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    Clinical Trial Results:
    A randomized phase II trial assessing Sorafenib (Nexavar®) in combination with irinotecan in metastatic colorectal cancer patients with KRAS mutated tumours after failure of all active drugs known to be effective.

    Summary
    EudraCT number
    		 2012-000644-94
    Trial protocol
    		 FR  
    Global end of trial date
    28 Jul 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Apr 2023
    First version publication date
    21 Apr 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    VA_2012/01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01715441
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    INSTITUT REGIONAL DU CANCER DE MONTPELLIER Cancer de Montpellier
    Sponsor organisation address
    208 Rue des Apothicaires, Montpellier, France, 34298
    Public contact
    Madame Aurore MOUSSION, Institut régional du Cancer de Montpellier (ICM), 33 04 67 61 31 02, aurore.moussion@icm.unicancer.fr
    Scientific contact
    Madame Aurore MOUSSION, Institut régional du Cancer de Montpellier (ICM), 33 04 67 61 31 02, aurore.moussion@icm.unicancer.fr
    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
    09 Dec 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Dec 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Jul 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the median progression free survival defined as the time from randomization to disease progression according to RECIST criteria (Version 1.1) or death from any cause
    Protection of trial subjects
    In order to ensure the protection of the rights, safety and well-being of trial subjects, this clinical trial was performed in compliance with the principles laid down in the declaration of Helsinki, good Clinical Practice and European regulation.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Sep 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Safety
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 173
    Worldwide total number of subjects
    173
    EEA total number of subjects
    173
    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)
    109
    From 65 to 84 years
    64
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Baseline evaluations were performed for all patients prior to randomization to determine study eligibility.

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

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 NEXIRI
    Arm description
    		 Nexavar + Irinotecan
    Arm type
    		 Experimental

    Investigational medicinal product name
    NEXAVAR
    Investigational medicinal product code
    SORAFENIB
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400 mg twice daily (total dose 800 mg/day).

    Investigational medicinal product name
    IRINOTECAN
    Investigational medicinal product code
    IRINOTECAN
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Intravenous infusion irinotecan 120 mg/m2 over 90 minutes (D1=D15) at Cycle 1, 150 mg/m² at C2 if no diarrhea > grade 1 and no other toxicity > grade 2, and 180 mg/m² at C3 in the same conditions. 1 course = 15 days and 1 cycle = 4 weeks.

    Arm title
    		 IRINOTECAN
    Arm description
    		 Irinotecan alone
    Arm type
    		 Active comparator

    Investigational medicinal product name
    IRINOTECAN
    Investigational medicinal product code
    IRINOTECAN
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Intravenous infusion irinotecan 180 mg/m2 over 90 minutes (D1=D15) with cross over to irinotecan and sorafenib combination at progression.

    Arm title
    		 SORAFENIB
    Arm description
    		 Sorafenib alone
    Arm type
    		 Active comparator

    Investigational medicinal product name
    NEXAVAR
    Investigational medicinal product code
    SORAFENIB
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral sorafenib 400 mg twice daily (total dose 800 mg/day) with cross over to irinotecan and sorafenib combination at progression.

    Number of subjects in period 1
    		NEXIRI IRINOTECAN SORAFENIB
    Started
    59
    57
    57
    Completed
    59
    57
    57

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    NEXIRI
    Reporting group description
    		 Nexavar + Irinotecan

    Reporting group title
    IRINOTECAN
    Reporting group description
    		 Irinotecan alone

    Reporting group title
    SORAFENIB
    Reporting group description
    		 Sorafenib alone

