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    Clinical Trial Results:
    Open-label, multi-center, randomized, phase II study evaluating the addition of bevacizumab to chemotherapy in childhood and adolescent patients presenting with metastatic rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcoma

    Summary
    EudraCT number
    2007-005017-19
    Trial protocol
    GB   FR   NL   IT   BE   ES   PL   DE   CZ   Outside EU/EEA  
    Global end of trial date
    30 Apr 2019

    Results information
    Results version number
    v3(current)
    This version publication date
    20 Dec 2019
    First version publication date
    07 Aug 2016
    Other versions
    v1 , v2
    Version creation reason
    • Correction of full data set
    Correction made to Subject number by country data.

    Trial information

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    Trial identification
    Sponsor protocol code
    BO20924
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00643565
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland,
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000056-PIP01-07
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Apr 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Apr 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    An open-label, multi-center, randomized, Phase 2 study designed to evaluate the benefit of the addition of bevacizumab to chemotherapy in participants presenting with metastatic rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcoma.
    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
    29 Jul 2008
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 7
    Country: Number of subjects enrolled
    Poland: 5
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    United Kingdom: 35
    Country: Number of subjects enrolled
    Belgium: 8
    Country: Number of subjects enrolled
    France: 59
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Italy: 20
    Country: Number of subjects enrolled
    Brazil: 2
    Country: Number of subjects enrolled
    Israel: 3
    Country: Number of subjects enrolled
    Chile: 1
    Country: Number of subjects enrolled
    Czech Republic: 2
    Worldwide total number of subjects
    154
    EEA total number of subjects
    148
    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)
    6
    Children (2-11 years)
    77
    Adolescents (12-17 years)
    71
    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
    Participants with metastatic rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcoma underwent screening assessments. An eligibility screening form was completed documenting the investigator's assessment of each screened participant with regard to inclusion and exclusion criteria. A screening failure log was maintained by the investigator.

    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
    Chemotherapy
    Arm description
    Participants received 9 cycles of induction chemotherapy (4 cycles of IVADo-containing chemotherapy i.e. with ifosfamide [I], vincristine [V], actinomycin D [A] and doxorubicin [Do] followed by 5 cycles of IVA-containing chemotherapy [i.e. without doxorubicin]) administered every 3 weeks as per institutional practice. As per the investigator evaluation, participants had option to undergo local therapy (radiotherapy and/or surgery) during last 3 cycles of IVA (i.e. from Cycle 6 to Cycle 9). During maintenance treatment phase, participants received vinorelbine- and cyclophosphamide-containing chemotherapy (as per institutional practice) on Days 1 and 15 of 4-week cycles for a total of 12 cycles.
    Arm type
    Active comparator

    Investigational medicinal product name
    Ifosfamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received ifosfamide at 3 grams per square meter (g/m^2) on Day 1 and Day 2 of each cycle for the first 9 cycles only.

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received vincristine at 1.5 milligrams per square meter (mg/m^2) (maximum single dose of 2 mg) every week for first 7 weeks and then on Day 1 of each cycle up to Cycle 9.

    Investigational medicinal product name
    Actinomycin D
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received actinomycin D at 1.5 mg/m^2 (maximum single dose of 2 mg) on Day 1 of each cycle for the first 9 cycles only.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received doxorubicin at 30 mg/m^2 on Day 1 and Day 2 from Cycles 1 to 4 only.

    Investigational medicinal product name
    Vinorelbine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received vinorelbine at 25 mg/m^2 on Days 1, 8, and 15 of each cycle for 12 cycles of maintenance therapy phase.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received cyclophosphamide at 25 mg/m^2 every day for the entire duration of the cycle (i.e. 28 days).

    Arm title
    Bevacizumab + Chemotherapy
    Arm description
    Participants received continuous intravenous (IV) infusion of bevacizumab (7.5 milligrams per kilogram [mg/kg] every 3 weeks) on Day 1 of 3-week cycles followed by induction chemotherapy (4cycles of IVADo-containing chemotherapy followed by 5 cycles of IVA-containing chemotherapy) as per institutional practice for a total of 9 cycles during induction treatment phase. As per the investigator decision, local therapy (radiotherapy and/or surgery) was expected to start after 4 weeks of the last bevacizumab administration in the induction phase and resumed to bevacizumab in maintenance phase at least 4 weeks after the last dose of local therapy. During maintenance treatment phase, participants received IV infusion of bevacizumab (5 mg/kg every 2 weeks) followed by vinorelbine- and cyclophosphamide-containing chemotherapy (as per institutional practice) on Days 1 and 15 of 4-week cycles for a total of 12 cycles.
    Arm type
    Experimental

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    RO4876646
    Other name
    Avastin
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received IV infusion of bevacizumab at 7.5 mg/kg every 3 weeks in 3-week cycles for 9 cycles during induction treatment phase and at 5 mg/kg every 2 weeks in 4-weeks cycles for a total of 12 weeks.

    Investigational medicinal product name
    Ifosfamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received ifosfamide at 3 g/m^2 on Day 1 and Day 2 of each cycle for the first 9 cycles only.

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received vincristine at 1.5 mg/m^2 (maximum single dose of 2 mg) every week for first 7 weeks and then on Day 1 of each cycle up to Cycle 9.

