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    Clinical Trial Results:
    A Randomized, Double-Blind, Phase 3 Study Evaluating The Efficacy And Safety Of ABP 215 Compared With Bevacizumab In Subjects With Advanced Non-Small Cell Lung Cancer

    Summary
    EudraCT number
    		 2013-000738-36
    Trial protocol
    		 HU   CZ   DE   IT   ES   NL   GR   BG   PL  
    Global end of trial date
    23 Jul 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Jul 2016
    First version publication date
    28 Jul 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    20120265
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01966003
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Amgen, Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, CA, United States, 91320
    Public contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Scientific contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.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
    23 Jul 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Jul 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective for this study was to compare the efficacy of ABP 215 with bevacizumab.
    Protection of trial subjects
    This study was conducted in accordance with the Note for Guidance on GCP (ICH Harmonised Tripartite Guideline E6 (R1); FDA CFR (21 CFR § 50, 56, 312)), Declaration of Helsinki, and all applicable regulatory requirements. This study was conducted in compliance with Institutional Review Board (IRB)/Independent Ethics Committee (IEC) and International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines - including Title 21 Part 56 of the US Code of Federal Regulations (CFR) relating to IRBs/IECs and GCP as described in the US Food and Drug Administration (FDA) CFR (21 CFR § 50, 56, 312) - in accordance with applicable ICH regulations regarding clinical safety data management (E2A, E2B(R3)), European Community directives 2001/20, 2001/83, 2003/94 and 2005/28 as enacted into local law, and with ICH guidelines regarding scientific integrity (E4, E8, E9, and E10). In addition this study adhered to all local regulatory requirements and requirements for data protection. The investigator explained the benefits and risks of participation in the study to each subject or the subject’s legally acceptable representative and obtained written informed consent. Written informed consent was required to be obtained prior to the subject entering the study and before initiation of any study-related procedure (including administration of investigational product [IP]).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Nov 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Russian Federation: 113
    Country: Number of subjects enrolled
    Hungary: 78
    Country: Number of subjects enrolled
    Romania: 78
    Country: Number of subjects enrolled
    Poland: 54
    Country: Number of subjects enrolled
    Greece: 26
    Country: Number of subjects enrolled
    Bulgaria: 15
    Country: Number of subjects enrolled
    Czech Republic: 11
    Country: Number of subjects enrolled
    Spain: 44
    Country: Number of subjects enrolled
    Italy: 25
    Country: Number of subjects enrolled
    Netherlands: 9
    Country: Number of subjects enrolled
    United States: 45
    Country: Number of subjects enrolled
    Mexico: 9
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    Australia: 50
    Country: Number of subjects enrolled
    Taiwan: 5
    Country: Number of subjects enrolled
    Hong Kong: 1
    Country: Number of subjects enrolled
    Germany: 76
    Worldwide total number of subjects
    642
    EEA total number of subjects
    416
    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)
    390
    From 65 to 84 years
    252
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 101 sites (14 sites in the US, 11 in Russia, 10 in Australia, 9 in Germany, 8 in Poland, 7 in Hungary, 7 in Romania, 6 in Italy, 6 in Spain, 5 in Bulgaria, 5 in Greece, 3 in the Czech Republic, 3 in Mexico, 3 in Taiwan, 2 in the Netherlands, 1 in Canada, and 1 in Hong Kong).

    Pre-assignment
    Screening details
    		 Eligible participants were randomized in a 1:1 ratio to receive ABP 215 or bevacizumab. Subjects were stratified by geographic region (Eastern Europe vs Western Europe vs Asia Pacific/Other vs North America), Eastern Cooperative Oncology Group (ECOG) performance status (0 vs 1), and sex.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ABP 215
    Arm description
    		 Participants received 15 mg/kg ABP 215 administered as an intravenous (IV) infusion every 3 weeks (Q3W) for 6 cycles and carboplatin and paclitaxel chemotherapy Q3W for at least 4 and not more than 6 cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ABP 215
    Investigational medicinal product code
    ABP 215
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered 15 mg/kg Q3W by IV infusion

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Paraplatin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered at an area under the concentration-time curve (AUC) 6 by IV infusion Q3W

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Taxol
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered 200 mg/m² IV Q3W

