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    Clinical Trial Results:
    Sequential first-line therapy in metastatic colorectal cancer with Capecitabine/FUFA, Irinotecan and Bevacizumab - Capecitabine/FUFA plus Bevacizumab versus Capecitabine/FUFA plus Irinotecan plus Bevacizumab as first-line therapy in metastatic colorectal cancer -

    Summary
    EudraCT number
    		 2009-013099-38
    Trial protocol
    		 DE  
    Global end of trial date
    16 Sep 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Sep 2021
    First version publication date
    29 Sep 2021
    Other versions
    Summary report(s)
    		 Final Report ACCORDING TO § 42B (2) German Drug Law

    Trial information

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    Trial identification
    Sponsor protocol code
    ML22011
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Klinikum der Universität München - Grosshadern
    Sponsor organisation address
    Marchioninistraße 15, München, Germany, 81377
    Public contact
    Medizinische Klinik III AG Onkologie, Klinikum der Universität München - Grosshadern, +49 89 4400 0, onkologiestudien@med.uni-muenchen.de
    Scientific contact
    Medizinische Klinik III AG Onkologie, Klinikum der Universität München - Grosshadern, +49 89 4400 0, onkologiestudien@med.uni-muenchen.de
    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
    27 Jan 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Sep 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Sep 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Evaluation of effectiveness in correlation to tolerability of both therapy schemes in patients with metastatic colorectal cancer without Prior therapy.
    Protection of trial subjects
    The present study was developed for those patients, who do not necessarily require treatment with primary combination chemotherapy according to the recommendations of the S3 guideline (Group 3, Schmiegel 2008). Patients with multiple metastases that are not primarily resectable and for whom the option for resection after the metastases have regressed is unlikely. The patients should be in a good general state of health (ECOG 0-1) and exhibit an oligo- or asymptomatic disease (group 3 according to the S3 guideline).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Dec 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy
    Long term follow-up duration
    		 36 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 434
    Worldwide total number of subjects
    434
    EEA total number of subjects
    434
    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)
    293
    From 65 to 84 years
    138
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Investigating an optimal first-line treatment, the current study compares a sequential escalation strategy starting with FP 1 Bev plus the addition of Iri at disease progression with initial use of the three-drug regimen (FP 1 Iri 1 Bev).

    Pre-assignment period milestones
    Number of subjects started
    		 434
    Number of subjects completed
    		 421

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Protocol deviation: 1
    Reason: Number of subjects
    		 Terminated study before treatment start: 12
    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Capecitabine plus bevacizumab
    Arm description
    		 Capecitabine: 2 x 1,250 mg/m2 Day 1-14 followed by a 1 week break Bevacizumab: 7.5 mg/kg Day 1 The regimen is repeated at 3-week intervals Treatment will be continued until progression or toxicity. If progression occurs, the scheme will be escalated: from capecitabine plus bevacizumab to XELIRI plus bevacizumab or from FUFA plus bevacizumab to FOLFIRI and bevacizumab.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Capecitabine: 2 x 1,250 mg/m2 Day 1-14 followed by a 1 week break

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Bevacizumab: 7.5 mg/kg Day 1

    Arm title
    		 5-FUFA plus bevacizumab
    Arm description
    		 Folinic acid (racemic) 400 mg/m² IV, 120 min Day 1 5-FU 400 mg/m² bolus Day 1 5-FU 2,400 mg/m² IV for 46 h Day 1-2 Bevacizumab: 5.0 mg/kg Day 1 The regimen is repeated at 2-week intervals Treatment will be continued until progression or toxicity. If progression occurs, the scheme will be escalated: from capecitabine plus bevacizumab to XELIRI plus bevacizumab or from FUFA plus bevacizumab to FOLFIRI and bevacizumab
    Arm type
    		 Active comparator

    Investigational medicinal product name
    5-FU bolus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Injection
    Dosage and administration details
    5-FU 400 mg/m² bolus Day 1

    Investigational medicinal product name
    5-FU
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    5-FU 2,400 mg/m² IV for 46 h Day 1-2

    Investigational medicinal product name
    Folinic acid (racemic)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Folinic acid (racemic) 400 mg/m² IV, 120 min Day 1

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Bevacizumab: 5.0 mg/kg Day 1

    Number of subjects in period 1 [1]
    		Capecitabine plus bevacizumab 5-FUFA plus bevacizumab
    Started
    212
    209
    Completed
    212
    209
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Transmitted numbers of subjects are correct.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Capecitabine plus bevacizumab
    Reporting group description
    		 Capecitabine: 2 x 1,250 mg/m2 Day 1-14 followed by a 1 week break Bevacizumab: 7.5 mg/kg Day 1 The regimen is repeated at 3-week intervals Treatment will be continued until progression or toxicity. If progression occurs, the scheme will be escalated: from capecitabine plus bevacizumab to XELIRI plus bevacizumab or from FUFA plus bevacizumab to FOLFIRI and bevacizumab.

    Reporting group title
    5-FUFA plus bevacizumab
    Reporting group description
    		 Folinic acid (racemic) 400 mg/m² IV, 120 min Day 1 5-FU 400 mg/m² bolus Day 1 5-FU 2,400 mg/m² IV for 46 h Day 1-2 Bevacizumab: 5.0 mg/kg Day 1 The regimen is repeated at 2-week intervals Treatment will be continued until progression or toxicity. If progression occurs, the scheme will be escalated: from capecitabine plus bevacizumab to XELIRI plus bevacizumab or from FUFA plus bevacizumab to FOLFIRI and bevacizumab

    Reporting group values
    		 Capecitabine plus bevacizumab 5-FUFA plus bevacizumab Total
    Number of subjects
    		 212 209 421
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 151 132 283
        From 65-84 years
    		 60 75 135
        85 years and over
    		 1 2 3
    Age continuous
    Units: years
        median (full range (min-max))
    		 71 (43 to 87) 69 (42 to 88) -
    Gender categorical
    Units: Subjects
        Female
    		 137 144 281
        Male
    		 75 65 140
    ECOG Performance status
    Units: Subjects
        ECOG 0
    		 127 124 251
        ECOG 1
    		 85 83 168
        unkown
    		 0 2 2
    Onset of metastases
    Units: Subjects
        Synchronous
    		 151 145 296
        Metachronous
    		 57 59 116
        Unknown
    		 4 5 9
    Site of primary tumor
    Units: Subjects
        Left (splenic flexurerectum)
    		 140 138 278
        Right (transverse coloncecum)
    		 68 64 132
        Unknown
    		 4 7 11
    No. of metastatic sites
    Units: Subjects
        1 Metastase
    		 74 75 149
        >= 2 Metastases
    		 133 126 259
        unkown
    		 5 8 13
    Fluoropyrimidine used
    Units: Subjects
        Capecitabine
    		 151 136 287
        Infusional fluorouracil
    		 61 73 134

