
         subjects affected / exposed
    0 / 56 (0.00%)
    2 / 60 (3.33%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    VOMITING
         subjects affected / exposed
    3 / 56 (5.36%)
    6 / 60 (10.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    6 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    BLISTER
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 60 (1.67%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RASH
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 60 (1.67%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    URTICARIA
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 60 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    PROTEINURIA
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 60 (1.67%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    CATHETER SITE INFECTION
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 60 (1.67%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DEVICE RELATED INFECTION
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 60 (1.67%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DEVICE RELATED SEPSIS
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 60 (1.67%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GASTROENTERITIS
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 60 (1.67%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HERPES ZOSTER
         subjects affected / exposed
    2 / 56 (3.57%)
    2 / 60 (3.33%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    INFECTION
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 60 (1.67%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    KLEBSIELLA BACTERAEMIA
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 60 (1.67%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    1 / 56 (1.79%)
    1 / 60 (1.67%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PSEUDOMONAS INFECTION
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 60 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SKIN INFECTION
         subjects affected / exposed
    1 / 56 (1.79%)
    2 / 60 (3.33%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SOFT TISSUE INFECTION
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 60 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SUBCUTANEOUS ABSCESS
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 60 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    TONSILLITIS
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 60 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    VASCULAR DEVICE INFECTION
         subjects affected / exposed
    0 / 56 (0.00%)
    3 / 60 (5.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    1 / 56 (1.79%)
    1 / 60 (1.67%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Chemoradiation + TMZ Chemoradiation + Bevacizumab + TMZ Bevacizumab + TMZ Young Patient Cohort (YPC)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    56 / 56 (100.00%)
    58 / 60 (96.67%)
    3 / 3 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    SKIN PAPILLOMA
         subjects affected / exposed
    3 / 56 (5.36%)
    0 / 60 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    3
    0
    0
    Vascular disorders
    HYPERTENSION
         subjects affected / exposed
    1 / 56 (1.79%)
    7 / 60 (11.67%)
    1 / 3 (33.33%)
         occurrences all number
    1
    10
    2
    HYPOTENSION
         subjects affected / exposed
    2 / 56 (3.57%)
    4 / 60 (6.67%)
    0 / 3 (0.00%)
         occurrences all number
    2
    4
    0
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    4 / 56 (7.14%)
    6 / 60 (10.00%)
    0 / 3 (0.00%)
         occurrences all number
    7
    6
    0
    FATIGUE
         subjects affected / exposed
    32 / 56 (57.14%)
    26 / 60 (43.33%)
    0 / 3 (0.00%)
         occurrences all number
    44
    36
    0
    INFLUENZA LIKE ILLNESS
         subjects affected / exposed
    3 / 56 (5.36%)
    1 / 60 (1.67%)
    0 / 3 (0.00%)
         occurrences all number
    4
    2
    0
    PYREXIA
         subjects affected / exposed
    16 / 56 (28.57%)
    15 / 60 (25.00%)
    1 / 3 (33.33%)
         occurrences all number
    27
    31
    2
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    12 / 56 (21.43%)
    19 / 60 (31.67%)
    0 / 3 (0.00%)
         occurrences all number
    17
    30
    0
    EPISTAXIS
         subjects affected / exposed
    4 / 56 (7.14%)
    12 / 60 (20.00%)
    0 / 3 (0.00%)