    Arm title
    		 Bevacizumab
    Arm description
    		 Participants received bevacizumab 15 mg/kg administered as an intravenous (IV) infusion every 3 weeks (Q3W) for 6 cycles and carboplatin and paclitaxel chemotherapy Q3W for at least 4 and not more than 6 cycles.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin®
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    15 mg/kg Q3W by IV infusion

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Taxol
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered 200 mg/m² IV Q3W

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Paraplatin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered at an area under the concentration-time curve (AUC) 6 by IV infusion Q3W

    Number of subjects in period 1
    		ABP 215 Bevacizumab
    Started
    328
    314
    Received Study Drug
    324
    309
    Completed
    58
    44
    Not completed
    270
    270
         Consent withdrawn by subject
    29
    19
         Physician decision
    12
    13
         Plan to receive commercial bevacizumab
    44
    67
         Death
    43
    36
         Other
    1
    1
         Plan to receive non-study anticancer therapy
    131
    127
         Lost to follow-up
    4
    3
         Protocol deviation
    6
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ABP 215
    Reporting group description
    		 Participants received 15 mg/kg ABP 215 administered as an intravenous (IV) infusion every 3 weeks (Q3W) for 6 cycles and carboplatin and paclitaxel chemotherapy Q3W for at least 4 and not more than 6 cycles.

    Reporting group title
    Bevacizumab
    Reporting group description
    		 Participants received bevacizumab 15 mg/kg administered as an intravenous (IV) infusion every 3 weeks (Q3W) for 6 cycles and carboplatin and paclitaxel chemotherapy Q3W for at least 4 and not more than 6 cycles.

    Reporting group values
    		 ABP 215 Bevacizumab Total
    Number of subjects
    		 328 314 642
    Age Categorical
    Units: Subjects
        < 65 years
    		 199 191 390
        ≥ 65 years
    		 129 123 252
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.6 ± 9.09 61.6 ± 8.88 -
    Gender Categorical
    Units: Subjects
        Female
    		 132 126 258
        Male
    		 196 188 384
    Geographic Region
    Units: Subjects
        Eastern Europe
    		 189 186 375
        Western Europe
    		 78 76 154
        North America
    		 31 26 57
        Asia Pacific/Other
    		 30 26 56
    Eastern Cooperative Oncology Group (ECOG) Performance Status
    Units: Subjects
        Grade 0
    		 127 117 244
        Grade 1
    		 201 197 398

    End points

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    End points reporting groups
    Reporting group title
    ABP 215
    Reporting group description
    		 Participants received 15 mg/kg ABP 215 administered as an intravenous (IV) infusion every 3 weeks (Q3W) for 6 cycles and carboplatin and paclitaxel chemotherapy Q3W for at least 4 and not more than 6 cycles.

    Reporting group title
    Bevacizumab
    Reporting group description
    		 Participants received bevacizumab 15 mg/kg administered as an intravenous (IV) infusion every 3 weeks (Q3W) for 6 cycles and carboplatin and paclitaxel chemotherapy Q3W for at least 4 and not more than 6 cycles.

    Primary: Percentage of Participants with an Objective Response

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    End point title
    		 Percentage of Participants with an Objective Response
    End point description
    Tumor assessments were performed by central, independent, blinded radiologists according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 using computed tomography (CT) or magnetic resonance imaging (MRI) scans of the chest and abdomen. Objective response is defined as a best overall response of partial response (PR) or complete response (CR) as defined by RECIST v1.1. All participants who did not meet the criteria for CR or PR at the end of the study were considered non-responders. The primary analysis for ORR was based on the intent-to-treat (ITT) population (all randomized subjects).
    End point type
    Primary
    End point timeframe
    Weeks 7, 13, 19, and approximately every 9 weeks thereafter. The mean (STD) actual follow-up time from randomization was 4.7 (3.04) and 5.0 (3.17) months for ABP 215 and bevacizumab, respectively.
    End point values
    		 ABP 215 Bevacizumab
    Number of subjects analysed
    328
    314
    Units: percentage of participants
        number (not applicable)
    39
    41.7
    Statistical analysis title
    		 Risk Ratio (ABP 215/Bevacizumab)
    Statistical analysis description
    The risk ratio and 90% confidence interval (CI) were estimated using a generalized linear model adjusted for the stratification factors (region, sex, and ECOG performance status).
    Comparison groups
    ABP 215 v Bevacizumab
    Number of subjects included in analysis
    642
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [1]
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.93
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.09
    Notes
    [1] - Clinical equivalence of the primary endpoint was demonstrated by comparing the 2-sided 90% CI of the risk ratio in ORR between ABP 215 and bevacizumab with an equivalence margin of (0.67, 1.5).
    Statistical analysis title
    		 Risk Difference (ABP 215 - Bevacizumab)
    Statistical analysis description
    Risk difference and 90% CI were estimated using a generalized linear model adjusted for the randomization stratification factors geographic region, ECOG performance status, and sex.
    Comparison groups
    ABP 215 v Bevacizumab
    Number of subjects included in analysis
    642
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -2.9
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -9.26
         upper limit
    		 3.45