    End points

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    End points reporting groups
    Reporting group title
    Capecitabine plus bevacizumab
    Reporting group description
    		 Capecitabine: 2 x 1,250 mg/m2 Day 1-14 followed by a 1 week break Bevacizumab: 7.5 mg/kg Day 1 The regimen is repeated at 3-week intervals Treatment will be continued until progression or toxicity. If progression occurs, the scheme will be escalated: from capecitabine plus bevacizumab to XELIRI plus bevacizumab or from FUFA plus bevacizumab to FOLFIRI and bevacizumab.

    Reporting group title
    5-FUFA plus bevacizumab
    Reporting group description
    		 Folinic acid (racemic) 400 mg/m² IV, 120 min Day 1 5-FU 400 mg/m² bolus Day 1 5-FU 2,400 mg/m² IV for 46 h Day 1-2 Bevacizumab: 5.0 mg/kg Day 1 The regimen is repeated at 2-week intervals Treatment will be continued until progression or toxicity. If progression occurs, the scheme will be escalated: from capecitabine plus bevacizumab to XELIRI plus bevacizumab or from FUFA plus bevacizumab to FOLFIRI and bevacizumab

    Primary: Time to failure of strategy

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    End point title
    		 Time to failure of strategy
    End point description
    • Time to failure of treatment strategy (TFS) will be determined as the primary endpoint. In the control arm, this corresponds to the time from randomisation to definitive progression under XELIRI/FOLFIRI + bevacizumab (PFS-1) (allowing for the possible resumption after initial response, pause of therapy and subsequent progression). In the experimental arm, an escalation to the combination XELIRI or FOLFIRI + bevacizumab can take place, if capecitabine/FUFA + bevacizumab fails (PFS-1). Failure of this treatment strategy is defined as second progression (PFS-2). • If a comparable TFS is achieved in both treatment arms, a side effect analysis will be used to help in defining the better treatment strategy. Treatment-associated toxicity will be evaluated as analysis of all grade 2-5 toxicities (according to NCI CTCAE, Version 4.0) divided by the number of treatment cycles administered during the total TFS period.
    End point type
    Primary
    End point timeframe
    the time from randomisation to definitive progression under XELIRI/FOLFIRI + bevacizumab (PFS-1) . In the experimental arm, an escalation to the combination XELIRI or FOLFIRI + bevacizumab can take place, if capecitabine/FUFA + bevacizumab fails (PFS-1)
    End point values
    		 Capecitabine plus bevacizumab 5-FUFA plus bevacizumab
    Number of subjects analysed
    194
    186
    Units: months
        median (confidence interval 90%)
    9.6 (8.6 to 10.6)
    9.9 (8.8 to 10.6)
    Attachments
    		 Kaplan-Meier-TFS
    Statistical analysis title
    		 TFS
    Comparison groups
    Capecitabine plus bevacizumab v 5-FUFA plus bevacizumab
    Number of subjects included in analysis
    380
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.86
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 1.02
    Variability estimate
    Standard deviation

    Secondary: Response Data

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    End point title
    		 Response Data
    End point description
    End point type
    Secondary
    End point timeframe
    • Overall survival (OS) in both treatment arms, including 60-day mortality • PFS-1 (progression-free survival) in both treatment arms (decentralised recording by study sites)
    End point values
    		 Capecitabine plus bevacizumab 5-FUFA plus bevacizumab
    Number of subjects analysed
    212
    209
    Units: months
    median (confidence interval 95%)
        OS
    21.9 (20.2 to 25.0)
    23.5 (20.9 to 27.9)
        PFS-1
    8.0 (6.9 to 9.9)
    9.9 (8.7 to 10.9)
    Statistical analysis title
    		 Overall Response Rate - ORR
    Comparison groups
    Capecitabine plus bevacizumab v 5-FUFA plus bevacizumab
    Number of subjects included in analysis
    421
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 = 0.005
    Method
    		 Logrank
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.34
         upper limit
    		 0.74
    Variability estimate
    Standard deviation
    Statistical analysis title
    		 Progression Free Survival - PFS1
    Comparison groups
    Capecitabine plus bevacizumab v 5-FUFA plus bevacizumab
    Number of subjects included in analysis
    421
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 < 0.001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.57
         upper limit
    		 0.85
    Variability estimate
    Standard deviation
    Statistical analysis title
    		 Overall Survival - OS
    Comparison groups
    Capecitabine plus bevacizumab v 5-FUFA plus bevacizumab
    Number of subjects included in analysis
    421
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 = 0.14
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 1.06
    Variability estimate
    Standard deviation

    Secondary: objective response rate (ORR)

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    End point title
    		 objective response rate (ORR)
    End point description
    End point type
    Secondary
    End point timeframe
    • Response rate (ORR) (decentralised recording by study sites)
    End point values
    		 Capecitabine plus bevacizumab 5-FUFA plus bevacizumab
    Number of subjects analysed
    212
    209
    Units: subjects
        CR/PR
    80
    117
    Statistical analysis title
    		 Objective Response Rate - ORR
    Comparison groups
    5-FUFA plus bevacizumab v Capecitabine plus bevacizumab
    Number of subjects included in analysis
    421
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 = 0.0002
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.477
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.323
         upper limit
    		 0.704
    Variability estimate
    Standard deviation

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events include all events that occur in a patient / participant in a clinical study following administration of a medicinal product. A causal association with this treatment is not a requirement here.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.1
    Reporting groups
    Reporting group title
    Capecitabine plus bevacizumab
    Reporting group description
    		 Capecitabine: 2 x 1,250 mg/m2 Day 1-14 followed by a 1 week break Bevacizumab: 7.5 mg/kg Day 1 The regimen is repeated at 3-week intervals Treatment will be continued until progression or toxicity. If progression occurs, the scheme will be escalated: from capecitabine plus bevacizumab to XELIRI plus bevacizumab or from FUFA plus bevacizumab to FOLFIRI and bevacizumab.