    Investigational medicinal product name
    Actinomycin D
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received actinomycin D at 1.5 mg/m^2 (maximum single dose of 2 mg) on Day 1 of each cycle for the first 9 cycles only.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received doxorubicin at 30 mg/m^2 on Day 1 and Day 2 from Cycles 1 to 4 only.

    Investigational medicinal product name
    Vinorelbine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received vinorelbine at 25 mg/m^2 on Days 1, 8, and 15 of each cycle for 12 cycles of maintenance therapy phase.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received cyclophosphamide at 25 mg/m^2 every day for the entire duration of the cycle (i.e. 28 days).

    Number of subjects in period 1
    Chemotherapy Bevacizumab + Chemotherapy
    Started
    80
    74
    Completed
    7
    7
    Not completed
    73
    67
         Did Not Cooperate
    -
    1
         Protocol deviation
    3
    -
         Death
    12
    11
         Recurrence Of Disease
    2
    1
         Progression Of Disease
    18
    14
         Refused Treat/Did Not Cooperate
    -
    1
         Unknown
    7
    8
         Adverse event, non-fatal
    5
    8
         Administrative/Other
    22
    16
         Consent withdrawn by subject
    4
    1
         Lost to follow-up
    -
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Chemotherapy
    Reporting group description
    Participants received 9 cycles of induction chemotherapy (4 cycles of IVADo-containing chemotherapy i.e. with ifosfamide [I], vincristine [V], actinomycin D [A] and doxorubicin [Do] followed by 5 cycles of IVA-containing chemotherapy [i.e. without doxorubicin]) administered every 3 weeks as per institutional practice. As per the investigator evaluation, participants had option to undergo local therapy (radiotherapy and/or surgery) during last 3 cycles of IVA (i.e. from Cycle 6 to Cycle 9). During maintenance treatment phase, participants received vinorelbine- and cyclophosphamide-containing chemotherapy (as per institutional practice) on Days 1 and 15 of 4-week cycles for a total of 12 cycles.

    Reporting group title
    Bevacizumab + Chemotherapy
    Reporting group description
    Participants received continuous intravenous (IV) infusion of bevacizumab (7.5 milligrams per kilogram [mg/kg] every 3 weeks) on Day 1 of 3-week cycles followed by induction chemotherapy (4cycles of IVADo-containing chemotherapy followed by 5 cycles of IVA-containing chemotherapy) as per institutional practice for a total of 9 cycles during induction treatment phase. As per the investigator decision, local therapy (radiotherapy and/or surgery) was expected to start after 4 weeks of the last bevacizumab administration in the induction phase and resumed to bevacizumab in maintenance phase at least 4 weeks after the last dose of local therapy. During maintenance treatment phase, participants received IV infusion of bevacizumab (5 mg/kg every 2 weeks) followed by vinorelbine- and cyclophosphamide-containing chemotherapy (as per institutional practice) on Days 1 and 15 of 4-week cycles for a total of 12 cycles.

    Reporting group values
    Chemotherapy Bevacizumab + Chemotherapy Total
    Number of subjects
    80 74 154
    Age categorical
    Units: Subjects
        Infants and toddlers (28 days-23 months)
    3 3 6
        Children (2-11 years)
    39 38 77
        Adolescents (12-17 years)
    38 33 71
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    10.5 ± 4.8 10.3 ± 4.9 -
    Gender categorical
    Units: Subjects
        Female
    40 29 69
        Male
    40 45 85

    End points

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    End points reporting groups
    Reporting group title
    Chemotherapy
    Reporting group description
    Participants received 9 cycles of induction chemotherapy (4 cycles of IVADo-containing chemotherapy i.e. with ifosfamide [I], vincristine [V], actinomycin D [A] and doxorubicin [Do] followed by 5 cycles of IVA-containing chemotherapy [i.e. without doxorubicin]) administered every 3 weeks as per institutional practice. As per the investigator evaluation, participants had option to undergo local therapy (radiotherapy and/or surgery) during last 3 cycles of IVA (i.e. from Cycle 6 to Cycle 9). During maintenance treatment phase, participants received vinorelbine- and cyclophosphamide-containing chemotherapy (as per institutional practice) on Days 1 and 15 of 4-week cycles for a total of 12 cycles.

    Reporting group title
    Bevacizumab + Chemotherapy
    Reporting group description
    Participants received continuous intravenous (IV) infusion of bevacizumab (7.5 milligrams per kilogram [mg/kg] every 3 weeks) on Day 1 of 3-week cycles followed by induction chemotherapy (4cycles of IVADo-containing chemotherapy followed by 5 cycles of IVA-containing chemotherapy) as per institutional practice for a total of 9 cycles during induction treatment phase. As per the investigator decision, local therapy (radiotherapy and/or surgery) was expected to start after 4 weeks of the last bevacizumab administration in the induction phase and resumed to bevacizumab in maintenance phase at least 4 weeks after the last dose of local therapy. During maintenance treatment phase, participants received IV infusion of bevacizumab (5 mg/kg every 2 weeks) followed by vinorelbine- and cyclophosphamide-containing chemotherapy (as per institutional practice) on Days 1 and 15 of 4-week cycles for a total of 12 cycles.