    Secondary: Duration of Response

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    End point title
    		 Duration of Response
    End point description
    Duration of response (DOR) was calculated as the time from the first objective response (PR or CR) to disease progression per RECIST v1.1 based on the central, independent, blinded radiologists’ review. DOR was only calculated for participants with a response. For responders not meeting the criterion for progression by the end of the study, DOR was censored at the date of the last evaluable tumor assessment.
    End point type
    Secondary
    End point timeframe
    Weeks 7, 13, 19, and approximately every 9 weeks thereafter. The mean (STD) actual follow-up time from randomization was 4.7 (3.04) and 5.0 (3.17) months for ABP 215 and bevacizumab, respectively.
    End point values
    		 ABP 215 Bevacizumab
    Number of subjects analysed
    128
    131
    Units: months
        median (confidence interval 95%)
    5.8 (4.9 to 7.7)
    5.6 (5.1 to 6.3)
    Statistical analysis title
    		 Hazard Ratio for Duration of Response
    Statistical analysis description
    The hazard ratio for ABP 215 relative to bevacizumab is based on a stratified Cox proportional hazards model. Stratification factors are geographic region, ECOG performance status, and sex.
    Comparison groups
    ABP 215 v Bevacizumab
    Number of subjects included in analysis
    259
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.76
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.51
         upper limit
    		 1.14

    Secondary: Progression-free Survival

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    End point title
    		 Progression-free Survival
    End point description
    Progression-free survival (PFS) was defined as the time from the randomization date to the date of disease progression using RECIST v1.1 based on the central, independent, blinded radiologists’ review, or death. Subjects who were alive and did not meet the criteria for progression by the end of the study were censored at their last evaluable disease assessment date. Subjects with no evaluable tumor assessments after randomization who did not die by the end of the study had their PFS times censored on the randomization date.
    End point type
    Secondary
    End point timeframe
    Weeks 7, 13, 19, and approximately every 9 weeks thereafter. The mean (STD) actual follow-up time from randomization was 4.7 (3.04) and 5.0 (3.17) months for ABP 215 and bevacizumab, respectively.
    End point values
    		 ABP 215 Bevacizumab
    Number of subjects analysed
    328
    314
    Units: months
        median (confidence interval 95%)
    6.6 (6.3 to 7.9)
    7.9 (6.6 to 8.2)
    Statistical analysis title
    		 Hazard Ratio for Progression-free Survival
    Statistical analysis description
    The hazard ratio for ABP 215 relative to bevacizumab was based on a stratified Cox proportional hazards model. Stratification factors are geographic region, ECOG performance status, and sex.
    Comparison groups
    ABP 215 v Bevacizumab
    Number of subjects included in analysis
    642
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.03
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 1.29

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    19 weeks
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    ABP 215
    Reporting group description
    		 Participants received 15 mg/kg ABP 215 administered as an intravenous (IV) infusion every 3 weeks (Q3W) for 6 cycles and carboplatin and paclitaxel chemotherapy Q3W for at least 4 and not more than 6 cycles.

    Reporting group title
    Bevacizumab
    Reporting group description
    		 Participants received bevacizumab 15 mg/kg administered as an intravenous (IV) infusion every 3 weeks (Q3W) for 6 cycles and carboplatin and paclitaxel chemotherapy Q3W for at least 4 and not more than 6 cycles.