         occurrences all number
    4
    19
    0
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    5 / 56 (8.93%)
    7 / 60 (11.67%)
    0 / 3 (0.00%)
         occurrences all number
    11
    8
    0
    RHINORRHOEA
         subjects affected / exposed
    2 / 56 (3.57%)
    7 / 60 (11.67%)
    0 / 3 (0.00%)
         occurrences all number
    2
    7
    0
    Psychiatric disorders
    ANXIETY
         subjects affected / exposed
    2 / 56 (3.57%)
    5 / 60 (8.33%)
    0 / 3 (0.00%)
         occurrences all number
    2
    6
    0
    INSOMNIA
         subjects affected / exposed
    7 / 56 (12.50%)
    2 / 60 (3.33%)
    0 / 3 (0.00%)
         occurrences all number
    9
    2
    0
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    6 / 56 (10.71%)
    3 / 60 (5.00%)
    0 / 3 (0.00%)
         occurrences all number
    6
    3
    0
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    3 / 56 (5.36%)
    1 / 60 (1.67%)
    0 / 3 (0.00%)
         occurrences all number
    3
    1
    0
    HEART RATE INCREASED
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 60 (1.67%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    1
    NEUTROPHIL COUNT DECREASED
         subjects affected / exposed
    17 / 56 (30.36%)
    16 / 60 (26.67%)
    1 / 3 (33.33%)
         occurrences all number
    32
    29
    1
    NEUTROPHIL COUNT INCREASED
         subjects affected / exposed
    3 / 56 (5.36%)
    1 / 60 (1.67%)
    0 / 3 (0.00%)
         occurrences all number
    3
    1
    0
    PLATELET COUNT DECREASED
         subjects affected / exposed
    19 / 56 (33.93%)
    18 / 60 (30.00%)
    1 / 3 (33.33%)
         occurrences all number
    46
    42
    2
    WEIGHT DECREASED
         subjects affected / exposed
    3 / 56 (5.36%)
    6 / 60 (10.00%)
    0 / 3 (0.00%)
         occurrences all number
    3
    8
    0
    WHITE BLOOD CELL COUNT DECREASED
         subjects affected / exposed
    14 / 56 (25.00%)
    16 / 60 (26.67%)
    1 / 3 (33.33%)
         occurrences all number
    28
    32
    1
    WHITE BLOOD CELL COUNT INCREASED
         subjects affected / exposed
    4 / 56 (7.14%)
    2 / 60 (3.33%)
    0 / 3 (0.00%)
         occurrences all number
    5
    2
    0
    Injury, poisoning and procedural complications
    RADIATION INJURY
         subjects affected / exposed
    3 / 56 (5.36%)
    1 / 60 (1.67%)
    0 / 3 (0.00%)
         occurrences all number
    3
    1
    0
    RADIATION SKIN INJURY
         subjects affected / exposed
    4 / 56 (7.14%)
    5 / 60 (8.33%)
    0 / 3 (0.00%)
         occurrences all number
    4
    5
    0
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    2 / 56 (3.57%)
    3 / 60 (5.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    5
    0
    DYSGEUSIA
         subjects affected / exposed
    4 / 56 (7.14%)
    0 / 60 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    4
    0
    0
    HEADACHE
         subjects affected / exposed
    32 / 56 (57.14%)
    34 / 60 (56.67%)
    0 / 3 (0.00%)
         occurrences all number
    66
    63
    0
    INTRACRANIAL PRESSURE INCREASED
         subjects affected / exposed
    3 / 56 (5.36%)
    1 / 60 (1.67%)
    0 / 3 (0.00%)
         occurrences all number
    3
    1
    0
    PARAESTHESIA
         subjects affected / exposed
    4 / 56 (7.14%)
    1 / 60 (1.67%)
    0 / 3 (0.00%)
         occurrences all number
    5
    1
    0
    SEIZURE
         subjects affected / exposed
    5 / 56 (8.93%)
    2 / 60 (3.33%)
    0 / 3 (0.00%)
         occurrences all number
    10
    2
    0
    SOMNOLENCE
         subjects affected / exposed
    3 / 56 (5.36%)
    0 / 60 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    5
    0
    0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    6 / 56 (10.71%)
    5 / 60 (8.33%)
    0 / 3 (0.00%)
         occurrences all number
    13
    9
    0
    LEUKOPENIA
         subjects affected / exposed
    6 / 56 (10.71%)
    3 / 60 (5.00%)
    0 / 3 (0.00%)
         occurrences all number
    11
    3
    0
    LYMPHOPENIA
         subjects affected / exposed
    3 / 56 (5.36%)
    0 / 60 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    4
    0
    0
    NEUTROPENIA
         subjects affected / exposed
    12 / 56 (21.43%)
    9 / 60 (15.00%)
    0 / 3 (0.00%)
         occurrences all number
    26
    19
    0
    THROMBOCYTOPENIA
         subjects affected / exposed
    8 / 56 (14.29%)
    10 / 60 (16.67%)
    0 / 3 (0.00%)