    Primary: Percentage of Participants Who Experienced Event-Free Survival (EFS) Events as Per Independent Review Committee (IRC) Assessment

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    End point title
    Percentage of Participants Who Experienced Event-Free Survival (EFS) Events as Per Independent Review Committee (IRC) Assessment [1]
    End point description
    EFS events included tumor progression (IRC assessed), no evidence of response after 3 cycles of induction (derived from IRC assessment), second primary cancer, or death due to any cause. Data for participants who had not experienced an event by the time of clinical cut-off were censored at the date of the last disease assessment prior to the clinical cut-off date. Data for participants who did not have any post-baseline disease assessments were censored at the time of randomization. Tumor progression was defined using Response Evaluation Criteria in Solid Tumors version 1.0 (RECIST v1.0) as at least a 20 percent (%) increase in the disease measurement, taking as reference the smallest disease measurement recorded since the start of treatment, or appearance of one or more new lesions, or evidence of clinical progression and unequivocal progression of existing non-target lesions. Intent-to-treat (ITT) population included all participants randomized to the treatment group in the study
    End point type
    Primary
    End point timeframe
    Screening up to approximately 6.75 years (assessed at screening, Cycles 4, 7 of induction phase, Cycles 1, 4, 7, 10 of maintenance, then every 3 months for 1.5 years and thereafter every 6 months for 2.5 years)
    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: No statistical analysis was planned for this endpoint.
    End point values
    Chemotherapy Bevacizumab + Chemotherapy
    Number of subjects analysed
    80
    74
    Units: percentage of participants
        number (not applicable)
    52.5
    68.9
    No statistical analyses for this end point

    Primary: EFS Duration as Per IRC Assessment

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    End point title
    EFS Duration as Per IRC Assessment
    End point description
    EFS was defined as the time between randomization and occurrence of EFS event (described in endpoint "Percentage of Participants Who Experienced EFS Events as Per IRC"). Median EFS was estimated using Kaplan-Meier estimates and 95% confidence intervals (CI) for median was computed using the method of Brookmeyer and Crowley. ITT population.
    End point type
    Primary
    End point timeframe
    Screening up to approximately 6.75 years (assessed at screening, Cycles 4, 7 of induction phase, Cycles 1, 4, 7, 10 of maintenance, then every 3 months for 1.5 years and thereafter every 6 months for 2.5 years)
    End point values
    Chemotherapy Bevacizumab + Chemotherapy
    Number of subjects analysed
    80
    74
    Units: months
        median (confidence interval 95%)
    14.85 (10.84 to 35.88)
    20.63 (15.15 to 24.87)
    Statistical analysis title
    EFS Duration as Per IRC Assessment
    Comparison groups
    Bevacizumab + Chemotherapy v Chemotherapy
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7189 [2]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.93
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.61
         upper limit
    1.41
    Notes
    [2] - The HR was calculated based on a stratified Cox proportional hazards model, with stratification factors of age and histology/disease risk.

    Secondary: Percentage of Participants with Objective Response Prior to First Local Therapy Assessed by RECIST v1.0 Criteria

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    End point title
    Percentage of Participants with Objective Response Prior to First Local Therapy Assessed by RECIST v1.0 Criteria
    End point description
    Objective response prior to first local therapy (surgery and/or radiotherapy) was defined as complete response (CR) or partial response (PR) determined on two consecutive occasions greater than equal to (>=) 4 weeks apart. Tumor response were assessed as per IRC using RECIST 1.0. CR was defined as disappearance of all target and non-target lesions. If immunocytology was available, no disease was to be detected by that methodology. PR was defined as at least a 30% decrease in the disease measurement, taking as reference the disease measurement done to confirm measurable disease at study entry. ITT population.
    End point type
    Secondary
    End point timeframe
    Screening up to end approximately 6.75 years
    End point values
    Chemotherapy Bevacizumab + Chemotherapy
    Number of subjects analysed
    80
    74
    Units: percentage of participants
        number (confidence interval 95%)
    36 (25.23 to 47.91)
    54 (40.94 to 66.61)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Experienced EFS Events Among Participants Who Had Objective Response

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    End point title
    Percentage of Participants Who Experienced EFS Events Among Participants Who Had Objective Response
    End point description
    EFS events was described in endpoint "Percentage of Participants Who Experienced EFS Events as Per IRC" and in endpoint "Percentage of Participants with Objective Response Prior to First Local Therapy Assessed by RECIST v1.0 Criteria". ITT population. Here, number of participants analyzed = participants who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Screening up to end approximately 6.75 years
    End point values
    Chemotherapy Bevacizumab + Chemotherapy
    Number of subjects analysed
    27
    34
    Units: percentage of participants
        number (not applicable)
    40.7
    76.5
    No statistical analyses for this end point

    Secondary: Duration of Response

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    End point title
    Duration of Response
    End point description
    Duration of Response was defined as the time between first objective response and the occurrence of an EFS event (described in endpoint "Percentage of Participants Who Experienced EFS Events as Per IRC"). Objective response is defined in Outcome Measure “Percentage of Participants With Objective Response Prior to First Local Therapy Assessed by RECIST v1.0 Criteria”. Median duration of response was estimated using Kaplan-Meier estimates and 95% CI for median was computed using the method of Brookmeyer and Crowley. ITT population. Here, number of participants analyzed = participants who were evaluable for this outcome measure. Here, “99.9” and “999.9”was used as median and upper limit of 95% CI, respectively, as data was not estimable because of higher number (more than 50%) of censored participants in this arm group.
    End point type
    Secondary
    End point timeframe
    Screening up to end approximately 6.75 years
    End point values
    Chemotherapy Bevacizumab + Chemotherapy
    Number of subjects analysed
    27
    34
    Units: months
        median (confidence interval 95%)
    99.9 (10.18 to 999.9)
    17.48 (12.29 to 25.23)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Died