    Serious adverse events
    		 ABP 215 Bevacizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    85 / 324 (26.23%)
    71 / 309 (22.98%)
         number of deaths (all causes)
    13
    11
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to bone
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 324 (0.31%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism arterial
         subjects affected / exposed
    1 / 324 (0.31%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    1 / 324 (0.31%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Prophylaxis
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    2 / 324 (0.62%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Fatigue
         subjects affected / exposed
    2 / 324 (0.62%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    2 / 324 (0.62%)
    2 / 309 (0.65%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 324 (0.31%)
    2 / 309 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchial fistula
         subjects affected / exposed
    1 / 324 (0.31%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 324 (0.31%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    3 / 324 (0.93%)
    4 / 309 (1.29%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    2 / 324 (0.62%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    3 / 324 (0.93%)
    5 / 309 (1.62%)
         occurrences causally related to treatment / all
    0 / 3
    5 / 6
         deaths causally related to treatment / all
    0 / 2
    1 / 2
    Pleural effusion
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    2 / 324 (0.62%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary artery thrombosis
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    5 / 324 (1.54%)
    6 / 309 (1.94%)
         occurrences causally related to treatment / all
    1 / 5
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 324 (0.62%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Hallucinations, mixed
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Brain contusion
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute left ventricular failure
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute myocardial infarction
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 324 (0.31%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paroxysmal arrhythmia
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (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
    Brain oedema
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebral ischaemia
         subjects affected / exposed
    2 / 324 (0.62%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    2 / 324 (0.62%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic cerebral infarction
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    2 / 324 (0.62%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 324 (0.62%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 324 (0.93%)
    6 / 309 (1.94%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    11 / 324 (3.40%)
    8 / 309 (2.59%)
         occurrences causally related to treatment / all
    0 / 14
    2 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercoagulation
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Neutropenia
         subjects affected / exposed
    6 / 324 (1.85%)
    3 / 309 (0.97%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    2 / 324 (0.62%)
    2 / 309 (0.65%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 309 (0.32%)
         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
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal haemorrhage
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (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 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    3 / 324 (0.93%)
    2 / 309 (0.65%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea haemorrhagic
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    1 / 324 (0.31%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Large intestinal haemorrhage
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 324 (0.31%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mesenteric artery embolism
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 324 (0.62%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    2 / 324 (0.62%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 324 (0.62%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatitis
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash generalised
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous emphysema
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 324 (0.31%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess soft tissue
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus hepatitis
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    0 / 324 (0.00%)
    2 / 309 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 324 (0.31%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 324 (0.00%)
    2 / 309 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pilonidal cyst
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    6 / 324 (1.85%)
    5 / 309 (1.62%)
         occurrences causally related to treatment / all
    1 / 6
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pseudomonas infection
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    2 / 324 (0.62%)
    2 / 309 (0.65%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 324 (0.31%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Septic shock
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 309 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 324 (0.00%)
    2 / 309 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 309 (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
    		 ABP 215 Bevacizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    286 / 324 (88.27%)
    276 / 309 (89.32%)
    Investigations
    Weight decreased
         subjects affected / exposed
    18 / 324 (5.56%)
    16 / 309 (5.18%)
         occurrences all number
    19
    16
    Vascular disorders
    Hypertension
         subjects affected / exposed
    51 / 324 (15.74%)
    41 / 309 (13.27%)
         occurrences all number
    66
    70
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    13 / 324 (4.01%)
    25 / 309 (8.09%)
         occurrences all number
    17
    33
    Headache
         subjects affected / exposed
    28 / 324 (8.64%)
    24 / 309 (7.77%)
         occurrences all number
    30
    32
    Neuropathy peripheral
         subjects affected / exposed
    56 / 324 (17.28%)
    38 / 309 (12.30%)
         occurrences all number
    86
    60
    Paraesthesia
         subjects affected / exposed
    28 / 324 (8.64%)
    40 / 309 (12.94%)
         occurrences all number
    34
    50
    Peripheral sensory neuropathy
         subjects affected / exposed
    18 / 324 (5.56%)
    16 / 309 (5.18%)
         occurrences all number
    23
    34
    Polyneuropathy
         subjects affected / exposed
    20 / 324 (6.17%)
    22 / 309 (7.12%)
         occurrences all number
    26
    28
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    65 / 324 (20.06%)
    60 / 309 (19.42%)
         occurrences all number
    111
    92
    Leukopenia
         subjects affected / exposed
    23 / 324 (7.10%)
    23 / 309 (7.44%)
         occurrences all number
    38
    56
    Neutropenia
         subjects affected / exposed
    55 / 324 (16.98%)
    60 / 309 (19.42%)
         occurrences all number
    113
    112
    Thrombocytopenia
         subjects affected / exposed
    47 / 324 (14.51%)
    43 / 309 (13.92%)
         occurrences all number
    83
    79
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    49 / 324 (15.12%)
    42 / 309 (13.59%)
         occurrences all number
    91
    62
    Fatigue
         subjects affected / exposed
    57 / 324 (17.59%)
    59 / 309 (19.09%)
         occurrences all number
    70
    84
    Pyrexia
         subjects affected / exposed
    19 / 324 (5.86%)
    20 / 309 (6.47%)
         occurrences all number
    22
    27
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    36 / 324 (11.11%)
    36 / 309 (11.65%)
         occurrences all number
    39
    48
    Diarrhoea
         subjects affected / exposed
    39 / 324 (12.04%)
    55 / 309 (17.80%)
         occurrences all number
    51
    79
    Gingival bleeding
         subjects affected / exposed
    9 / 324 (2.78%)
    19 / 309 (6.15%)
         occurrences all number
    9
    22
    Nausea
         subjects affected / exposed
    82 / 324 (25.31%)
    95 / 309 (30.74%)
         occurrences all number
    124
    159
    Stomatitis
         subjects affected / exposed
    15 / 324 (4.63%)
    18 / 309 (5.83%)
         occurrences all number
    17
    26
    Vomiting
         subjects affected / exposed
    37 / 324 (11.42%)
    41 / 309 (13.27%)
         occurrences all number
    44
    54
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    26 / 324 (8.02%)
    21 / 309 (6.80%)
         occurrences all number
    30
    21
    Dyspnoea
         subjects affected / exposed
    24 / 324 (7.41%)
    24 / 309 (7.77%)
         occurrences all number
    26
    28
    Epistaxis
         subjects affected / exposed
    44 / 324 (13.58%)
    39 / 309 (12.62%)
         occurrences all number
    48
    60
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    140 / 324 (43.21%)
    127 / 309 (41.10%)
         occurrences all number
    167
    159
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    26 / 324 (8.02%)
    19 / 309 (6.15%)
         occurrences all number
    39
    25
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    23 / 324 (7.10%)
    29 / 309 (9.39%)
         occurrences all number
    25
    48
    Back pain
         subjects affected / exposed
    14 / 324 (4.32%)
    19 / 309 (6.15%)
         occurrences all number
    15
    22
    Bone pain
         subjects affected / exposed
    20 / 324 (6.17%)
    25 / 309 (8.09%)
         occurrences all number
    24
    33
    Myalgia
         subjects affected / exposed
    39 / 324 (12.04%)
    44 / 309 (14.24%)
         occurrences all number
    78
    76
    Pain in extremity
         subjects affected / exposed
    24 / 324 (7.41%)
    20 / 309 (6.47%)
         occurrences all number
    28
    20
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    54 / 324 (16.67%)
    42 / 309 (13.59%)
         occurrences all number
    65
    52