         occurrences all number
    20
    31
    0
    Ear and labyrinth disorders
    EAR PAIN
         subjects affected / exposed
    2 / 56 (3.57%)
    3 / 60 (5.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    3
    0
    Eye disorders
    EYE PAIN
         subjects affected / exposed
    4 / 56 (7.14%)
    1 / 60 (1.67%)
    0 / 3 (0.00%)
         occurrences all number
    4
    1
    0
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    10 / 56 (17.86%)
    12 / 60 (20.00%)
    1 / 3 (33.33%)
         occurrences all number
    17
    18
    1
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    6 / 56 (10.71%)
    7 / 60 (11.67%)
    0 / 3 (0.00%)
         occurrences all number
    7
    9
    0
    CONSTIPATION
         subjects affected / exposed
    12 / 56 (21.43%)
    18 / 60 (30.00%)
    0 / 3 (0.00%)
         occurrences all number
    19
    29
    0
    DENTAL CARIES
         subjects affected / exposed
    0 / 56 (0.00%)
    3 / 60 (5.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    3
    0
    DIARRHOEA
         subjects affected / exposed
    13 / 56 (23.21%)
    14 / 60 (23.33%)
    2 / 3 (66.67%)
         occurrences all number
    19
    22
    2
    NAUSEA
         subjects affected / exposed
    24 / 56 (42.86%)
    22 / 60 (36.67%)
    0 / 3 (0.00%)
         occurrences all number
    49
    38
    0
    ORAL PAIN
         subjects affected / exposed
    0 / 56 (0.00%)
    3 / 60 (5.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    3
    0
    TOOTHACHE
         subjects affected / exposed
    3 / 56 (5.36%)
    3 / 60 (5.00%)
    0 / 3 (0.00%)
         occurrences all number
    3
    3
    0
    VOMITING
         subjects affected / exposed
    29 / 56 (51.79%)
    36 / 60 (60.00%)
    2 / 3 (66.67%)
         occurrences all number
    65
    89
    3
    Skin and subcutaneous tissue disorders
    ALOPECIA
         subjects affected / exposed
    34 / 56 (60.71%)
    19 / 60 (31.67%)
    0 / 3 (0.00%)
         occurrences all number
    34
    20
    0
    DERMATITIS
         subjects affected / exposed
    5 / 56 (8.93%)
    1 / 60 (1.67%)
    0 / 3 (0.00%)
         occurrences all number
    5
    1
    0
    DRY SKIN
         subjects affected / exposed
    2 / 56 (3.57%)
    4 / 60 (6.67%)
    0 / 3 (0.00%)
         occurrences all number
    2
    4
    0
    ERYTHEMA
         subjects affected / exposed
    2 / 56 (3.57%)
    7 / 60 (11.67%)
    0 / 3 (0.00%)
         occurrences all number
    2
    9
    0
    PRURITUS
         subjects affected / exposed
    5 / 56 (8.93%)
    5 / 60 (8.33%)
    0 / 3 (0.00%)
         occurrences all number
    5
    6
    0
    PURPURA
         subjects affected / exposed
    0 / 56 (0.00%)
    4 / 60 (6.67%)
    0 / 3 (0.00%)
         occurrences all number
    0
    10
    0
    RASH
         subjects affected / exposed
    1 / 56 (1.79%)
    11 / 60 (18.33%)
    2 / 3 (66.67%)
         occurrences all number
    4
    17
    2
    SKIN STRIAE
         subjects affected / exposed
    5 / 56 (8.93%)
    0 / 60 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    5
    0
    0
    URTICARIA
         subjects affected / exposed
    5 / 56 (8.93%)
    8 / 60 (13.33%)
    0 / 3 (0.00%)
         occurrences all number
    8
    10
    0
    Renal and urinary disorders
    PROTEINURIA
         subjects affected / exposed
    0 / 56 (0.00%)
    15 / 60 (25.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    27
    0
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    3 / 56 (5.36%)
    6 / 60 (10.00%)
    0 / 3 (0.00%)
         occurrences all number
    4
    6
    0
    BACK PAIN
         subjects affected / exposed
    3 / 56 (5.36%)
    4 / 60 (6.67%)
    0 / 3 (0.00%)
         occurrences all number
    3
    4
    0
    MUSCULOSKELETAL PAIN
         subjects affected / exposed
    5 / 56 (8.93%)
    2 / 60 (3.33%)
    0 / 3 (0.00%)
         occurrences all number
    5
    2
    0
    NECK PAIN
         subjects affected / exposed
    3 / 56 (5.36%)
    2 / 60 (3.33%)
    0 / 3 (0.00%)
         occurrences all number
    4
    2
    0
    PAIN IN EXTREMITY
         subjects affected / exposed
    4 / 56 (7.14%)
    3 / 60 (5.00%)
    1 / 3 (33.33%)
         occurrences all number
    5
    3
    1
    Infections and infestations
    CANDIDA INFECTION
         subjects affected / exposed
    2 / 56 (3.57%)
    0 / 60 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    4