    Reporting group title
    5-FUFA plus bevacizumab
    Reporting group description
    		 Folinic acid (racemic) 400 mg/m² IV, 120 min Day 1 5-FU 400 mg/m² bolus Day 1 5-FU 2,400 mg/m² IV for 46 h Day 1-2 Bevacizumab: 5.0 mg/kg Day 1 The regimen is repeated at 2-week intervals Treatment will be continued until progression or toxicity. If progression occurs, the scheme will be escalated: from capecitabine plus bevacizumab to XELIRI plus bevacizumab or from FUFA plus bevacizumab to FOLFIRI and bevacizumab

    Serious adverse events
    		 Capecitabine plus bevacizumab 5-FUFA plus bevacizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    29 / 212 (13.68%)
    68 / 210 (32.38%)
         number of deaths (all causes)
    3
    4
         number of deaths resulting from adverse events
    1
    3
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    8 / 212 (3.77%)
    4 / 210 (1.90%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hiccups
         subjects affected / exposed
    2 / 212 (0.94%)
    4 / 210 (1.90%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myopathy
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    3 / 212 (1.42%)
    6 / 210 (2.86%)
         occurrences causally related to treatment / all
    0 / 81
    2 / 103
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 212 (0.47%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    other
         subjects affected / exposed
    6 / 212 (2.83%)
    3 / 210 (1.43%)
         occurrences causally related to treatment / all
    0 / 37
    0 / 25
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Respiratory distress
         subjects affected / exposed
    2 / 212 (0.94%)
    5 / 210 (2.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 212 (0.47%)
    2 / 210 (0.95%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vomiting
         subjects affected / exposed
    4 / 212 (1.89%)
    5 / 210 (2.38%)
         occurrences causally related to treatment / all
    1 / 35
    2 / 53
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound healing complications
         subjects affected / exposed
    5 / 212 (2.36%)
    5 / 210 (2.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Chills
         subjects affected / exposed
    5 / 212 (2.36%)
    6 / 210 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    4 / 212 (1.89%)
    5 / 210 (2.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    20 / 212 (9.43%)
    19 / 210 (9.05%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fever
         subjects affected / exposed
    24 / 212 (11.32%)
    38 / 210 (18.10%)
         occurrences causally related to treatment / all
    0 / 3
    4 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    10 / 212 (4.72%)
    17 / 210 (8.10%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 7
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hand-Foot-Syndrome
         subjects affected / exposed
    26 / 212 (12.26%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 100
    0 / 61
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucositis/Stomatitis
         subjects affected / exposed
    1 / 212 (0.47%)
    2 / 210 (0.95%)
         occurrences causally related to treatment / all
    0 / 64
    1 / 50
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Social circumstances
    Sudden death
         subjects affected / exposed
    2 / 212 (0.94%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Fall
         subjects affected / exposed
    5 / 212 (2.36%)
    3 / 210 (1.43%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Withdrawal syndrome
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Enterocele
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medical device implantation
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural site reaction
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    7 / 212 (3.30%)
    2 / 210 (0.95%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood pressure increased
         subjects affected / exposed
    4 / 212 (1.89%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorder
         subjects affected / exposed
    2 / 212 (0.94%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 212 (0.47%)
    2 / 210 (0.95%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac toxicity
         subjects affected / exposed
    13 / 212 (6.13%)
    11 / 210 (5.24%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardial-ischemic event
         subjects affected / exposed
    3 / 212 (1.42%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiovascular disorder
         subjects affected / exposed
    2 / 212 (0.94%)
    4 / 210 (1.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    4 / 212 (1.89%)
    2 / 210 (0.95%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    2 / 212 (0.94%)
    3 / 210 (1.43%)
         occurrences causally related to treatment / all
    0 / 137
    1 / 135
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 212 (0.94%)
    7 / 210 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 32
    0 / 26
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    3 / 212 (1.42%)
    3 / 210 (1.43%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental disorder
         subjects affected / exposed
    2 / 212 (0.94%)
    3 / 210 (1.43%)
         occurrences causally related to treatment / all
    0 / 128
    0 / 123
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    27 / 212 (12.74%)
    18 / 210 (8.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurological disorder
         subjects affected / exposed
    5 / 212 (2.36%)
    3 / 210 (1.43%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    10 / 212 (4.72%)
    9 / 210 (4.29%)
         occurrences causally related to treatment / all
    0 / 125
    0 / 121
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    4 / 212 (1.89%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Abscesses fistulae
         subjects affected / exposed
    7 / 212 (3.30%)
    7 / 210 (3.33%)
         occurrences causally related to treatment / all
    1 / 5
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal haemorrhage
         subjects affected / exposed
    2 / 212 (0.94%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ascites
         subjects affected / exposed
    3 / 212 (1.42%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bleeding/hemorrhage
         subjects affected / exposed
    6 / 212 (2.83%)
    3 / 210 (1.43%)
         occurrences causally related to treatment / all
    0 / 44
    1 / 45
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bicarbonate decreased
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 212 (0.47%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 31
    0 / 27
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    2 / 212 (0.94%)
    11 / 210 (5.24%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematologic toxicity
         subjects affected / exposed
    5 / 212 (2.36%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 147
    0 / 161
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatologic toxicity
         subjects affected / exposed
    2 / 212 (0.94%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 128
    0 / 123
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    5 / 212 (2.36%)
    4 / 210 (1.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    26 / 212 (12.26%)
    23 / 210 (10.95%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PCO2 decreased
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PO2 decreased
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 212 (0.94%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thromboembolic event
         subjects affected / exposed
    18 / 212 (8.49%)
    21 / 210 (10.00%)
         occurrences causally related to treatment / all
    5 / 37
    4 / 33
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Thrombosis (any)