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Apr 2013
    The primary purposes of Amendment 1 were the following: • Modify the restrictions on chemotherapy pretreatment regimens and treatment regimens for chemotherapy-associated toxicities to accommodate differing international standards • Clarify that the scheduling of tumor assessments should be independent of treatment delays • Add an ADA sample to be collected approximately 6 months after the end of treatment visit for subjects still on study • Clarify that screening radiologic assessment must be MRI or CT and must include both the chest and abdomen • Clarify that abstinence must be true abstinence to be an acceptable method of birth control • Clarify that the study duration was approximately 25 weeks „h Specify that if chemotherapy was delayed due to toxicity, IP should be given according to the original schedule (ie, Q3W) • Clarify that the treatment period ends 21 days after the last dose of study medication or study-specified chemotherapy.
    24 Mar 2014
    The primary purposes of Amendment 2 were the following: • Clarify the entry criteria to o more clearly specify the exclusionary periods for certain medical histories o specify that subjects with low dose anti-coagulation therapy for peripheral port patency were permitted • Revised the primary analysis to be based on the ITT analysis set and updated power calculations. • Clarify the definition of end of the clinical study as 21 days after the last subject on study receives the last dose of IP and/or chemotherapy • Clarify and update the recommended dose adjustments • Update the definition of DOR to reflect that response confirmation is not required and to specify that response and progression were defined by modified RECIST v1.1 • Specify that CT or MRI performed as routine standard of care, prior to the subject signing informed consent, could be used for screening purposes, as long as the assessments were performed within 28 days before randomization, and that baseline assessment (physical examination, vital signs, and clinical laboratory assessments) could be performed 1 day before treatment.

    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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