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    Clinical Trial Results:
    Randomized phase II trial of bevacizumab (AVASTIN®) in combination with gemcitabine or attenuated doses of cisplatin and gemcitabine as first-line treatment of elderly patients with advanced, metastatic nonsquamous non-small cell lung cancer

    Summary
    EudraCT number
    		 2008-008739-27
    Trial protocol
    		 IT  
    Global end of trial date
    02 Jul 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Jun 2016
    First version publication date
    10 Jun 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ML21868
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01077713
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    17 Apr 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Jul 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effects of bevacizumab + gemcitabine combination and bevacizumab + cisplatin + gemcitabine combination in elderly participants with non-squamous NSCLC by using progression-free rate (PFR) at 6 months as primary endpoint.
    Protection of trial subjects
    The study was conducted under the provisions of the Declaration of Helsinki, and in accordance with the International Conference on Harmonization (ICH) Consolidated Guideline on Good Clinical Practice (GCP).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Feb 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 86
    Worldwide total number of subjects
    86
    EEA total number of subjects
    86
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    86
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Overall, 86 participants were enrolled and all of them were randomised.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Bevacizumab + Gemcitabine
    Arm description
    		 Participants received bevacizumab 7.5 milligram per kilogram (mg/kg) intravenous (IV) infusion on Day 1 and gemcitabine 1200 milligrams per square meter (mg/m^2) IV infusion on Days 1-8 of each 21-day cycle for maximum of 6 cycles. After Cycle 6, participants continued treatment with bevacizumab 7.5 mg/kg on IV infusion Day 1 of every 21-day cycle until progressive disease, death, or intolerable toxicity.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab (7.5 mg/kg) was administered as an IV infusion initially over a 90-minute period. If the first infusion was well tolerated, then the second infusion could be delivered over a 60-minute period. If the 60-minute infusion was well tolerated, all subsequent infusions could be delivered over a 30-minute period.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gemcitabine (1200 mg/m^2) was administered over a 30-minute IV infusion.

    Arm title
    		 Bevacizumab + Gemcitabine + Cisplatin
    Arm description
    		 Participants received bevacizumab 7.5 mg/kg IV infusion and cisplatin 60 mg/m^2 IV infusion on Day 1 and gemcitabine 1000 mg/m^2 IV infusion on Days 1-8 of each 21-day cycle for maximum of 6 cycles. After Cycle 6, participants continued treatment with bevacizumab 7.5 mg/kg IV infusion on Day 1 of every 21 day cycle until progressive disease, death, or intolerable toxicity.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab (7 mg/kg) was administered as an IV infusion initially over a 90-minute period. If the first infusion was well tolerated, then the second infusion could be delivered over a 60-minute period. If the 60-minute infusion was well tolerated, all subsequent infusions could be delivered over a 30-minute period.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gemcitabine (1200 mg/m^2) was administered over a 30-minute iv infusion.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cisplatin 60 (mg/m^2) was administered over a 1-hour IV infusion.

    Number of subjects in period 1
    		Bevacizumab + Gemcitabine Bevacizumab + Gemcitabine + Cisplatin
    Started
    44
    42
    Completed
    8
    6
    Not completed
    36
    36
         Adverse event, serious fatal
    28
    29
         Consent withdrawn by subject
    1
    2
         Adverse event, non-fatal
    2
    1
         Progressive Disease (PD)
    -
    1
         Unspecified
    4
    2
         Lost to follow-up
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Bevacizumab + Gemcitabine
    Reporting group description
    		 Participants received bevacizumab 7.5 milligram per kilogram (mg/kg) intravenous (IV) infusion on Day 1 and gemcitabine 1200 milligrams per square meter (mg/m^2) IV infusion on Days 1-8 of each 21-day cycle for maximum of 6 cycles. After Cycle 6, participants continued treatment with bevacizumab 7.5 mg/kg on IV infusion Day 1 of every 21-day cycle until progressive disease, death, or intolerable toxicity.

    Reporting group title
    Bevacizumab + Gemcitabine + Cisplatin
    Reporting group description
    		 Participants received bevacizumab 7.5 mg/kg IV infusion and cisplatin 60 mg/m^2 IV infusion on Day 1 and gemcitabine 1000 mg/m^2 IV infusion on Days 1-8 of each 21-day cycle for maximum of 6 cycles. After Cycle 6, participants continued treatment with bevacizumab 7.5 mg/kg IV infusion on Day 1 of every 21 day cycle until progressive disease, death, or intolerable toxicity.