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    End point title
    Percentage of Participants Who Died
    End point description
    ITT population.
    End point type
    Secondary
    End point timeframe
    Screening up to approximately 10.75 years (assessed at screening, Cycles 4, 7 of induction phase, Cycles 1, 4, 7, 10 of maintenance, then every 3 months for 1.5 years and thereafter every 6 months for 2.5 years.
    End point values
    Chemotherapy Bevacizumab + Chemotherapy
    Number of subjects analysed
    80
    74
    Units: percentage of participants
        number (not applicable)
    50
    51.4
    No statistical analyses for this end point

    Secondary: Overall Survival Duration

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    End point title
    Overall Survival Duration
    End point description
    Overall survival was defined as the time between randomization and death due to any cause. Participants without an event were censored at the last time they were known to be alive. Median overall survival was estimated using Kaplan-Meier estimates and 95% CI for median was computed using the method of Brookmeyer and Crowley. ITT population. Here number of participants analyzed = participants available for the analysis of this outcome measure. Here, "999" was used as upper limit of 95% CI, which was not estimable because of higher number (more than 50%) of censored participants in this arm group.
    End point type
    Secondary
    End point timeframe
    Screening up to approximately 10.75 years (assessed at screening, Cycles 4, 7 of induction phase, Cycles 1, 4, 7, 10 of maintenance, then every 3 months for 1.5 years and thereafter every 6 months for 2.5 years)
    End point values
    Chemotherapy Bevacizumab + Chemotherapy
    Number of subjects analysed
    80
    74
    Units: months
        median (confidence interval 95%)
    24.02 (17.97 to 999)
    32.79 (25.33 to 999)
    Statistical analysis title
    Chemotherapy, Bevacizumab + Chemotherapy
    Comparison groups
    Chemotherapy v Bevacizumab + Chemotherapy
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3211 [3]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.51
         upper limit
    1.25
    Notes
    [3] - The HR was calculated based on a stratified Cox proportional hazards model, with stratification factors of age and histology/disease risk.

    Secondary: Area Under the Curve at Steady State (AUCss) of Bevacizumab

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    End point title
    Area Under the Curve at Steady State (AUCss) of Bevacizumab [4]
    End point description
    AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. AUCss is expressed in milligrams times days per milliliter (mg*day/mL). Pharmacokinetic (PK)-evaluable population included all randomized participants for whom at least one blood sample was taken for PK assessment following bevacizumab administration. Only participants who received bevacizumab were to be analyzed for PK assessment.
    End point type
    Secondary
    End point timeframe
    Pre- and within 3 hours post-dose on Days 1, 8, and 15 of Cycle 1, Day 1 of Cycle 2-4 of induction phase (1 cycle = 3 weeks)
    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: The PK data were analyzed for bevacizumab, which was not administered to Chemotherapy arm group.
    End point values
    Bevacizumab + Chemotherapy
    Number of subjects analysed
    70
    Units: mg*day/mL
        arithmetic mean (standard deviation)
    1010 ± 256
    No statistical analyses for this end point

    Secondary: Volume of Distribution of Bevacizumab

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    End point title
    Volume of Distribution of Bevacizumab [5]
    End point description
    Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state. PK-evaluable population. Only participants who received bevacizumab were to be analyzed for PK assessment.
    End point type
    Secondary
    End point timeframe
    Pre- and within 3 hours post-dose on Days 1, 8, and 15 of Cycle 1, Day 1 of Cycle 2-4 of induction phase (1 cycle = 3 weeks)
    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: The PK data were analyzed for bevacizumab, which was not administered to Chemotherapy arm group.
    End point values
    Bevacizumab + Chemotherapy
    Number of subjects analysed
    70
    Units: mL
        arithmetic mean (standard deviation)
    2070 ± 891
    No statistical analyses for this end point

    Secondary: Half-Life of Bevacizumab

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    End point title
    Half-Life of Bevacizumab [6]
    End point description
    Half-life is the time measured for the plasma concentration to decrease by one half. PK-evaluable population. Only participants who received bevacizumab were to be analyzed for PK assessment.
    End point type
    Secondary
    End point timeframe
    Pre- and within 3 hours post-dose on Days 1, 8, and 15 of Cycle 1, Day 1 of Cycle 2-4 of induction phase (1 cycle = 3 weeks)
    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: The PK data were analyzed for bevacizumab, which was not administered to Chemotherapy arm group.
    End point values
    Bevacizumab + Chemotherapy
    Number of subjects analysed
    70
    Units: days
        arithmetic mean (standard deviation)
    20.8 ± 8.58
    No statistical analyses for this end point