    Reporting group values
    		 NEXIRI IRINOTECAN SORAFENIB Total
    Number of subjects
    		 59 57 57
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        median (full range (min-max))
    		 63 (35 to 81) 62 (35 to 77) 60 (31 to 82) -
    Gender categorical
    Units: Subjects
        Female
    		 24 26 23 73
        Male
    		 35 31 34 100
    Clinical exam
    Units: Subjects
        Normal
    		 44 41 43 128
        Abnormal
    		 15 14 14 43
        Missing
    		 0 2 0 2
    pT Classification
    Units: Subjects
        Tx
    		 15 8 11 34
        T1
    		 2 0 0 2
        T2
    		 4 1 4 9
        T3
    		 22 33 27 82
        T4a-T4b
    		 16 15 15 46
    pN Classification
    Units: Subjects
        Nx
    		 14 8 11 33
        N0
    		 12 6 11 29
        N1a-1b
    		 19 20 15 54
        N2a-2b
    		 14 23 20 57
    pM Classification
    Units: Subjects
        M0
    		 0 1 0 1
        M1
    		 59 56 57 172
    Synchronous metastasis
    Units: Subjects
        NO
    		 19 21 19 59
        YES
    		 40 36 38 114
    Histologic type
    Units: Subjects
        Well or moderately differenciated adenocarcinoma
    		 49 48 49 146
        Poorly or undifferenciated adenocarcinoma
    		 3 2 3 8
        adenocarcinoma with unspecified differentiation
    		 5 3 1 9
        colloidal mucosal adenocarcinoma
    		 2 3 3 8
        Missing
    		 0 1 1 2
    WHO
    Units: Subjects
        OMS 0
    		 26 18 21 65
        OMS 1
    		 32 37 36 105
        OMS 2
    		 0 1 0 1
        Missing
    		 1 1 0 2
    Clinic exam
    Units: Subjects
        Normal
    		 44 41 43 128
        Abnormal
    		 15 14 14 43
        Missing
    		 0 2 0 2
    Body Mass Index
    Units: Subjects
        Underweight range
    		 7 3 3 13
        Healthy weight range
    		 24 29 26 79
        Overweight range
    		 26 24 24 74
        Obese range
    		 1 1 2 4
        Missing
    		 1 0 2 3
    History
    Units: Subjects
        No
    		 18 20 25 63
        Yes
    		 41 37 32 110
    Initial symptoms
    Units: Subjects
        No
    		 24 15 16 55
        Yes
    		 35 42 41 118
    Maximal grade symptom
    Units: Subjects
        Grade 0
    		 24 15 16 55
        Grade 1
    		 20 14 17 51
        Grade 2
    		 11 23 19 53
        Grade 3
    		 4 5 5 14
    Concomitant treatment for symptom
    Units: Subjects
        No
    		 18 16 24 58
        Yes
    		 17 26 17 60
        Not applicable
    		 24 15 16 55
    Primary tumor location
    Units: Subjects
        Left colon
    		 34 23 26 83
        Right colon
    		 25 23 19 67
        Other
    		 0 11 12 23
    Metastasis
    Units: Subjects
        Synchronous
    		 40 36 40 116
        Metachronous
    		 19 21 17 57
    Previous adjuvant chemotherapy
    Units: Subjects
        Adjuvant chemotherapy
    		 29 29 27 85
        No adjuvant chemotherapy
    		 30 28 30 88
    Previous palliative chemotherapy
    Units: Subjects
        Palliative line
    		 52 51 52 155
        No palliative line
    		 7 6 5 18
    Ras mutation location
    Units: Subjects
        Kras
    		 50 51 51 152
        Nras
    		 2 1 0 3
        Location not done
    		 7 5 6 18
    Ras mutation location by exon
    Units: Subjects
        KRAS : exon 2
    		 49 50 49 148
        KRAS : exon 3
    		 0 1 2 3
        RAS : exon 4
    		 1 0 0 1
        NRAS : exon 2
    		 1 1 0 2
        NRAS : exon 3
    		 1 0 0 1
        Location not done
    		 7 5 6 18
    Weight
    Units: kilogram(s)
        median (full range (min-max))
    		 70.5 (42 to 110) 68.5 (43.8 to 107) 70.5 (45 to 112) -
    Height
    Units: centimetre
        median (full range (min-max))
    		 169 (153 to 183) 170 (145 to 195) 170.5 (152 to 186) -
    Body surface area
    Units: square metre
        median (full range (min-max))
    		 1.79 (1.39 to 2.21) 1.79 (1.32 to 2.19) 1.85 (1.41 to 2.29) -

    End points

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    End points reporting groups
    Reporting group title
    NEXIRI
    Reporting group description
    		 Nexavar + Irinotecan

    Reporting group title
    IRINOTECAN
    Reporting group description
    		 Irinotecan alone

    Reporting group title
    SORAFENIB
    Reporting group description
    		 Sorafenib alone

    Subject analysis set title
    Efficacy ARM A
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All randomized patients who started chemotherapy treatment, assigned to the arm where they were actually treated.