    Reporting group values
    		 Bevacizumab + Gemcitabine Bevacizumab + Gemcitabine + Cisplatin Total
    Number of subjects
    		 44 42 86
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 74.2 ( 3.2 ) 73.8 ( 3.5 ) -
    Gender, Male/Female
    Units: participants
        Female
    		 16 12 28
        Male
    		 28 30 58

    End points

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    End points reporting groups
    Reporting group title
    Bevacizumab + Gemcitabine
    Reporting group description
    		 Participants received bevacizumab 7.5 milligram per kilogram (mg/kg) intravenous (IV) infusion on Day 1 and gemcitabine 1200 milligrams per square meter (mg/m^2) IV infusion on Days 1-8 of each 21-day cycle for maximum of 6 cycles. After Cycle 6, participants continued treatment with bevacizumab 7.5 mg/kg on IV infusion Day 1 of every 21-day cycle until progressive disease, death, or intolerable toxicity.

    Reporting group title
    Bevacizumab + Gemcitabine + Cisplatin
    Reporting group description
    		 Participants received bevacizumab 7.5 mg/kg IV infusion and cisplatin 60 mg/m^2 IV infusion on Day 1 and gemcitabine 1000 mg/m^2 IV infusion on Days 1-8 of each 21-day cycle for maximum of 6 cycles. After Cycle 6, participants continued treatment with bevacizumab 7.5 mg/kg IV infusion on Day 1 of every 21 day cycle until progressive disease, death, or intolerable toxicity.

    Primary: Percentage of participants alive and without progressive disease at Month 6

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    End point title
    		 Percentage of participants alive and without progressive disease at Month 6 [1]
    End point description
    Disease progression was assessed according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.1. Disease progression was defined at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study and absolute increase of at least 5 millimeter (mm), progression of existing non-target lesions, or presence of new lesions. All participants randomized set (RND) included all participants who provided informed consent and who were randomized to study medication. Intent-to-treat (ITT) set included all participants who provided informed consent and who were randomized to study medication who received at least one dose of any study medication; participants were classified according to treatment received.
    End point type
    Primary
    End point timeframe
    Month 6
    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: As this endpoint is descriptive in nature, no statistical analysis was performed.
    End point values
    		 Bevacizumab + Gemcitabine Bevacizumab + Gemcitabine + Cisplatin
    Number of subjects analysed
    43
    40
    Units: percentage of participants
        number (confidence interval 95%)
    25.6 (12.5 to 38.6)
    30 (15.8 to 44.2)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Disease Progression or Death

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    End point title
    		 Percentage of Participants with Disease Progression or Death
    End point description
    Disease progression was assessed according to RECIST criteria version 1.1. Disease progression was defined at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study and absolute increase of at least 5 mm, progression of existing non-target lesions, or presence of new lesions. Analysis was performed on ITT set.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 15 of Cycles 3 and 6, and then every 3 months until disease progression, death, or consent withdrawal (up to 53 months)
    End point values
    		 Bevacizumab + Gemcitabine Bevacizumab + Gemcitabine + Cisplatin
    Number of subjects analysed
    43
    40
    Units: percentage of participants
        number (not applicable)
    86
    90
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    PFS was defined as the interval between the date of randomization and the first documentation of progressive disease or death from any cause. Disease progression was assessed according to RECIST criteria version 1.1. Disease progression was defined at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study and absolute increase of at least 5 mm, progression of existing non-target lesions, or presence of new lesions. PFS was estimated using Kaplan Meier method. Analysis was performed on ITT set.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 15 of Cycles 3 and 6, and then every 3 months until disease progression, death or consent withdrawal (up to 53 months)
    End point values
    		 Bevacizumab + Gemcitabine Bevacizumab + Gemcitabine + Cisplatin
    Number of subjects analysed
    43
    40
    Units: months
        median (confidence interval 95%)
    4.33 (2.2 to 5.97)
    6.82 (4.49 to 8.52)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Alive at 12 Months After Randomization