         subjects affected / exposed
    5 / 212 (2.36%)
    5 / 210 (2.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    1 / 212 (0.47%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Cholangitis
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    1 / 212 (0.47%)
    2 / 210 (0.95%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    28 / 212 (13.21%)
    46 / 210 (21.90%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    21 / 212 (9.91%)
    17 / 210 (8.10%)
         occurrences causally related to treatment / all
    1 / 111
    5 / 124
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    GI perforation
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    2 / 212 (0.94%)
    2 / 210 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    10 / 212 (4.72%)
    8 / 210 (3.81%)
         occurrences causally related to treatment / all
    1 / 10
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Intestinal ischaemia
         subjects affected / exposed
    2 / 212 (0.94%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 212 (0.47%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin reaction
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 58
    1 / 59
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus ureteric
         subjects affected / exposed
    2 / 212 (0.94%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    1 / 212 (0.47%)
    4 / 210 (1.90%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal disorder
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    2 / 212 (0.94%)
    5 / 210 (2.38%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Urinary retention
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract disorder
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (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
    Febrile infection
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fistula
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    14 / 212 (6.60%)
    16 / 210 (7.62%)
         occurrences causally related to treatment / all
    1 / 102
    1 / 102
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Capecitabine plus bevacizumab 5-FUFA plus bevacizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    212 / 212 (100.00%)
    210 / 210 (100.00%)
    Surgical and medical procedures
    Anastomotic complication
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences all number
    0
    1
    Catheter site ulcer
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Ageusia
         subjects affected / exposed
    2 / 212 (0.94%)
    4 / 210 (1.90%)
         occurrences all number
    2
    4
    Allergy
         subjects affected / exposed
    1 / 212 (0.47%)
    2 / 210 (0.95%)
         occurrences all number
    1
    2
    Alopecia
         subjects affected / exposed
    52 / 212 (24.53%)
    89 / 210 (42.38%)
         occurrences all number
    52
    89
    Anxiety
         subjects affected / exposed
    2 / 212 (0.94%)
    3 / 210 (1.43%)
         occurrences all number
    2
    3
    Bronchospasm
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences all number
    0
    1
    Cachexia
         subjects affected / exposed
    1 / 212 (0.47%)
    1 / 210 (0.48%)
         occurrences all number
    1
    1
    Chest discomfort
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences all number
    0
    0
    Death/Sudden death
         subjects affected / exposed
    2 / 212 (0.94%)
    0 / 210 (0.00%)
         occurrences all number
    2
    0
    Decreased appetite
         subjects affected / exposed
    34 / 212 (16.04%)
    43 / 210 (20.48%)
         occurrences all number
    34
    43
    Dehydration
         subjects affected / exposed
    2 / 212 (0.94%)
    11 / 210 (5.24%)
         occurrences all number
    2
    11
    Dizziness
         subjects affected / exposed
    32 / 212 (15.09%)
    26 / 210 (12.38%)
         occurrences all number
    32
    26
    Dry mouth
         subjects affected / exposed
    5 / 212 (2.36%)
    7 / 210 (3.33%)
         occurrences all number
    5
    7
    Dysgeusia
         subjects affected / exposed
    20 / 212 (9.43%)
    13 / 210 (6.19%)
         occurrences all number
    20
    13
    Dyspepsia
         subjects affected / exposed
    9 / 212 (4.25%)
    9 / 210 (4.29%)
         occurrences all number
    9
    9
    Dysphagia
         subjects affected / exposed
    4 / 212 (1.89%)
    5 / 210 (2.38%)
         occurrences all number
    4
    5
    Dysphonia
         subjects affected / exposed
    18 / 212 (8.49%)
    8 / 210 (3.81%)
         occurrences all number
    18
    8
    Dyspnoea
         subjects affected / exposed
    20 / 212 (9.43%)
    19 / 210 (9.05%)
         occurrences all number
    20
    19
    Dyspnoea exertional
         subjects affected / exposed
    5 / 212 (2.36%)
    5 / 210 (2.38%)
         occurrences all number
    5
    5
    Dysuria
         subjects affected / exposed
    1 / 212 (0.47%)
    4 / 210 (1.90%)
         occurrences all number
    1
    4
    Eating disorder
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences all number
    0
    1
    Enterocele
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences all number
    0
    1
    Eructation
         subjects affected / exposed
    1 / 212 (0.47%)
    1 / 210 (0.48%)
         occurrences all number
    1
    1
    Extravasation
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences all number
    1
    0
    Faecal incontinence
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences all number
    1
    0
    Faecaloma
         subjects affected / exposed
    1 / 212 (0.47%)
    4 / 210 (1.90%)
         occurrences all number
    1
    4
    Faeces discoloured
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    8 / 212 (3.77%)
    4 / 210 (1.90%)
         occurrences all number
    8
    4
    Feeling cold
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences all number
    0
    1
    Fistula
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences all number
    0
    1
    Flatulence
         subjects affected / exposed
    2 / 212 (0.94%)
    2 / 210 (0.95%)
         occurrences all number
    2
    2
    Flushing
         subjects affected / exposed
    1 / 212 (0.47%)
    3 / 210 (1.43%)
         occurrences all number
    1
    3
    Frequent bowel movements
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences all number
    0
    1
    Gait disturbance
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences all number
    0
    1
    General physical health deterioration
         subjects affected / exposed
    1 / 212 (0.47%)
    17 / 210 (8.10%)
         occurrences all number
    1
    17
    Haemorrhoids
         subjects affected / exposed
    4 / 212 (1.89%)
    3 / 210 (1.43%)
         occurrences all number
    4
    3
    Hallucination
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences all number
    1
    0
    Hand-foot syndrome
         subjects affected / exposed
    100 / 212 (47.17%)
    61 / 210 (29.05%)
         occurrences all number
    100
    61
    Hernia
         subjects affected / exposed
    2 / 212 (0.94%)
    0 / 210 (0.00%)
         occurrences all number
    2
    0
    Hiccups
         subjects affected / exposed
    2 / 212 (0.94%)
    4 / 210 (1.90%)
         occurrences all number
    2
    4
    Hot flush
         subjects affected / exposed
    1 / 212 (0.47%)
    1 / 210 (0.48%)
         occurrences all number
    1
    1
    Hyperaesthesia
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences all number
    0
    1
    Hypercalcaemia
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences all number
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    1 / 212 (0.47%)
    2 / 210 (0.95%)
         occurrences all number
    1
    2
    Hyperhidrosis
         subjects affected / exposed
    1 / 212 (0.47%)