    Subject analysis set title
    Global survival ARM A
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients randomized and counted in the treatment arm in which they were randomized.

    Subject analysis set title
    Tolerance
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients randomized and counted in the treatment arm in which they were randomized.

    Subject analysis set title
    Efficacy ARM B
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All randomized patients who started chemotherapy treatment, assigned to the arm where they were actually treated.

    Subject analysis set title
    Efficacy ARM C
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All patients randomized and counted in the treatment arm in which they were randomized.

    Subject analysis set title
    Efficacy after crossover (ARM B + ARM C)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients randomized and counted in the treatment arm in which they were randomized.

    Subject analysis set title
    Global survival ARM B
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients randomized and counted in the treatment arm in which they were randomized.

    Subject analysis set title
    Global survival ARM C
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients randomized and counted in the treatment arm in which they were randomized.

    Subject analysis set title
    Progression-free survival ARM A
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients randomized and counted in the treatment arm in which they were randomized.

    Subject analysis set title
    Progression-free survival ARM B
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients randomized and counted in the treatment arm in which they were randomized.

    Subject analysis set title
    Progression-free survival ARM C
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients randomized and counted in the treatment arm in which they were randomized.

    Primary: Non-progression rate

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    End point title
    		 Non-progression rate [1]
    End point description
    End point type
    Primary
    End point timeframe
    2 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed for endpoints.
    End point values
    		 Efficacy ARM A Efficacy ARM B Efficacy ARM C Efficacy after crossover (ARM B + ARM C)
    Number of subjects analysed
    57
    56
    57
    69
    Units: percent
        number (not applicable)
    52.6
    21.4
    19.3
    42
    No statistical analyses for this end point

    Secondary: Disease control rate

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    End point title
    		 Disease control rate
    End point description
    End point type
    Secondary
    End point timeframe
    Overall treatment
    End point values
    		 Efficacy ARM A Efficacy ARM B Efficacy ARM C Efficacy after crossover (ARM B + ARM C)
    Number of subjects analysed
    57
    56
    57
    69
    Units: percent
        number (not applicable)
    50.9
    23.2
    19.3
    42
    No statistical analyses for this end point

    Secondary: Progression-free survival

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    End point title
    		 Progression-free survival
    End point description
    End point type
    Secondary
    End point timeframe
    Overall study
    End point values
    		 Progression-free survival ARM A Progression-free survival ARM B Progression-free survival ARM C
    Number of subjects analysed
    59
    57
    57
    Units: month
        median (confidence interval 95%)
    3.6 (2 to 4.2)
    1.7 (1.7 to 1.8)
    2 (1.8 to 2.3)
    Attachments
    		 Progression-free survival curve
    Kaplan-Meier curve
    No statistical analyses for this end point

    Secondary: Global survival

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    End point title
    		 Global survival
    End point description
    End point type
    Secondary
    End point timeframe
    Overall study
    End point values
    		 Global survival ARM A Global survival ARM B Global survival ARM C
    Number of subjects analysed
    59
    57
    57
    Units: Months
        median (confidence interval 95%)
    7.2 (6 to 9)
    6.3 (5 to 8)
    5.6 (4 to 8)
    No statistical analyses for this end point

    Secondary: Median irinotecan relative dose-intensity

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    End point title
    		 Median irinotecan relative dose-intensity [2]
    End point description
    End point type
    Secondary
    End point timeframe
    During chemotherapy
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was performed for endpoints.
    End point values
    		 NEXIRI IRINOTECAN
    Number of subjects analysed
    59
    57
    Units: percent
        median (confidence interval 95%)
    76.3 (48 to 103)
    101.8 (51 to 108)
    No statistical analyses for this end point

    Secondary: Median Sorafenib relative dose-intensity

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    End point title
    		 Median Sorafenib relative dose-intensity [3]
    End point description
    End point type
    Secondary
    End point timeframe
    During Chemotherapy
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was performed for endpoints.
    End point values
    		 NEXIRI SORAFENIB
    Number of subjects analysed
    59
    57
    Units: percent
        median (confidence interval 95%)
    74.6 (21 to 118)
    77.7 (26 to 101)
    No statistical analyses for this end point