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    End point title
    		 Percentage of Participants Alive at 12 Months After Randomization
    End point description
    Analysis was performed on ITT set.
    End point type
    Secondary
    End point timeframe
    From randomization to one year
    End point values
    		 Bevacizumab + Gemcitabine Bevacizumab + Gemcitabine + Cisplatin
    Number of subjects analysed
    43
    40
    Units: percentage of participants
        number (confidence interval 95%)
    37.2 (22.8 to 51.7)
    47.5 (32 to 63)
    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
    Analysis was performed on ITT set.
    End point type
    Secondary
    End point timeframe
    From randomization to death or end of the study (up to 53 months)
    End point values
    		 Bevacizumab + Gemcitabine Bevacizumab + Gemcitabine + Cisplatin
    Number of subjects analysed
    43
    40
    Units: percentage of participants
        number (not applicable)
    69.8
    72.5
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS was defined as the interval between the date of randomization and death from any cause. OS was estimated using Kaplan Meier method. Analysis was performed on ITT set.
    End point type
    Secondary
    End point timeframe
    From randomization to death or end of the study (up to 53 months)
    End point values
    		 Bevacizumab + Gemcitabine Bevacizumab + Gemcitabine + Cisplatin
    Number of subjects analysed
    43
    40
    Units: months
        median (confidence interval 95%)
    5.66 (3.38 to 13)
    12 (9.93 to 19.6)
    No statistical analyses for this end point

    Secondary: Percentage of Participants by Best Overall Response

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    End point title
    		 Percentage of Participants by Best Overall Response
    End point description
    Best overall response was defined as the best response recorded from the start of the treatment until disease progression/recurrence, assessed according to RECIST criteria version 1.1. Complete Response (CR): disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters), no progression in non-target lesion, and no new lesion; Progressive Disease (PD): at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study and absolute increase of at least 5 mm, progression of existing non-target lesions, or presence of new lesions; Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Analysis was performed on ITT set.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 15 of Cycles 3 and 6, and then every 3 months until disease progression, death or consent withdrawal (up to 53 months)
    End point values
    		 Bevacizumab + Gemcitabine Bevacizumab + Gemcitabine + Cisplatin
    Number of subjects analysed
    43
    40
    Units: percentage of participants
    number (not applicable)
        CR
    0
    0
        PR
    14
    35
        SD
    39.5
    37.5
        PD
    16.3
    12.5
        Not Assessable
    30.2
    15
    No statistical analyses for this end point

    Secondary: Percentage of Participants with an Objective Response

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    End point title
    		 Percentage of Participants with an Objective Response
    End point description
    Objective response was defined as having a CR or PR according to a RECIST criteria version 1.1. CR was defined as disappearance of all target and non-target lesions and no new lesions. PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters), no progression in non-target lesion, and no new lesion. Analysis was performed on ITT set.
    End point type
    Secondary
    End point timeframe
    Cycle 3 Day 15, Cycle 6 Day 15 and at Month 6
    End point values
    		 Bevacizumab + Gemcitabine Bevacizumab + Gemcitabine + Cisplatin
    Number of subjects analysed
    43
    40
    Units: percentage of participants
    number (confidence interval 95%)
        Cycle 3
    11.6 (2.05 to 21.2)
    27.5 (13.7 to 41.3)
        Cycle 6
    9.3 (0.62 to 18)
    15 (3.93 to 26.1)
        Month 6
    4.7 (0 to 10.9)
    10 (0.7 to 19.3)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Disease Control

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    End point title
    		 Percentage of Participants With Disease Control
    End point description
    CR/PR/SD was measured by RECIST criteria version 1.1. CR was defined as disappearance of all target and non-target lesions and no new lesions. PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters), no progression in non-target lesion, and no new lesion. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD was defined as at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study and absolute increase of at least 5 mm, progression of existing non-target lesions, or presence of new lesions. Analysis was performed on ITT set.
    End point type
    Secondary
    End point timeframe
    Cycle 3 Day 15, Cycle 6 Day 15 and at Month 6
    End point values
    		 Bevacizumab + Gemcitabine Bevacizumab + Gemcitabine + Cisplatin
    Number of subjects analysed
    43
    40
    Units: percentage of participants
    number (confidence interval 95%)
        Cycle 3
    53.5 (38.6 to 68.4)
    67.5 (53 to 82)
        Cycle 6
    27.9 (14.5 to 41.3)
    37.5 (22.5 to 52.5)
        Month 6
    25.6 (12.5 to 38.6)
    30 (15.8 to 44.2)
    No statistical analyses for this end point