    Secondary: Clearance (CL) of Bevacizumab

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    End point title
    Clearance (CL) of Bevacizumab [7]
    End point description
    CL is a quantitative measure of the rate at which a drug substance is removed from the body. CL is expressed in milliliters per day (mL/day). PK-evaluable population. Only participants who received bevacizumab were to be analyzed for PK assessment.
    End point type
    Secondary
    End point timeframe
    Pre- and within 3 hours post-dose on Days 1, 8, and 15 of Cycle 1, Day 1 of Cycle 2-4 of induction phase (1 cycle = 3 weeks)
    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: The PK data were analyzed for bevacizumab, which was not administered to Chemotherapy arm group.
    End point values
    Bevacizumab + Chemotherapy
    Number of subjects analysed
    70
    Units: mL/day
        arithmetic mean (standard deviation)
    167 ± 76.4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Screening up to approximately 10.75 years
    Adverse event reporting additional description
    The safety-evaluable population included all randomized participants who received any dose of study treatment.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Chemotherapy
    Reporting group description
    Participants received 9 cycles of induction chemotherapy (4 cycles of IVADo-containing chemotherapy followed by 5 cycles of IVA-containing chemotherapy administered every 3 weeks as per institutional practice. As per the investigator evaluation, participants had option to undergo local therapy (radiotherapy and/or surgery) during last 3 cycles of IVA (i.e. from Cycle 6 to Cycle 9). During maintenance treatment phase, participants received vinorelbine- and cyclophosphamide-containing chemotherapy (as per institutional practice) on Day 1 and 15 of 4-week cycles for a total of 12 cycles.

    Reporting group title
    Bevacizumab + Chemotherapy
    Reporting group description
    Participants received continuous IV infusion of bevacizumab (7.5 mg/kg every 3 weeks) on Day 1 of 3-week cycles followed by induction chemotherapy (4 cycles of IVADo-containing chemotherapy followed by 5 cycles of IVA-containing chemotherapy) as per institutional practice for a total of 9 cycles during induction treatment phase. As per the investigator decision, local therapy (radiotherapy and/or surgery) was expected to start after 4 weeks of the last bevacizumab administration in the induction phase and resumed to bevacizumab in maintenance phase at least 4 weeks after the last dose of local therapy. During maintenance treatment phase, participants received IV infusion of bevacizumab (5 mg/kg every 2 weeks) followed by vinorelbine- and cyclophosphamide-containing chemotherapy (as per institutional practice) on Days 1 and 15 of 4-week cycles for a total of 12 cycles.