    6 / 210 (2.86%)
         occurrences all number
    1
    6
    Hyperkalaemia
         subjects affected / exposed
    3 / 212 (1.42%)
    4 / 210 (1.90%)
         occurrences all number
    3
    4
    Hypertension
         subjects affected / exposed
    137 / 212 (64.62%)
    135 / 210 (64.29%)
         occurrences all number
    137
    135
    Hyperuricemia
         subjects affected / exposed
    24 / 212 (11.32%)
    25 / 210 (11.90%)
         occurrences all number
    24
    25
    Hypoaesthesia
         subjects affected / exposed
    7 / 212 (3.30%)
    9 / 210 (4.29%)
         occurrences all number
    7
    9
    Hypoalbuminaemia
         subjects affected / exposed
    2 / 212 (0.94%)
    6 / 210 (2.86%)
         occurrences all number
    2
    6
    Hypocalcaemia
         subjects affected / exposed
    7 / 212 (3.30%)
    9 / 210 (4.29%)
         occurrences all number
    7
    9
    Hypomagnesaemia
         subjects affected / exposed
    3 / 212 (1.42%)
    1 / 210 (0.48%)
         occurrences all number
    3
    1
    Hyponatraemia
         subjects affected / exposed
    5 / 212 (2.36%)
    4 / 210 (1.90%)
         occurrences all number
    5
    4
    Hypotension
         subjects affected / exposed
    4 / 212 (1.89%)
    4 / 210 (1.90%)
         occurrences all number
    4
    4
    Icterus
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences all number
    1
    0
    Ileus
         subjects affected / exposed
    10 / 212 (4.72%)
    8 / 210 (3.81%)
         occurrences all number
    10
    8
    Incisional hernia
         subjects affected / exposed
    1 / 212 (0.47%)
    1 / 210 (0.48%)
         occurrences all number
    1
    1
    Increased bronchial secretion
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences all number
    1
    0
    Inguinal hernia
         subjects affected / exposed
    1 / 212 (0.47%)
    1 / 210 (0.48%)
         occurrences all number
    1
    1
    Initial insomnia
         subjects affected / exposed
    1 / 212 (0.47%)
    2 / 210 (0.95%)
         occurrences all number
    1
    2
    International normalised ratio increased
         subjects affected / exposed
    1 / 212 (0.47%)
    1 / 210 (0.48%)
         occurrences all number
    1
    1
    Intestinal ischaemia
         subjects affected / exposed
    2 / 212 (0.94%)
    0 / 210 (0.00%)
         occurrences all number
    2
    0
    Joint swelling
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences all number
    0
    1
    Laceration
         subjects affected / exposed
    0 / 212 (0.00%)
    3 / 210 (1.43%)
         occurrences all number
    0
    3
    Lacrimation increased
         subjects affected / exposed
    4 / 212 (1.89%)
    0 / 210 (0.00%)
         occurrences all number
    4
    0
    Lipase decreased
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences all number
    1
    0
    Lipase increased
         subjects affected / exposed
    2 / 212 (0.94%)
    2 / 210 (0.95%)
         occurrences all number
    2
    2
    Malaise
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences all number
    1
    0
    Memory impairment
         subjects affected / exposed
    0 / 212 (0.00%)
    2 / 210 (0.95%)
         occurrences all number
    0
    2
    Mental disorder
         subjects affected / exposed
    128 / 212 (60.38%)
    123 / 210 (58.57%)
         occurrences all number
    128
    123
    Microangiopathy
         subjects affected / exposed
    0 / 212 (0.00%)
    2 / 210 (0.95%)
         occurrences all number
    0
    2
    Mucosal dryness
         subjects affected / exposed
    1 / 212 (0.47%)
    1 / 210 (0.48%)
         occurrences all number
    1
    1
    Mucositis/Stomatitis
         subjects affected / exposed
    64 / 212 (30.19%)
    50 / 210 (23.81%)
         occurrences all number
    64
    50
    Muscle spasms
         subjects affected / exposed
    5 / 212 (2.36%)
    6 / 210 (2.86%)
         occurrences all number
    5
    6
    Muscular weakness
         subjects affected / exposed
    1 / 212 (0.47%)
    1 / 210 (0.48%)
         occurrences all number
    1
    1
    Myopathy
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences all number
    0
    1
    Myosclerosis
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences all number
    1
    0
    Nail changes/Paronychia
         subjects affected / exposed
    6 / 212 (2.83%)
    11 / 210 (5.24%)
         occurrences all number
    6
    11
    Nasal congestion
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences all number
    0
    1
    Nasal discomfort
         subjects affected / exposed
    1 / 212 (0.47%)
    1 / 210 (0.48%)
         occurrences all number
    1
    1
    Nasal dryness
         subjects affected / exposed
    1 / 212 (0.47%)
    6 / 210 (2.86%)
         occurrences all number
    1
    6
    Nasal inflammation
         subjects affected / exposed
    2 / 212 (0.94%)
    1 / 210 (0.48%)
         occurrences all number
    2
    1
    Nausea
         subjects affected / exposed
    81 / 212 (38.21%)
    103 / 210 (49.05%)
         occurrences all number
    81
    103
    Neutropenic sepsis
         subjects affected / exposed
    1 / 212 (0.47%)
    1 / 210 (0.48%)
         occurrences all number
    1
    1
    Night sweats
         subjects affected / exposed
    2 / 212 (0.94%)
    7 / 210 (3.33%)
         occurrences all number
    2
    7
    Odynophagia
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences all number
    1
    0
    Onycholysis
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences all number
    1
    0
    Onychoclasis
         subjects affected / exposed
    7 / 212 (3.30%)
    5 / 210 (2.38%)
         occurrences all number
    7
    5
    Onychomadesis
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences all number
    0
    1
    Onychomycosis
         subjects affected / exposed
    2 / 212 (0.94%)
    3 / 210 (1.43%)
         occurrences all number
    2
    3
    Osteonecrosis
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences all number
    1
    0
    Other
         subjects affected / exposed
    37 / 212 (17.45%)
    25 / 210 (11.90%)
         occurrences all number
    37
    25
    PCO2 decreased
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences all number
    1
    0
    PO2 decreased
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences all number
    1
    0
    Pain
         subjects affected / exposed
    125 / 212 (58.96%)
    121 / 210 (57.62%)
         occurrences all number
    125
    121
    Palpitations
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences all number
    1
    0
    Performance status decreased
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences all number
    0
    1
    Pleural effusion
         subjects affected / exposed
    2 / 212 (0.94%)
    1 / 210 (0.48%)
         occurrences all number
    2
    1
    Pleurisy
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences all number
    0
    1
    Pollakiuria
         subjects affected / exposed
    0 / 212 (0.00%)
    2 / 210 (0.95%)
         occurrences all number
    0
    2
    Procedural site reaction
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences all number
    0
    1
    Productive cough
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences all number
    1
    0
    Prothrombin time prolonged
         subjects affected / exposed
    2 / 212 (0.94%)
    1 / 210 (0.48%)
         occurrences all number
    2
    1
    Respiratory distress
         subjects affected / exposed
    3 / 212 (1.42%)
    2 / 210 (0.95%)
         occurrences all number
    3
    2
    Rhinorrhoea
         subjects affected / exposed
    3 / 212 (1.42%)
    2 / 210 (0.95%)
         occurrences all number
    3
    2
    Salivary hypersecretion
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences all number