    Secondary: Duration of Response (DoR)

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    End point title
    		 Duration of Response (DoR)
    End point description
    DoR was defined for participants who had achieved an objective response (CR/PR) (whichever status was recorded first) as the time period from 1st documentation of a response to the date of 1st occurrence of investigator documented disease progression or death. CR was defined as disappearance of all target and non-target lesions and no new lesions. PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters), no progression in non-target lesion, and no new lesion. Disease progression as increase by at least 20% in the sum of the longest diameters of each target lesion, taking as a reference the smallest sum of the longest diameters or appearance of one or more new lesions. DoR was estimated using Kaplan Meier method. Here "99999" represents data not available as tt was not possible to estimate statistic using Kaplan-Meier because upper bound of 95% confidence interval was not reached. Analysis was done on ITT set.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 15 of Cycles 3 and 6, and then every 3 months until disease progression, death or consent withdrawal (up to 53 months)
    End point values
    		 Bevacizumab + Gemcitabine Bevacizumab + Gemcitabine + Cisplatin
    Number of subjects analysed
    6
    14
    Units: months
        median (confidence interval 95%)
    5.23 (3.93 to 99999)
    5.97 (2.2 to 9.08)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline to 28 days after last dose of any study drug (up to 54 months)
    Adverse event reporting additional description
    Safety set included all participants in the RND set who received at least one dose of any study medication. Participants were classified according to treatment received.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.0
    Reporting groups
    Reporting group title
    Bevacizumab + Gemcitabine
    Reporting group description
    		 Participants received bevacizumab 7.5 mg/kg IV infusion on Day 1 and gemcitabine 1200 mg/m^2 IV infusion on Days 1-8 of each 21-day cycle for maximum of 6 cycles. After Cycle 6, participants continued treatment with bevacizumab 7.5 mg/kg on IV infusion Day 1 of every 21-day cycle until progressive disease, death, or intolerable toxicity.

    Reporting group title
    Bevacizumab + Gemcitabine + Cisplatin
    Reporting group description
    		 Participants received bevacizumab 7.5 mg/kg IV infusion and cisplatin 60 mg/m^2 IV infusion on Day 1 and gemcitabine 1000 mg/m^2 IV infusion on Days 1-8 of each 21-day cycle for maximum of 6 cycles. After Cycle 6, participants continued treatment with bevacizumab 7.5 mg/kg IV infusion on Day 1 of every 21 day cycle until progressive disease, death, or intolerable toxicity.