    Serious adverse events
    Chemotherapy Bevacizumab + Chemotherapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    68 / 79 (86.08%)
    66 / 71 (92.96%)
         number of deaths (all causes)
    40
    37
         number of deaths resulting from adverse events
    Vascular disorders
    Hypotension
         subjects affected / exposed
    2 / 79 (2.53%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Microangiopathy
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venoocclusive disease
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Central venous catheter removal
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour necrosis
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Face oedema
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 79 (1.27%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired healing
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    7 / 79 (8.86%)
    10 / 71 (14.08%)
         occurrences causally related to treatment / all
    14 / 14
    18 / 18
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    15 / 79 (18.99%)
    14 / 71 (19.72%)
         occurrences causally related to treatment / all
    19 / 26
    3 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Performance status decreased
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis in device
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Erectile dysfunction
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Foot fracture
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pneumothorax
         subjects affected / exposed
    1 / 79 (1.27%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haematoma
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular procedure complication
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Torus fracture
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Recall phenomenon
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheostomy malfunction
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular access complication
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Candida test positive
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil toxic granulation present
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    3 / 79 (3.80%)
    5 / 71 (7.04%)
         occurrences causally related to treatment / all
    2 / 3
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial thrombosis
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiotoxicity
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Fanconi syndrome
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 79 (2.53%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 79 (1.27%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    1 / 5
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoventilation
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 79 (1.27%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 79 (1.27%)
    2 / 71 (2.82%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 79 (3.80%)
    4 / 71 (5.63%)
         occurrences causally related to treatment / all
    8 / 8
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile bone marrow aplasia
         subjects affected / exposed
    9 / 79 (11.39%)
    19 / 71 (26.76%)
         occurrences causally related to treatment / all
    24 / 24
    49 / 49
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    47 / 79 (59.49%)
    46 / 71 (64.79%)
         occurrences causally related to treatment / all
    134 / 135
    120 / 120
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    3 / 79 (3.80%)
    2 / 71 (2.82%)
         occurrences causally related to treatment / all
    4 / 4
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial nerve disorder
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    2 / 79 (2.53%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    0 / 79 (0.00%)
    2 / 71 (2.82%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurotoxicity
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral sensorimotor neuropathy
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 79 (2.53%)
    4 / 71 (5.63%)
         occurrences causally related to treatment / all
    1 / 2
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic encephalopathy
         subjects affected / exposed
    2 / 79 (2.53%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vocal cord paresis
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Eyelid oedema
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 71 (1.41%)
         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
    2 / 79 (2.53%)
    2 / 71 (2.82%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fissure
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal inflammation
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 79 (1.27%)
    2 / 71 (2.82%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    3 / 79 (3.80%)
    4 / 71 (5.63%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    2 / 79 (2.53%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal obstruction
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    3 / 79 (3.80%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    4 / 79 (5.06%)
    3 / 71 (4.23%)
         occurrences causally related to treatment / all
    5 / 5
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    7 / 79 (8.86%)
    8 / 71 (11.27%)
         occurrences causally related to treatment / all
    7 / 8
    10 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 79 (1.27%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 79 (2.53%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysuria
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder necrosis
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    4 / 79 (5.06%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    3 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proteinuria
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Erythema multiforme
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash papular
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin disorder
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin exfoliation
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device malfunction
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 79 (1.27%)
    4 / 71 (5.63%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    2 / 79 (2.53%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    2 / 79 (2.53%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 79 (2.53%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophagia
         subjects affected / exposed
    1 / 79 (1.27%)
    2 / 71 (2.82%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 79 (1.27%)
    2 / 71 (2.82%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 79 (1.27%)
    2 / 71 (2.82%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 79 (0.00%)
    2 / 71 (2.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Candida sepsis
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    2 / 79 (2.53%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis bacterial
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 79 (1.27%)
    3 / 71 (4.23%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    5 / 79 (6.33%)
    3 / 71 (4.23%)
         occurrences causally related to treatment / all
    4 / 8
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonas infection
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salmonellosis
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 79 (3.80%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal bacteraemia
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicella
         subjects affected / exposed
    0 / 79 (0.00%)
    2 / 71 (2.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 79 (1.27%)
    2 / 71 (2.82%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulvitis
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular Device Infection
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    3 / 79 (3.80%)
    4 / 71 (5.63%)
         occurrences causally related to treatment / all
    4 / 4
    6 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Chemotherapy Bevacizumab + Chemotherapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    78 / 79 (98.73%)
    71 / 71 (100.00%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    3 / 79 (3.80%)
    4 / 71 (5.63%)
         occurrences all number
    3
    5
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 79 (1.27%)
    4 / 71 (5.63%)
         occurrences all number
    1
    5
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    10 / 79 (12.66%)
    17 / 71 (23.94%)
         occurrences all number
    12
    23
    Chest pain
         subjects affected / exposed
    6 / 79 (7.59%)
    4 / 71 (5.63%)
         occurrences all number
    7
    4
    Fatigue
         subjects affected / exposed
    16 / 79 (20.25%)
    18 / 71 (25.35%)
         occurrences all number
    27
    26
    Mucosal inflammation
         subjects affected / exposed
    38 / 79 (48.10%)
    42 / 71 (59.15%)
         occurrences all number
    54
    74
    Pain
         subjects affected / exposed
    10 / 79 (12.66%)
    5 / 71 (7.04%)
         occurrences all number
    11
    6
    Pyrexia
         subjects affected / exposed
    33 / 79 (41.77%)
    27 / 71 (38.03%)
         occurrences all number
    73
    46
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    7 / 79 (8.86%)
    9 / 71 (12.68%)
         occurrences all number
    7
    9
    Insomnia
         subjects affected / exposed
    2 / 79 (2.53%)
    5 / 71 (7.04%)
         occurrences all number
    2
    5
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    1 / 79 (1.27%)
    7 / 71 (9.86%)
         occurrences all number
    1
    8
    Radiation skin injury
         subjects affected / exposed
    12 / 79 (15.19%)
    8 / 71 (11.27%)
         occurrences all number
    12
    9