    Secondary: Grade 3-4 adverse events of any kind

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    End point title
    		 Grade 3-4 adverse events of any kind
    End point description
    End point type
    Secondary
    End point timeframe
    During chemotherapy
    End point values
    		 NEXIRI IRINOTECAN SORAFENIB
    Number of subjects analysed
    57
    56
    57
    Units: Subjects
        Grade 3-4 adverse events of any kind
    48
    33
    48
        No grade 3-4 adverse events of any kind
    9
    23
    9
    No statistical analyses for this end point

    Secondary: Grade 3-4 gastrointestinal adverse events

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    End point title
    		 Grade 3-4 gastrointestinal adverse events
    End point description
    End point type
    Secondary
    End point timeframe
    During chemotherapy
    End point values
    		 NEXIRI IRINOTECAN SORAFENIB
    Number of subjects analysed
    57
    56
    57
    Units: Subjects
        Grade 3-4 gastrointestinal adverse events
    20
    7
    13
        No Grade 3-4 gastrointestinal adverse events
    37
    49
    44
    No statistical analyses for this end point

    Other pre-specified: Progression-free survival according to genotype of cycline D1

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    End point title
    		 Progression-free survival according to genotype of cycline D1
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Overall study
    End point values
    		 Progression-free survival ARM A Progression-free survival ARM B Progression-free survival ARM C
    Number of subjects analysed
    45
    45
    40
    Units: months
    median (confidence interval 95%)
        Cycline D1 polymorphism A/A
    5.3 (1.6 to 5.7)
    1.7 (0.8 to 2.0)
    1.9 (1.6 to 3.9)
        Cycline D1 polymorphism other than A/A
    3.1 (1.9 to 4.9)
    1.7 (1.6 to 1.8)
    1.9 (1.7 to 2.1)
    No statistical analyses for this end point

    Other pre-specified: Global survival according to genotype of Cycline D1

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    End point title
    		 Global survival according to genotype of Cycline D1
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Overall study
    End point values
    		 Global survival ARM A Global survival ARM B Global survival ARM C
    Number of subjects analysed
    45
    45
    40
    Units: Months
    median (confidence interval 95%)
        Cycline D1 polymorphism A/A
    19.6 (4.8 to 19.6)
    9 (1.4 to 11.7)
    8.1 (3.0 to 13.9)
        Cycline D1 polymorphism other than A/A
    7 (5.0 to 9.4)
    6.2 (3.8 to 7.7)
    4.4 (3.6 to 7.5)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    During treatment then until 6 months after the end of treatment.
    Adverse event reporting additional description
    Analyses are performed on randomized patients who started chemotherapy treatment. Therefore, three patients who did not receive any treatment (chemotherapy) are excluded. Each patient is assigned to the treatment arm actually received.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    4
    Reporting groups
    Reporting group title
    ARM A : NEXIRI
    Reporting group description
    		 Patients who were randomized in the ARM A and having received experimental treatment by NEXIRI (Nexavar + Irinotécan).

    Reporting group title
    ARM B : IRINOTECAN
    Reporting group description
    		 Patients randomized in the ARM B, Sorafenib alone.

    Reporting group title
    ARM C: SORAFENIB
    Reporting group description
    		 Patients randomized in the ARM C, Sorafenib alone.

    Reporting group title
    CROSSOVER from ARM B, C to NEXIRI
    Reporting group description
    		 The trial provides for crossover at tumor progression (documented on a TAP scan) for patients randomized to the two "monotherapy" arms. They will then receive the combination of Sorafenib and Irinotecan (NEXIRI).