    0
    1
    CONJUNCTIVITIS
         subjects affected / exposed
    5 / 56 (8.93%)
    1 / 60 (1.67%)
    0 / 3 (0.00%)
         occurrences all number
    5
    1
    0
    HERPES ZOSTER
         subjects affected / exposed
    3 / 56 (5.36%)
    2 / 60 (3.33%)
    0 / 3 (0.00%)
         occurrences all number
    3
    2
    0
    INFLUENZA
         subjects affected / exposed
    1 / 56 (1.79%)
    3 / 60 (5.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    3
    0
    NASOPHARYNGITIS
         subjects affected / exposed
    6 / 56 (10.71%)
    10 / 60 (16.67%)
    0 / 3 (0.00%)
         occurrences all number
    6
    10
    0
    OTITIS MEDIA ACUTE
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 60 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    PHARYNGITIS
         subjects affected / exposed
    4 / 56 (7.14%)
    0 / 60 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    4
    0
    0
    RHINITIS
         subjects affected / exposed
    9 / 56 (16.07%)
    8 / 60 (13.33%)
    0 / 3 (0.00%)
         occurrences all number
    10
    9
    0
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    7 / 56 (12.50%)
    3 / 60 (5.00%)
    2 / 3 (66.67%)
         occurrences all number
    7
    6
    4
    VIRAL INFECTION
         subjects affected / exposed
    0 / 56 (0.00%)
    3 / 60 (5.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    3
    0
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    21 / 56 (37.50%)
    17 / 60 (28.33%)
    0 / 3 (0.00%)
         occurrences all number
    28
    22
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Apr 2012
    Added a cohort of 10 younger patients below 3 years of age into a separate arm of the main study for treatment at the request of the EMA Pediatric Committee (PDCO). Added the availability of a baseline MRI scan to the inclusion criteria. Added EFS as determined by the CRRC as secondary endpoint. Added an interim pharmacokinetic (PK) analysis for the first 10 patients randomised to the bevacizumab arm in order to align with the paediatric investigation plan (PIP) requirement.
    14 Jul 2013
    Modified the primary endpoint to become a blinded site-independent central radiology committee reviewed EFS, and consequently implemented a site-independent central radiology review process for the primary endpoint. Clarified that assessment of efficacy and disease progression or recurrence evaluation were to be performed according to the Wen et al 2010 publication. Added secondary endpoints of ORR and functional changes in tumor diffusion/perfusion MRI (multi modal imaging) for correlative analysis with structural imaging and efficacy outcome measures. The endpoints of Health Utility Index (HUI) and intelligence quotient (IQ) measurements, which were previously exploratory endpoints, were redefined as secondary endpoints. Extended the study population to patients with selected tumors in the infratentorial region (i.e., cerebellar or peduncular localized HGG) characterized by relatively similar history of disease as supratentorial HGGs, similar treatment options and response, and prognostically and biologically distinct from the more aggressive brainstem tumors (i.e., diffuse intrinsic pontine gliomas, medulla oblongata, or other midbrain tumours).
    11 Sep 2014
    Added collection of safety data to ensure compliance to the PIP’s key binding elements, risk management plan (RMP) and post marketing commitment (PMC) requirements: growth and development, including fertility and sexual development, health-related quality of life, neuropsychological function and bone toxicities. Updated sections “end of study” and “duration of study” to: Extend the follow-up duration from 3 to 5 years in order to collect long-term safety data and OS as per the agreed PIP. Clarified treatment options following independent data monitoring committee (iDMC) recommendations based on the futility analysis. The statistical section was also updated accordingly. Removed the minimum requirement of 10 patients to be enrolled in the Young Patient Cohort to align with PDCO in its positive opinion on a modification of a PIP. A positive PDCO Opinion was received in December 2013 and the EMA decision was issued on 22 January 2014 (P/0005/2014). Updated the duration of study of the Young Patient Cohort to align with the main study.

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

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