    Radiation Injury
         subjects affected / exposed
    1 / 79 (1.27%)
    4 / 71 (5.63%)
         occurrences all number
    1
    4
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 79 (2.53%)
    6 / 71 (8.45%)
         occurrences all number
    2
    7
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    3 / 79 (3.80%)
    4 / 71 (5.63%)
         occurrences all number
    3
    5
    Haemoglobin decreased
         subjects affected / exposed
    13 / 79 (16.46%)
    7 / 71 (9.86%)
         occurrences all number
    27
    18
    Neutrophil count decreased
         subjects affected / exposed
    4 / 79 (5.06%)
    3 / 71 (4.23%)
         occurrences all number
    7
    15
    Platelet count decreased
         subjects affected / exposed
    5 / 79 (6.33%)
    4 / 71 (5.63%)
         occurrences all number
    13
    13
    Weight decreased
         subjects affected / exposed
    27 / 79 (34.18%)
    22 / 71 (30.99%)
         occurrences all number
    31
    26
    White blood cell count decreased
         subjects affected / exposed
    2 / 79 (2.53%)
    4 / 71 (5.63%)
         occurrences all number
    3
    6
    Cardiac disorders
    Left ventricular dysfunction
         subjects affected / exposed
    4 / 79 (5.06%)
    5 / 71 (7.04%)
         occurrences all number
    4
    5
    Tachycardia
         subjects affected / exposed
    4 / 79 (5.06%)
    1 / 71 (1.41%)
         occurrences all number
    4
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    13 / 79 (16.46%)
    19 / 71 (26.76%)
         occurrences all number
    20
    29
    Epistaxis
         subjects affected / exposed
    8 / 79 (10.13%)
    23 / 71 (32.39%)
         occurrences all number
    10
    57
    Oropharyngeal pain
         subjects affected / exposed
    7 / 79 (8.86%)
    9 / 71 (12.68%)
         occurrences all number
    10
    11
    Rhinorrhoea
         subjects affected / exposed
    6 / 79 (7.59%)
    4 / 71 (5.63%)
         occurrences all number
    6
    7
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    50 / 79 (63.29%)
    55 / 71 (77.46%)
         occurrences all number
    141
    128
    Febrile neutropenia
         subjects affected / exposed
    14 / 79 (17.72%)
    12 / 71 (16.90%)
         occurrences all number
    23
    16
    Leukopenia
         subjects affected / exposed
    11 / 79 (13.92%)
    13 / 71 (18.31%)
         occurrences all number
    30
    36
    Neutropenia
         subjects affected / exposed
    53 / 79 (67.09%)
    56 / 71 (78.87%)
         occurrences all number
    244
    264
    Thrombocytopenia
         subjects affected / exposed
    37 / 79 (46.84%)
    31 / 71 (43.66%)
         occurrences all number
    116
    101
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    6 / 79 (7.59%)
    7 / 71 (9.86%)
         occurrences all number
    7
    8
    Headache
         subjects affected / exposed
    16 / 79 (20.25%)
    32 / 71 (45.07%)
         occurrences all number
    23
    49
    Neuralgia
         subjects affected / exposed
    5 / 79 (6.33%)
    2 / 71 (2.82%)
         occurrences all number
    6
    2
    Neuropathy peripheral
         subjects affected / exposed
    2 / 79 (2.53%)
    9 / 71 (12.68%)
         occurrences all number
    2
    10
    Paraesthesia
         subjects affected / exposed
    3 / 79 (3.80%)
    6 / 71 (8.45%)
         occurrences all number
    3
    6
    Peripheral sensory neuropathy
         subjects affected / exposed
    2 / 79 (2.53%)
    5 / 71 (7.04%)
         occurrences all number
    3
    6
    Polyneuropathy
         subjects affected / exposed
    1 / 79 (1.27%)
    4 / 71 (5.63%)
         occurrences all number
    1
    4
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    4 / 79 (5.06%)
    5 / 71 (7.04%)
         occurrences all number
    4
    6
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    27 / 79 (34.18%)
    31 / 71 (43.66%)
         occurrences all number
    43
    58
    Abdominal pain upper
         subjects affected / exposed
    8 / 79 (10.13%)
    8 / 71 (11.27%)
         occurrences all number
    10
    12
    Anal fissure
         subjects affected / exposed
    5 / 79 (6.33%)
    13 / 71 (18.31%)
         occurrences all number
    7
    15
    Anal inflammation
         subjects affected / exposed
    4 / 79 (5.06%)
    6 / 71 (8.45%)
         occurrences all number
    7
    7
    Constipation
         subjects affected / exposed
    40 / 79 (50.63%)
    48 / 71 (67.61%)
         occurrences all number
    61
    95
    Diarrhoea
         subjects affected / exposed
    27 / 79 (34.18%)
    30 / 71 (42.25%)
         occurrences all number
    54
    56
    Dyspepsia
         subjects affected / exposed
    5 / 79 (6.33%)
    4 / 71 (5.63%)
         occurrences all number
    5
    4
    Mouth ulceration
         subjects affected / exposed
    4 / 79 (5.06%)
    3 / 71 (4.23%)
         occurrences all number
    4
    3
    Nausea
         subjects affected / exposed
    42 / 79 (53.16%)
    44 / 71 (61.97%)
         occurrences all number
    146
    145
    Oral pain
         subjects affected / exposed
    4 / 79 (5.06%)
    2 / 71 (2.82%)
         occurrences all number
    6
    2
    Stomatitis
         subjects affected / exposed
    23 / 79 (29.11%)
    15 / 71 (21.13%)
         occurrences all number
    29
    21
    Vomiting
         subjects affected / exposed
    61 / 79 (77.22%)
    64 / 71 (90.14%)
         occurrences all number
    186
    202
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    3 / 79 (3.80%)
    7 / 71 (9.86%)
         occurrences all number
    3
    10
    Haematuria
         subjects affected / exposed
    2 / 79 (2.53%)
    8 / 71 (11.27%)
         occurrences all number
    3
    9
    Proteinuria
         subjects affected / exposed
    4 / 79 (5.06%)
    4 / 71 (5.63%)
         occurrences all number
    6
    8
    Hepatobiliary disorders
    Hepatocellular injury
         subjects affected / exposed
    1 / 79 (1.27%)
    4 / 71 (5.63%)
         occurrences all number
    1
    4
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    22 / 79 (27.85%)
    17 / 71 (23.94%)
         occurrences all number
    23
    18
    Dry skin
         subjects affected / exposed
    2 / 79 (2.53%)
    5 / 71 (7.04%)
         occurrences all number
    2
    6
    Erythema
         subjects affected / exposed
    6 / 79 (7.59%)
    12 / 71 (16.90%)
         occurrences all number
    7
    13
    Pruritus
         subjects affected / exposed
    6 / 79 (7.59%)
    10 / 71 (14.08%)
         occurrences all number
    7
    14
    Rash
         subjects affected / exposed
    10 / 79 (12.66%)
    5 / 71 (7.04%)
         occurrences all number
    13
    6
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    8 / 79 (10.13%)
    10 / 71 (14.08%)
         occurrences all number
    10
    15
    Back pain
         subjects affected / exposed
    6 / 79 (7.59%)
    15 / 71 (21.13%)
         occurrences all number
    8
    23
    Bone pain
         subjects affected / exposed
    2 / 79 (2.53%)
    4 / 71 (5.63%)
         occurrences all number
    2
    6
    Myalgia
         subjects affected / exposed
    4 / 79 (5.06%)
    6 / 71 (8.45%)
         occurrences all number
    4
    9
    Pain in extremity
         subjects affected / exposed
    16 / 79 (20.25%)
    20 / 71 (28.17%)
         occurrences all number
    22
    30
    Pain in jaw
         subjects affected / exposed
    12 / 79 (15.19%)
    5 / 71 (7.04%)
         occurrences all number
    14
    5
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    18 / 79 (22.78%)
    21 / 71 (29.58%)
         occurrences all number
    21
    27
    Hypokalaemia
         subjects affected / exposed
    18 / 79 (22.78%)
    8 / 71 (11.27%)
         occurrences all number
    20
    9
    Hypomagnesaemia
         subjects affected / exposed
    5 / 79 (6.33%)
    2 / 71 (2.82%)
         occurrences all number
    5
    2
    Hyponatraemia
         subjects affected / exposed
    2 / 79 (2.53%)
    4 / 71 (5.63%)
         occurrences all number
    2
    4
    Hypophosphataemia
         subjects affected / exposed
    4 / 79 (5.06%)
    5 / 71 (7.04%)
         occurrences all number
    5
    7
    Infections and infestations
    Candida infection
         subjects affected / exposed
    5 / 79 (6.33%)
    0 / 71 (0.00%)
         occurrences all number
    5
    0
    Conjunctivitis
         subjects affected / exposed
    5 / 79 (6.33%)
    7 / 71 (9.86%)
         occurrences all number
    5
    7
    Ear infection
         subjects affected / exposed
    3 / 79 (3.80%)
    6 / 71 (8.45%)
         occurrences all number
    4
    7
    Herpes zoster
         subjects affected / exposed
    4 / 79 (5.06%)
    3 / 71 (4.23%)
         occurrences all number
    4
    3
    Infection
         subjects affected / exposed
    3 / 79 (3.80%)
    5 / 71 (7.04%)
         occurrences all number
    5
    5
    Nasopharyngitis
         subjects affected / exposed
    5 / 79 (6.33%)
    10 / 71 (14.08%)
         occurrences all number
    8
    15
    Oral candidiasis
         subjects affected / exposed
    7 / 79 (8.86%)
    5 / 71 (7.04%)
         occurrences all number
    11
    7
    Paronychia
         subjects affected / exposed
    0 / 79 (0.00%)
    5 / 71 (7.04%)
         occurrences all number
    0
    5
    Pharyngitis
         subjects affected / exposed
    0 / 79 (0.00%)
    4 / 71 (5.63%)
         occurrences all number
    0
    5
    Rhinitis
         subjects affected / exposed
    6 / 79 (7.59%)
    12 / 71 (16.90%)
         occurrences all number
    7
    20
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 79 (8.86%)
    9 / 71 (12.68%)
         occurrences all number
    13
    13
    Urinary tract infection
         subjects affected / exposed
    2 / 79 (2.53%)
    8 / 71 (11.27%)
         occurrences all number
    2
    8