    0
    1
    Sjogren's syndrome
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences all number
    1
    0
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences all number
    1
    0
    Subileus
         subjects affected / exposed
    1 / 212 (0.47%)
    1 / 210 (0.48%)
         occurrences all number
    1
    1
    Syncope
         subjects affected / exposed
    2 / 212 (0.94%)
    7 / 210 (3.33%)
         occurrences all number
    2
    7
    Thirst
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences all number
    0
    1
    Throat tightness
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences all number
    1
    0
    Thyroid-dysregulation
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences all number
    0
    1
    Tooth extraction
         subjects affected / exposed
    2 / 212 (0.94%)
    0 / 210 (0.00%)
         occurrences all number
    2
    0
    Varicose vein
         subjects affected / exposed
    0 / 212 (0.00%)
    3 / 210 (1.43%)
         occurrences all number
    0
    3
    Vertigo
         subjects affected / exposed
    4 / 212 (1.89%)
    1 / 210 (0.48%)
         occurrences all number
    4
    1
    Vomiting
         subjects affected / exposed
    35 / 212 (16.51%)
    53 / 210 (25.24%)
         occurrences all number
    35
    53
    Weight decreased
         subjects affected / exposed
    21 / 212 (9.91%)
    25 / 210 (11.90%)
         occurrences all number
    21
    25
    Weight increased
         subjects affected / exposed
    3 / 212 (1.42%)
    6 / 210 (2.86%)
         occurrences all number
    3
    6
    Withdrawal syndrome
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences all number
    0
    1
    Immune system disorders
    Arthritis
         subjects affected / exposed
    1 / 212 (0.47%)
    1 / 210 (0.48%)
         occurrences all number
    1
    1
    Chills
         subjects affected / exposed
    5 / 212 (2.36%)
    6 / 210 (2.86%)
         occurrences all number
    5
    6
    Product issues
    Device dislocation
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences all number
    1
    0
    Device related infection
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences all number
    1
    0
    Infusional-related allergic reaction
         subjects affected / exposed
    1 / 212 (0.47%)
    2 / 210 (0.95%)
         occurrences all number
    1
    2
    Medical device implantation
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences all number
    1
    0
    Overdose
         subjects affected / exposed
    1 / 212 (0.47%)
    3 / 210 (1.43%)
         occurrences all number
    1
    3
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences all number
    1
    0
    Contusion
         subjects affected / exposed
    3 / 212 (1.42%)
    0 / 210 (0.00%)
         occurrences all number
    3
    0
    Fall
         subjects affected / exposed
    5 / 212 (2.36%)
    3 / 210 (1.43%)
         occurrences all number
    5
    3
    Femoral neck fracture
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences all number
    1
    0
    Haematoma
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences all number
    0
    1
    Hand fracture
         subjects affected / exposed
    0 / 212 (0.00%)
    2 / 210 (0.95%)
         occurrences all number
    0
    2
    Rib fracture
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences all number
    0
    1
    Sepsis
         subjects affected / exposed
    1 / 212 (0.47%)
    2 / 210 (0.95%)
         occurrences all number
    1
    2
    Wound
         subjects affected / exposed
    1 / 212 (0.47%)
    2 / 210 (0.95%)
         occurrences all number
    1
    2
    Wound healing complications
         subjects affected / exposed
    5 / 212 (2.36%)
    5 / 210 (2.38%)
         occurrences all number
    5
    5
    Congenital, familial and genetic disorders
    Erectile dysfunction
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences all number
    0
    1
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    7 / 212 (3.30%)
    2 / 210 (0.95%)
         occurrences all number
    7
    2
    Blood pressure increased
         subjects affected / exposed
    4 / 212 (1.89%)
    1 / 210 (0.48%)
         occurrences all number
    4
    1
    Cardiac disorder
         subjects affected / exposed
    2 / 212 (0.94%)
    1 / 210 (0.48%)
         occurrences all number
    2
    1
    Cardiac failure
         subjects affected / exposed
    1 / 212 (0.47%)
    2 / 210 (0.95%)
         occurrences all number
    1
    2
    Cardiac toxicity
         subjects affected / exposed
    13 / 212 (6.13%)
    11 / 210 (5.24%)
         occurrences all number
    13
    11
    Cardial-ischemic event
         subjects affected / exposed
    3 / 212 (1.42%)
    0 / 210 (0.00%)
         occurrences all number
    3
    0
    Cardiomyopathy
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences all number
    1
    0
    Cardiovascular disorder
         subjects affected / exposed
    2 / 212 (0.94%)
    4 / 210 (1.90%)
         occurrences all number
    2
    4
    Cardiovascular insufficiency
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences all number
    1
    0
    Circulatory collapse
         subjects affected / exposed
    4 / 212 (1.89%)
    2 / 210 (0.95%)
         occurrences all number
    4
    2
    Tachycardia
         subjects affected / exposed
    5 / 212 (2.36%)
    3 / 210 (1.43%)
         occurrences all number
    5
    3
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences all number
    0
    1
    Cholinergic syndrome
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences all number
    0
    1
    Convulsion
         subjects affected / exposed
    3 / 212 (1.42%)
    0 / 210 (0.00%)
         occurrences all number
    3
    0
    Disturbance in attention
         subjects affected / exposed
    0 / 212 (0.00%)
    4 / 210 (1.90%)
         occurrences all number
    0
    4
    Nervous system disorder
         subjects affected / exposed
    27 / 212 (12.74%)
    18 / 210 (8.57%)
         occurrences all number
    27
    18
    Neurological disorder
         subjects affected / exposed
    5 / 212 (2.36%)
    3 / 210 (1.43%)
         occurrences all number
    5
    3
    PNP
         subjects affected / exposed
    27 / 212 (12.74%)
    18 / 210 (8.57%)
         occurrences all number
    27
    18
    Tremor
         subjects affected / exposed
    0 / 212 (0.00%)
    2 / 210 (0.95%)
         occurrences all number
    0
    2
    Blood and lymphatic system disorders
    Abscess limb
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences all number
    1
    0
    Abscesses fistulae
         subjects affected / exposed
    7 / 212 (3.30%)
    7 / 210 (3.33%)
         occurrences all number
    7
    7
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences all number
    1
    0
    Activated partial thromboplastin time shortened
         subjects affected / exposed
    16 / 212 (7.55%)
    13 / 210 (6.19%)
         occurrences all number
    16
    13
    Ascites
         subjects affected / exposed
    3 / 212 (1.42%)
    1 / 210 (0.48%)
         occurrences all number
    3
    1
    Bleeding/hemorrhage
         subjects affected / exposed
    2 / 212 (0.94%)
    6 / 210 (2.86%)
         occurrences all number
    2
    6
    Blood albumin decreased
         subjects affected / exposed
    2 / 212 (0.94%)
    6 / 210 (2.86%)
         occurrences all number
    2
    6
    Blood bicarbonate decreased
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences all number
    1
    0
    Blood creatinine decreased
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences all number
    0
    1
    Blood creatinine increased
         subjects affected / exposed
    31 / 212 (14.62%)
    27 / 210 (12.86%)
         occurrences all number
    31