    Serious adverse events
    		 ARM A : NEXIRI ARM B : IRINOTECAN ARM C: SORAFENIB CROSSOVER from ARM B, C to NEXIRI
    Total subjects affected by serious adverse events
         subjects affected / exposed
    23 / 57 (40.35%)
    17 / 56 (30.36%)
    26 / 57 (45.61%)
    17 / 69 (24.64%)
         number of deaths (all causes)
    8
    7
    13
    11
         number of deaths resulting from adverse events
    4
    5
    11
    7
    Vascular disorders
    Vena cava thrombosis
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    0 / 57 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ruptured aneurysm
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    1 / 57 (1.75%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Surgical and medical procedures
    Vertebra dorsal fracture
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    1 / 57 (1.75%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    2 / 57 (3.51%)
    1 / 56 (1.79%)
    3 / 57 (5.26%)
    3 / 69 (4.35%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
    0 / 4
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumoral fever
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    1 / 57 (1.75%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infectious fever
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    0 / 57 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    3 / 57 (5.26%)
    0 / 56 (0.00%)
    0 / 57 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Hyperthermia with urinary pain
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    1 / 57 (1.75%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Severe pain
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 56 (0.00%)
    0 / 57 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    General disorder
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 56 (0.00%)
    0 / 57 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General Health status deterioration
         subjects affected / exposed
    1 / 57 (1.75%)
    2 / 56 (3.57%)
    2 / 57 (3.51%)
    2 / 69 (2.90%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 2
    0 / 2
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    0 / 57 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax
         subjects affected / exposed
    2 / 57 (3.51%)
    0 / 56 (0.00%)
    0 / 57 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    Lung Embolism
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 56 (0.00%)
    1 / 57 (1.75%)
    2 / 69 (2.90%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 56 (0.00%)
    0 / 57 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 56 (1.79%)
    1 / 57 (1.75%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    0 / 57 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Febrile neutropenia
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 56 (0.00%)
    0 / 57 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac ischemia
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    1 / 57 (1.75%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardic infarction
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    1 / 57 (1.75%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Cardiovascular ischemia
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 56 (0.00%)
    0 / 57 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiopulmonary arrest
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    0 / 57 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Nervous system disorders
    Neurological disorder
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 56 (1.79%)
    0 / 57 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    0 / 57 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 56 (0.00%)
    2 / 57 (3.51%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 56 (0.00%)
    0 / 57 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea and vomiting
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 56 (1.79%)
    1 / 57 (1.75%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    1 / 57 (1.75%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation and vomiting
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 56 (1.79%)
    0 / 57 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 57 (3.51%)
    0 / 56 (0.00%)
    1 / 57 (1.75%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon perforation
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    1 / 57 (1.75%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 56 (1.79%)
    0 / 57 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 11
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    1 / 57 (1.75%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    icterus
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 56 (1.79%)
    0 / 57 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Subocclusion
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 56 (1.79%)
    0 / 57 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    1 / 57 (1.75%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholestatic icterus
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    1 / 57 (1.75%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    1 / 57 (1.75%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Epigastric pain
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 56 (0.00%)
    0 / 57 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    1 / 57 (1.75%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bilirubinuria
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 56 (0.00%)
    1 / 57 (1.75%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholinergic syndrome
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 56 (1.79%)
    0 / 57 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    1 / 57 (1.75%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Anal fissure
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 56 (0.00%)
    0 / 57 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Recto bladder fistula
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 56 (1.79%)
    0 / 57 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Occlusive syndrome
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 56 (1.79%)