    Serious adverse events
    		 Bevacizumab + Gemcitabine Bevacizumab + Gemcitabine + Cisplatin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 43 (39.53%)
    10 / 40 (25.00%)
         number of deaths (all causes)
    30
    29
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Embolism
         subjects affected / exposed
    1 / 43 (2.33%)
    2 / 40 (5.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Artrial fibrillation
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Surgical and medical procedures
    Hospitalisation
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    2 / 43 (4.65%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 43 (4.65%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    2 / 43 (4.65%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pulmonary oedema
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    2 / 43 (4.65%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Infections and infestations
    Bronchopneumonia
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Urinary tract infection
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Bevacizumab + Gemcitabine Bevacizumab + Gemcitabine + Cisplatin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    38 / 43 (88.37%)
    37 / 40 (92.50%)
    Investigations
    Blood creatine increased
         subjects affected / exposed
    0 / 43 (0.00%)
    4 / 40 (10.00%)
         occurrences all number
    0
    9
    Platelet count decreased
         subjects affected / exposed
    4 / 43 (9.30%)
    5 / 40 (12.50%)
         occurrences all number
    5
    10
    Vascular disorders
    Embolism
         subjects affected / exposed
    0 / 43 (0.00%)
    5 / 40 (12.50%)
         occurrences all number
    0
    7
    Hypertension
         subjects affected / exposed
    11 / 43 (25.58%)
    9 / 40 (22.50%)
         occurrences all number
    16
    12
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 43 (6.98%)
    8 / 40 (20.00%)
         occurrences all number
    4
    8
    Paraesthesia
         subjects affected / exposed
    0 / 43 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 43 (11.63%)
    12 / 40 (30.00%)
         occurrences all number
    7
    34
    Leukopenia
         subjects affected / exposed
    0 / 43 (0.00%)
    11 / 40 (27.50%)
         occurrences all number
    0
    39
    Neutropenia
         subjects affected / exposed
    12 / 43 (27.91%)
    23 / 40 (57.50%)
         occurrences all number
    27
    60
    Thrombocytopenia
         subjects affected / exposed
    5 / 43 (11.63%)
    16 / 40 (40.00%)
         occurrences all number
    8
    49
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    9 / 43 (20.93%)
    10 / 40 (25.00%)
         occurrences all number
    11
    17
    Chest pain
         subjects affected / exposed
    4 / 43 (9.30%)
    2 / 40 (5.00%)
         occurrences all number
    5
    2
    Fatigue
         subjects affected / exposed
    8 / 43 (18.60%)
    15 / 40 (37.50%)
         occurrences all number
    10
    34
    Mucosal inflammation
         subjects affected / exposed
    0 / 43 (0.00%)
    5 / 40 (12.50%)
         occurrences all number
    0
    7
    Pain
         subjects affected / exposed
    0 / 43 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Pyrexia
         subjects affected / exposed
    8 / 43 (18.60%)
    8 / 40 (20.00%)
         occurrences all number
    13
    11
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 43 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Abdominal pain upper
         subjects affected / exposed
    0 / 43 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Constipation
         subjects affected / exposed
    3 / 43 (6.98%)
    8 / 40 (20.00%)
         occurrences all number
    3
    8
    Diarrhoea
         subjects affected / exposed
    3 / 43 (6.98%)
    5 / 40 (12.50%)
         occurrences all number
    3
    8
    Nausea
         subjects affected / exposed
    8 / 43 (18.60%)
    17 / 40 (42.50%)
         occurrences all number
    12
    36
    Vomiting
         subjects affected / exposed
    5 / 43 (11.63%)
    6 / 40 (15.00%)
         occurrences all number
    7
    8
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 43 (9.30%)
    6 / 40 (15.00%)
         occurrences all number
    4
    7
    Dyspnoea
         subjects affected / exposed
    4 / 43 (9.30%)
    7 / 40 (17.50%)
         occurrences all number
    4
    7
    Epistaxis
         subjects affected / exposed
    0 / 43 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    3
    Haemoptysis
         subjects affected / exposed
    5 / 43 (11.63%)
    4 / 40 (10.00%)
         occurrences all number
    5
    4
    Productive cough
         subjects affected / exposed
    0 / 43 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    0
    3
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    5 / 43 (11.63%)
    0 / 40 (0.00%)
         occurrences all number
    6
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 43 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    0
    3
    Bone pain
         subjects affected / exposed
    5 / 43 (11.63%)
    4 / 40 (10.00%)
         occurrences all number
    5
    4
    Pain in extremity
         subjects affected / exposed
    3 / 43 (6.98%)
    0 / 40 (0.00%)
         occurrences all number
    3
    0
    Infections and infestations
    Tooth abscess
         subjects affected / exposed
    0 / 43 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    0 / 43 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    4
    Hypocalcaemia
         subjects affected / exposed
    0 / 43 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    0
    7
    Hyponatraemia
         subjects affected / exposed
    0 / 43 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Nov 2010
    The name of the sponsor Medical manager was changed; the exclusion criterion on radiotherapy was better clarified; specifications of end of treatment/study and of target population were better defined; the study schedule of assessments and the plan for follow-up were modified to meet the protocol definitions of adverse events reporting, and of clinical assessments and procedures; clarifications were given for the efficacy assessments; rules for the post-study provisional care were given; procedures for safety reporting and for reporting of adverse events of special interest were updated; the definition of the PP population for analysis was amended; procedures for central review of magnetic resonance imaging/computed tomography scan and for the data safety monitoring board were updated; procedures for publication of data have been updated; references for tumor assessment were updated in line with the adopted RECIST version 1.1 criteria.
    27 Sep 2013
    The name of the sponsor Medical manager was changed again; the definition for end of study was updated; the possibility of participation in the long-term extension study was offered to participants still on treatment with bevacizumab at end of study; the planned time for recruitment was extended; furthers specifications for the procedures of reporting of serious adverse events were added; the list of adverse events of special interest (and their definitions) was extended; clarifications for the efficacy and safety analysis were added; details on ethics and general study administration were added; the published reference for the ECOG performance status was added.

    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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