    27
    Blood glucose increased
         subjects affected / exposed
    2 / 212 (0.94%)
    1 / 210 (0.48%)
         occurrences all number
    2
    1
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences all number
    0
    1
    Blood uric acid increased
         subjects affected / exposed
    5 / 212 (2.36%)
    5 / 210 (2.38%)
         occurrences all number
    5
    5
    Blood urine present
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences all number
    1
    0
    Coagulation time prolonged
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences all number
    0
    1
    Electrolyte imbalance
         subjects affected / exposed
    27 / 212 (12.74%)
    27 / 210 (12.86%)
         occurrences all number
    27
    27
    Febrile neutropenia
         subjects affected / exposed
    3 / 212 (1.42%)
    3 / 210 (1.43%)
         occurrences all number
    3
    3
    Haematologic toxicity
         subjects affected / exposed
    147 / 212 (69.34%)
    161 / 210 (76.67%)
         occurrences all number
    147
    161
    Hyperalbuminaemia
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences all number
    0
    1
    Iron deficiency
         subjects affected / exposed
    1 / 212 (0.47%)
    1 / 210 (0.48%)
         occurrences all number
    1
    1
    Leukocytosis
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences all number
    1
    0
    Leukopenia
         subjects affected / exposed
    0 / 212 (0.00%)
    2 / 210 (0.95%)
         occurrences all number
    0
    2
    Lymphopenia
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences all number
    1
    0
    Neutropenia
         subjects affected / exposed
    0 / 212 (0.00%)
    2 / 210 (0.95%)
         occurrences all number
    0
    2
    Oedema
         subjects affected / exposed
    26 / 212 (12.26%)
    23 / 210 (10.95%)
         occurrences all number
    26
    23
    Protein total decreased
         subjects affected / exposed
    6 / 212 (2.83%)
    8 / 210 (3.81%)
         occurrences all number
    6
    8
    Proteinuria
         subjects affected / exposed
    8 / 212 (3.77%)
    10 / 210 (4.76%)
         occurrences all number
    8
    10
    Thrombocytopenia
         subjects affected / exposed
    2 / 212 (0.94%)
    1 / 210 (0.48%)
         occurrences all number
    2
    1
    Thromboembolic event
         subjects affected / exposed
    37 / 212 (17.45%)
    33 / 210 (15.71%)
         occurrences all number
    37
    33
    Thrombosis (any)
         subjects affected / exposed
    5 / 212 (2.36%)
    5 / 210 (2.38%)
         occurrences all number
    5
    5
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 212 (0.00%)
    2 / 210 (0.95%)
         occurrences all number
    0
    2
    Chromatopsia
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences all number
    1
    0
    Eye irritation
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences all number
    1
    0
    Ocular hyperaemia
         subjects affected / exposed
    2 / 212 (0.94%)
    0 / 210 (0.00%)
         occurrences all number
    2
    0
    Photophobia
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences all number
    0
    1
    Retinal detachment
         subjects affected / exposed
    1 / 212 (0.47%)
    1 / 210 (0.48%)
         occurrences all number
    1
    1
    Vision blurred
         subjects affected / exposed
    1 / 212 (0.47%)
    1 / 210 (0.48%)
         occurrences all number
    1
    1
    Visual impairment
         subjects affected / exposed
    5 / 212 (2.36%)
    1 / 210 (0.48%)
         occurrences all number
    5
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    3 / 212 (1.42%)
    10 / 210 (4.76%)
         occurrences all number
    3
    10
    Abdominal hernia
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences all number
    0
    1
    Anal haemorrhage
         subjects affected / exposed
    2 / 212 (0.94%)
    0 / 210 (0.00%)
         occurrences all number
    2
    0
    Anorectal discomfort
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences all number
    0
    1
    Cholangitis
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences all number
    1
    0
    Cholelithiasis
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences all number
    1
    0
    Cholestasis
         subjects affected / exposed
    1 / 212 (0.47%)
    2 / 210 (0.95%)
         occurrences all number
    1
    2
    Constipation
         subjects affected / exposed
    28 / 212 (13.21%)
    46 / 210 (21.90%)
         occurrences all number
    28
    46
    Diarrhoea
         subjects affected / exposed
    111 / 212 (52.36%)
    124 / 210 (59.05%)
         occurrences all number
    111
    124
    GI perforation
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences all number
    0
    1
    Gastritis
         subjects affected / exposed
    1 / 212 (0.47%)
    1 / 210 (0.48%)
         occurrences all number
    1
    1
    Gastrointestinal disorder
         subjects affected / exposed
    2 / 212 (0.94%)
    2 / 210 (0.95%)
         occurrences all number
    2
    2
    Gastrointestinal perforation
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences all number
    0
    1
    Gastrointestinal ulcer
         subjects affected / exposed
    1 / 212 (0.47%)
    1 / 210 (0.48%)
         occurrences all number
    1
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences all number
    1
    0
    Hepatobiliary disorders
    Hepatic steatosis
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences all number
    1
    0
    Hepatologic toxicity
         subjects affected / exposed
    128 / 212 (60.38%)
    123 / 210 (58.57%)
         occurrences all number
    128
    123
    Skin and subcutaneous tissue disorders
    Acneiform exanthema/Rash
         subjects affected / exposed
    16 / 212 (7.55%)
    13 / 210 (6.19%)
         occurrences all number
    16
    13
    Skin disorder
         subjects affected / exposed
    5 / 212 (2.36%)
    3 / 210 (1.43%)
         occurrences all number
    5
    3
    Skin reaction
         subjects affected / exposed
    58 / 212 (27.36%)
    59 / 210 (28.10%)
         occurrences all number
    58
    59
    Renal and urinary disorders
    Bladder discomfort
         subjects affected / exposed
    6 / 212 (2.83%)
    5 / 210 (2.38%)
         occurrences all number
    6
    5
    Calculus ureteric
         subjects affected / exposed
    2 / 212 (0.94%)
    0 / 210 (0.00%)
         occurrences all number
    2
    0
    Nitrite urine
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences all number
    1
    0
    Renal disorder
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences all number
    1
    0
    Renal failure
         subjects affected / exposed
    2 / 212 (0.94%)
    5 / 210 (2.38%)
         occurrences all number
    2
    5
    Urinary hesitation
         subjects affected / exposed
    1 / 212 (0.47%)
    1 / 210 (0.48%)
         occurrences all number
    1
    1
    Urinary retention
         subjects affected / exposed
    0 / 212 (0.00%)
    1 / 210 (0.48%)
         occurrences all number
    0
    1
    Urinary tract disorder
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences all number
    1
    0
    Endocrine disorders
    Endocrine disorder
         subjects affected / exposed
    1 / 212 (0.47%)
    1 / 210 (0.48%)
         occurrences all number
    1
    1
    Infections and infestations
    Febrile infection
         subjects affected / exposed
    1 / 212 (0.47%)
    0 / 210 (0.00%)
         occurrences all number
    1
    0
    Fever
         subjects affected / exposed
    24 / 212 (11.32%)
    38 / 210 (18.10%)
         occurrences all number
    24
    38
    Infection
         subjects affected / exposed
    102 / 212 (48.11%)
    102 / 210 (48.57%)
         occurrences all number
    102
    102