    0 / 57 (0.00%)
    2 / 69 (2.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Skin and subcutaneous tissue disorders
    Toxic epidermal necrolysis
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 56 (0.00%)
    0 / 57 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Degradation of scar ileostomy
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    1 / 57 (1.75%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary infection with fever
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    11 / 57 (19.30%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dilatation of the renal calyx
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    0 / 57 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrostomy tube disconnection
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 56 (0.00%)
    0 / 57 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uretero hydronephrosis
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 56 (1.79%)
    0 / 57 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    0 / 57 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Joint pain
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    1 / 57 (1.75%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    1 / 57 (1.75%)
    2 / 56 (3.57%)
    2 / 57 (3.51%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 2
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    0 / 57 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 56 (1.79%)
    0 / 57 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    0 / 57 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Dehydration
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    0 / 57 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 ARM A : NEXIRI ARM B : IRINOTECAN ARM C: SORAFENIB CROSSOVER from ARM B, C to NEXIRI
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    57 / 57 (100.00%)
    56 / 56 (100.00%)
    57 / 57 (100.00%)
    69 / 69 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    9 / 57 (15.79%)
    2 / 56 (3.57%)
    11 / 57 (19.30%)
    11 / 69 (15.94%)
         occurrences all number
    19
    2
    17
    20
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    52 / 57 (91.23%)
    43 / 56 (76.79%)
    43 / 57 (75.44%)
    64 / 69 (92.75%)
         occurrences all number
    204
    90
    73
    148
    Fever
         subjects affected / exposed
    8 / 57 (14.04%)
    12 / 56 (21.43%)
    13 / 57 (22.81%)
    19 / 69 (27.54%)
         occurrences all number
    9
    18
    15
    24
    Limbs oedema
         subjects affected / exposed
    2 / 57 (3.51%)
    2 / 56 (3.57%)
    5 / 57 (8.77%)
    4 / 69 (5.80%)
         occurrences all number
    2
    3
    6
    6
    Weight decreased
         subjects affected / exposed
    22 / 57 (38.60%)
    10 / 56 (17.86%)
    16 / 57 (28.07%)
    29 / 69 (42.03%)
         occurrences all number
    51
    16
    22
    43
    Pain
         subjects affected / exposed
    38 / 57 (66.67%)
    30 / 56 (53.57%)
    35 / 57 (61.40%)
    46 / 69 (66.67%)
         occurrences all number
    18
    53
    62
    77
    Immune system disorders
    Allergic reaction
         subjects affected / exposed
    2 / 57 (3.51%)
    0 / 56 (0.00%)
    1 / 57 (1.75%)
    3 / 69 (4.35%)
         occurrences all number
    2
    0
    1
    4
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    12 / 57 (21.05%)
    5 / 56 (8.93%)
    11 / 57 (19.30%)
    7 / 69 (10.14%)
         occurrences all number
    28
    11
    13
    19
    Post nasal discharge
         subjects affected / exposed
    6 / 57 (10.53%)
    7 / 56 (12.50%)
    4 / 57 (7.02%)
    7 / 69 (10.14%)
         occurrences all number
    19
    18
    7
    10
    Epistaxis
         subjects affected / exposed
    10 / 57 (17.54%)
    4 / 56 (7.14%)
    5 / 57 (8.77%)
    8 / 69 (11.59%)
         occurrences all number
    26
    7
    7
    13
    Lung oedema
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    0 / 57 (0.00%)
    1 / 69 (1.45%)
         occurrences all number
    0
    0
    0
    1
    Cough
         subjects affected / exposed
    14 / 57 (24.56%)
    15 / 56 (26.79%)
    6 / 57 (10.53%)
    15 / 69 (21.74%)
         occurrences all number
    29
    24
    9
    21
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    7 / 57 (12.28%)
    7 / 56 (12.50%)
    4 / 57 (7.02%)
    8 / 69 (11.59%)
         occurrences all number
    14
    13
    5
    13
    Investigations
    Amylase increased
         subjects affected / exposed
    11 / 57 (19.30%)
    10 / 56 (17.86%)
    8 / 57 (14.04%)
    12 / 69 (17.39%)
         occurrences all number
    19
    11
    8
    21
    Lipase increased
         subjects affected / exposed
    14 / 57 (24.56%)
    8 / 56 (14.29%)
    10 / 57 (17.54%)
    15 / 69 (21.74%)
         occurrences all number
    30
    13
    12
    24
    White blood cell count decreased
         subjects affected / exposed
    23 / 57 (40.35%)
    12 / 56 (21.43%)
    6 / 57 (10.53%)
    14 / 69 (20.29%)
         occurrences all number
    53
    17
    7
    24
    Neutrophil count decreased
         subjects affected / exposed
    25 / 57 (43.86%)
    14 / 56 (25.00%)
    5 / 57 (8.77%)
    15 / 69 (21.74%)
         occurrences all number
    50
    18
    6
    25
    Platelet count decreased
         subjects affected / exposed
    21 / 57 (36.84%)
    14 / 56 (25.00%)
    14 / 57 (24.56%)
    12 / 69 (17.39%)
         occurrences all number
    45
    30
    20
    20
    Cardiac disorders
    Prolonged QTc
         subjects affected / exposed
    1 / 57 (1.75%)
    1 / 56 (1.79%)
    0 / 57 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Thromboembolic event
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    2 / 57 (3.51%)
    4 / 69 (5.80%)
         occurrences all number
    0
    0
    2
    4
    Infarction
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    1 / 57 (1.75%)
    1 / 69 (1.45%)
         occurrences all number
    0
    0
    1
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    11 / 57 (19.30%)
    5 / 56 (8.93%)
    4 / 57 (7.02%)
    7 / 69 (10.14%)
         occurrences all number
    26
    8
    4
    16
    Dysgeusia