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Mar 2008
    Amended inclusion criteria as related to assessment of cardiac function and related sections as to cardiac toxicity, documenting the stress-velocity index information on smaller age ranges (less than [<] 1 year, versus 1 to 2 years, 2 to 3 years, >3 years). In healthy children less than 3 years of age, the minimal shortening fraction documented was between 35% and 45%, compared to between 28% and 38% for children aged 3 years and older. Adequate cardiac function at screen was redefined as shortening fraction (SF) >=28% for participants of at least 3 years of age, and SF >=35% for participants below 3 years of age. The diagnosis of congestive heart failure was redefined to include a decrease of SF below 28% for participants of at least 3 years of age and below 35% for participants below 3 years of age, or if the SF decreased by an absolute of >=10 percentile points from the previous test. Dose modification guidelines for doxorubicin and bevacizumab in cases of treatment-emergent cardiotoxicity events were rewritten to included the redefinitions above.
    22 Jan 2009
    This amendment was done to describe study design and endpoints, radiological tumor assessment. Statistical analysis plan was amended to add the futility analysis which was performed on 80 participants who completed 6 cycles. Due to new requirements for safety follow-up after randomization that extended study duration by 4 years, and with the requirement that the events of the primary endpoint were to be assessed by magnetic resonance imaging and evaluated by a central independent image reviewing committee, the schedule of assessments and study procedures section were completely revised to provide clear guidance for treating physicians and to allow for a meaningful review of trial efficacy data. Amended the study population criteria.
    30 May 2011
    Updated with increased investigational site from 50 to 60. Updated with possibility of omission of the first two doses of bevacizumab (induction therapy Cycles 1 and 2) for participants who presented with a surgical wound, bone fracture, or bleeding related to tumor oozing not satisfactorily healed at randomization or transient clotting diathesis or transient obstructive renal failure that had not resolved at randomization. Updated randomization timeframe from 4 weeks to 3 weeks for participants who underwent a major surgical procedure or open biopsy, or had suffered from a significant traumatic injury or bone fracture prior to study entry.

    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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