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Jul 2010
    To evaluate the tumor dynamics in all study patients, it is planned that too the follow-up examinations (every 3 months for a minimum of 36 Months after randomization) a computed tomography and a RECIST-compliant one Assessment of this carried out according to the RECIST criteria version 1.1 become. According to this amendment, these should be mandatory until the first one is established definitive progression (arm A) or the second definitive progression (arm B) respectively. Furthermore, instead of 10ml EDTA blood now 10ml PAXgene blood once at the start of the study therapy (or within the first two treatment cycles). All samples are, as described in the existing test plan in version 2.0 from 25.08.2010, sent to the central biobank at Klinikum Großhadern. In addition, this amendment indicates that the Responsibility for the area of ​​data management from the company "Scientific Service Pharma (WiSP) GmbH" to ClinAssess GmbH and that editorial changes were made throughout the test plan have been carried out (see also the test plan version 3.0 dated May 19, 2011 with highlighted changes). As part of this amendment, the study title was also modified, since the Existing study titles are not comprehensive and sufficiently precise Treatment options reflected within the study. The modified one According to the sequential (de) escalation options (the less intensive therapy arm (A) offers the possibility of escalation (after Progression), the more intensive therapy arm (B) offers the possibility of de-escalation (in the case of a stable disease state or toxicity) and can subsequently be re-escalated again (according to progression)) calculation.
    08 Feb 2013
    changes in the Formulation for study therapy made. It was the one so far existing formulation "Capecitabin" around the term "FUFA" (5-fluorouracil and Folinic acid), or the formulation "XELIRI" (capecitabine plus irinotecan) around the Term “FOLFIRI” (5-fluorouracil, folinic acid and irinotecan) added. A detailed All changes to this are not listed. As a result of the opening of the study to the infusional fluoropyrimidine was a further secondary study endpoint formulated, as well as the inclusion and exclusion criteria customized. The primary and secondary study objectives were for the better Understanding editorially revised but the content remains unchanged. Since the study with this amendment after the approval extension for Bevacizumab for “treatment beyond progression” will be continued as soon as it comes into force of this amendment Bevacizumab is no longer made available as study product. Corresponding changes were made in the test plan. The other changes in the test plan with regard to the translational Research project can be found listed in this amendment. In addition, this amendment indicates that responsibility for the field of biometrics and statistics from the company "Wissenschaftlicher Service Pharma (WiSP) GmbH ”was transferred to ClinAssess GmbH.
    09 Jun 2015
    The present change to the study plan of the ML22011 / AIOKRK0110 study is addressed editorial changes, updating of side effects, adding new ones secondary endpoints (e.g. risk group evaluation, co-morbidity, central, pseudonymized collection and evaluation of the CT images), as well as a reduction in Sample size planning. The current design sees the non-inferiority of the "time-to-failure" as the primary endpoint. of-strategy "(= TFS) from ARM A to ARM B. Although the sequential Therapy of metastatic colorectal cancer according to the current ESMO guideline as Therapy option and therefore the comparison of a sequence and an up-front Therapy appears interesting and necessary, in our view the primary endpoint is im current scientific context of the study is not unproblematic, as we have already done in Discussed in detail at the joint ethics committee meeting in April 2015 to have. After a detailed (including statistical) consultation with you, we will apply for this Amendments propose a reduction in power from 80% to 70%: This means a Case number reduction from 506 evaluable patients to 378 evaluable patients and thus an estimated total enrollment of 420-450 patients, depending on the proportion of evaluable patients. This goal is at an average recruitment of 7-8 Patients per month and a number of patients of 396 (as of June 8, 2015) by the end of 2015 very high probability achievable. This solution leaves the study with enough sample size to answering the primary hierarchically tested hypothesis and is also a good basis to evaluate the secondary endpoints (such as PFS, OS and molecular markers) in the Within a timely justifiable process.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30388045
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