         subjects affected / exposed
    5 / 57 (8.77%)
    7 / 56 (12.50%)
    3 / 57 (5.26%)
    8 / 69 (11.59%)
         occurrences all number
    8
    17
    5
    13
    Neuropathy peripheral
         subjects affected / exposed
    14 / 57 (24.56%)
    14 / 56 (25.00%)
    12 / 57 (21.05%)
    15 / 69 (21.74%)
         occurrences all number
    33
    24
    22
    25
    Paraesthesia
         subjects affected / exposed
    10 / 57 (17.54%)
    8 / 56 (14.29%)
    6 / 57 (10.53%)
    10 / 69 (14.49%)
         occurrences all number
    17
    11
    7
    16
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    40 / 57 (70.18%)
    37 / 56 (66.07%)
    29 / 57 (50.88%)
    50 / 69 (72.46%)
         occurrences all number
    91
    65
    54
    116
    Febrile neutropenia
         subjects affected / exposed
    3 / 57 (5.26%)
    0 / 56 (0.00%)
    0 / 57 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    5 / 57 (8.77%)
    2 / 56 (3.57%)
    1 / 57 (1.75%)
    2 / 69 (2.90%)
         occurrences all number
    11
    3
    1
    5
    Gastrointestinal disorders
    Anorexia
         subjects affected / exposed
    30 / 57 (52.63%)
    20 / 56 (35.71%)
    27 / 57 (47.37%)
    31 / 69 (44.93%)
         occurrences all number
    69
    37
    41
    57
    Ascites
         subjects affected / exposed
    4 / 57 (7.02%)
    1 / 56 (1.79%)
    1 / 57 (1.75%)
    5 / 69 (7.25%)
         occurrences all number
    6
    1
    1
    5
    Constipation
         subjects affected / exposed
    16 / 57 (28.07%)
    14 / 56 (25.00%)
    17 / 57 (29.82%)
    12 / 69 (17.39%)
         occurrences all number
    18
    21
    20
    16
    Diarrhoea
         subjects affected / exposed
    53 / 57 (92.98%)
    35 / 56 (62.50%)
    31 / 57 (54.39%)
    56 / 69 (81.16%)
         occurrences all number
    152
    63
    47
    126
    Dysphagia
         subjects affected / exposed
    3 / 57 (5.26%)
    4 / 56 (7.14%)
    4 / 57 (7.02%)
    6 / 69 (8.70%)
         occurrences all number
    8
    17
    5
    13
    Haemorrhoids
         subjects affected / exposed
    8 / 57 (14.04%)
    5 / 56 (8.93%)
    5 / 57 (8.77%)
    8 / 69 (11.59%)
         occurrences all number
    14
    7
    8
    11
    Mucositis/Stomatitis
         subjects affected / exposed
    19 / 57 (33.33%)
    12 / 56 (21.43%)
    14 / 57 (24.56%)
    18 / 69 (26.09%)
         occurrences all number
    30
    20
    23
    29
    Rectorrhagia
         subjects affected / exposed
    4 / 57 (7.02%)
    1 / 56 (1.79%)
    5 / 57 (8.77%)
    10 / 69 (14.49%)
         occurrences all number
    4
    1
    7
    10
    Gastrooesophageal reflux disease
         subjects affected / exposed
    7 / 57 (12.28%)
    2 / 56 (3.57%)
    6 / 57 (10.53%)
    4 / 69 (5.80%)
         occurrences all number
    13
    8
    6
    5
    Vomiting
         subjects affected / exposed
    26 / 57 (45.61%)
    16 / 56 (28.57%)
    11 / 57 (19.30%)
    20 / 69 (28.99%)
         occurrences all number
    43
    21
    16
    37
    Hepatobiliary disorders
    Hepaltagia
         subjects affected / exposed
    3 / 57 (5.26%)
    2 / 56 (3.57%)
    10 / 57 (17.54%)
    5 / 69 (7.25%)
         occurrences all number
    4
    2
    13
    8
    Skin and subcutaneous tissue disorders
    Hand and foot syndrome
         subjects affected / exposed
    24 / 57 (42.11%)
    2 / 56 (3.57%)
    35 / 57 (61.40%)
    24 / 69 (34.78%)
         occurrences all number
    74
    2
    65
    73
    Erythrodermia
         subjects affected / exposed
    7 / 57 (12.28%)
    1 / 56 (1.79%)
    4 / 57 (7.02%)
    4 / 69 (5.80%)
         occurrences all number
    9
    1
    4
    6
    Paronychia
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 56 (0.00%)
    0 / 57 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Pruritus
         subjects affected / exposed
    9 / 57 (15.79%)
    2 / 56 (3.57%)
    14 / 57 (24.56%)
    3 / 69 (4.35%)
         occurrences all number
    22
    3
    15
    6
    Rash maculo-papular
         subjects affected / exposed
    17 / 57 (29.82%)
    1 / 56 (1.79%)
    13 / 57 (22.81%)
    9 / 69 (13.04%)
         occurrences all number
    28
    1
    15
    14
    Dry skin
         subjects affected / exposed
    15 / 57 (26.32%)
    4 / 56 (7.14%)
    16 / 57 (28.07%)
    12 / 69 (17.39%)
         occurrences all number
    29
    6
    21
    26
    Alopecia
         subjects affected / exposed
    35 / 57 (61.40%)
    16 / 56 (28.57%)
    4 / 57 (7.02%)
    25 / 69 (36.23%)
         occurrences all number
    102
    32
    11
    55
    Renal and urinary disorders
    Fistula
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 56 (1.79%)
    0 / 57 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Renal failure
         subjects affected / exposed
    1 / 57 (1.75%)
    1 / 56 (1.79%)
    0 / 57 (0.00%)
    1 / 69 (1.45%)
         occurrences all number
    1
    1
    0
    1
    Urinary retention
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 56 (0.00%)
    1 / 57 (1.75%)
    0 / 69 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 57 (5.26%)
    3 / 56 (5.36%)
    4 / 57 (7.02%)
    3 / 69 (4.35%)
         occurrences all number
    8
    7
    6
    5
    Myalgia
         subjects affected / exposed
    4 / 57 (7.02%)
    4 / 56 (7.14%)
    5 / 57 (8.77%)
    4 / 69 (5.80%)
         occurrences all number
    11
    6
    5
    7
    Metabolism and nutrition disorders
    Hypocalcaemia
         subjects affected / exposed
    25 / 57 (43.86%)
    3 / 56 (5.36%)
    14 / 57 (24.56%)
    27 / 69 (39.13%)
         occurrences all number
    49
    6
    21
    44
    Hypokaliemia
         subjects affected / exposed
    13 / 57 (22.81%)
    4 / 56 (7.14%)
    7 / 57 (12.28%)
    17 / 69 (24.64%)
         occurrences all number
    19
    4
    9
    25
    Hypomagnesaemia
         subjects affected / exposed
    7 / 57 (12.28%)
    2 / 56 (3.57%)
    5 / 57 (8.77%)
    8 / 69 (11.59%)
         occurrences all number
    19
    2
    8
    10
    Hyponatraemia
         subjects affected / exposed
    15 / 57 (26.32%)
    10 / 56 (17.86%)
    17 / 57 (29.82%)
    9 / 69 (13.04%)
         occurrences all number
    20
    10
    20
    11

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Jan 2013
    -Addition of tomudex to provide a comprehensive list of molecules that can be given for the treatment of metastatic colorectal cancer. Tomudex can replace 5FU in cases of 5FU intolerance. -Acceptance of all KRAS mutated sequences so that the patient population with rare mutations is not missed for analysis. In the B and C monotherapy arms, by the time of cross-over, the patient's general condition may have deteriorated. A change from WHO = 2 at inclusion to WHO = 3 at the time of crossover will not allow these patients to be treated, which means that patients with a good general status of WHO ≤ 1 should be included in the trial. -The crossover must be performed at the time of a documented progression on the CT scan, otherwise clinicians could switch patients to arm A at the time of a rise, even small, of the markers or at the time of a small clinical evolution. -Addition of magnesium assay.
    11 Mar 2013
    -regorafenib has been granted a temporary approval in metastatic colorectal cancer. Addition of this molecule as a treatment that can be received by the patient before inclusion in the NEXIRI 2 trial.
    16 Sep 2013
    -Modification of the investigator list with the addition of various co-investigators in different centers already declared + change of the principal investigator of a center and addition of a new center.
    27 Jan 2014
    -Deletion of the circulating tumor cell (CTC) study -Addition and deletion of co-investigators -Deletion of an Investigator Centre

    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.
    The high value of 95 % interval of cycline D1 is not reported for NEXIRI arm but the database does not allow to leave an empty value so we put 20 to post results.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/32737004
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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