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    Clinical Trial Results:
    A Phase II pilot study to assess efficacy and safety of capecitabine and irinotecan plus bevacizumab followed by capecitabine and oxaliplatin plus bevacizumab or the reverse sequence in patients with metastatic colorectal cancer.

    Summary
    EudraCT number
    		 2011-002191-16
    Trial protocol
    		 AT  
    Global end of trial date
    31 Aug 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 May 2019
    First version publication date
    24 May 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ML25153
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02119026
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Medizinische Universität Wien
    Sponsor organisation address
    Waehringer Guertel 18-20, Vienna, Austria, 1090
    Public contact
    Univ.Klink f. Innere Medizin I, Medizinische Universität Wien, +43 140 4005462, werner.scheithauer@meduniwien.ac.at
    Scientific contact
    Univ.Klink f. Innere Medizin I, Medizinische Universität Wien, +43 140 4005462, werner.scheithauer@meduniwien.ac.at
    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
    06 Mar 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Aug 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Aug 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Determine the efficacy of modified XELIRI (Capecitabine and Irinotecan) in combination with bevacizumab followed by XELOX (Capecitabine and Oxaliplatin) in combination with bevacizumab at progression in comparison with the reverse sequence based on duration of disease control (DDC) .
    Protection of trial subjects
    In case a patient experienced severe chemotherapy-related toxicity or progressive disease, Investigators were allowed to modify, change or interrupt the chemotherapy regimen as appropriate. Patients received full supportive care including transfusion of blood products, antibiotics, antiemetic and pain treatment, where applicable. Adverse events and adverse drug reactions were followed continuously throughout the study.
    Background therapy
    		 Not applicable
    Evidence for comparator
    		 Several phase II studies evaluated the safety and efficacy of adding bevacizumab to XELOX and XELIRI regimen in metastatic colorectal cancer. XELOX or XELIRI + bevacizumab have been investigated in several trials, but not in an approach with clearly defined cross-wise XELIRI-XELOX change criteria. The addition of bevacizumab to an approach with clearly defined cross-wise XELIRI-XELOX change criteria combined with the concept of maintenance therapy seemed an attractive option to improve the results for patients with metastatic colorectal cancer.
    Actual start date of recruitment
    12 Apr 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 120
    Worldwide total number of subjects
    120
    EEA total number of subjects
    120
    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)
    51
    From 65 to 84 years
    69
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 FPI First patient in: 12-Apr-2012 LPI Last patient in: 23-Jan-2015 Last patient last visit LPLV: 31-Aug-2017 Assessed for eligibility: 126 patients Eligible and randomized: 120 patients (58 in Arm A and 62 in Arm B)

    Pre-assignment
    Screening details
    		 126 patients with metastatic colorectal cancer (according to RECIST criteria) who did not receive systemic treatment for their metastatic disease were screened for eligibility. 6 patients did not meet inclusion criteria and/or met exclusion criteria.

    Period 1
    Period 1 title
    1st-line treatment
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A
    Arm description
    		 1st-line treatment with XELIRI+Bevacizumab for 6 months (8 cycles): capecitabine : 800mg/m2 bid d1-14, bevacizumab 7,5 mg/kg given on day 1 q3w combined with irinotecan 200mg/m2 iv. d 1 q3w followed by maintenance treatment until progression: bevacizumab (7.5 mg/kg q3w) ± capecitabine (1000 mg/m2 bid, days 1-14 q3w); in case of progression followed by 2nd-line treatment XELOX+Bevacizumab for 4 months (6 cycles).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Xeloda
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    800mg/m2 bid d1-14 for 6 months (8 cycles) and 1000 mg/m2 bid, days 1-14 q3w optional during maintenance treatment until progression

    Investigational medicinal product name
    Bevcizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    7.5 mg/kg q3w for 8 cycles and during maintenance treatment until progression

    Investigational medicinal product name
    Irinotecan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Irinotecan 200mg/m2 iv. d 1 q3w for 6 months (8 cycles)

    Arm title
    		 Arm B
    Arm description
    		 1st-line treatment with XELOX+Bevacizumab for 6 months (8 cycles): capecitabine 1000mg/m2 bid d1-14, bevacizumab 7,5 mg/kg given on d1 q3w combined with oxaliplatin 130mg/m2 iv. d 1 q3w followed by maintenance treatment until progression: bevacizumab (7.5 mg/kg q3w) ± capecitabine (1000 mg/m2 bid, days 1-14 q3w); in case of progression followed by 2nd-line treatment XELIRI+Bevacizumab for 4 months (6 cycles)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Xeloda
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1000mg/m2 bid d1-14 for 6 months (8 cycles) and 1000 mg/m2 bid, days 1-14 q3w optional during maintenance treatment until progression

    Investigational medicinal product name
    Bevcizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    7.5 mg/kg q3w for 8 cycles and during maintenance treatment until progression

    Investigational medicinal product name
    Oxaliplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    130mg/m2 iv. d 1 q3w for 6 months (8 cycles)

    Number of subjects in period 1
    		Arm A Arm B
    Started
    58
    62
    Completed
    30
    24
    Not completed
    28
    38
         Adverse event, serious fatal
    3
    6
         Consent withdrawn by subject
    4
    10
         Physician decision
    4
    8
         Surgery of metastases
    1
    -
         Adverse event, non-fatal
    6
    8
         Patient condition
    3
    4
         Complete remission until EOS
    1
    1
         Lost to follow-up
    2
    -
         Lack of efficacy
    3
    1
         Protocol deviation
    1
    -
    Period 2
    Period 2 title
    2nd-line treatment
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A
    Arm description
    		 2nd-line treatment XELOX+Bevacizumab for 4 months (6 cycles): capecitabine 1000mg/m2 bid d1-14, bevacizumab 7,5 mg/kg given on d1 q3w combined with oxaliplatin 130mg/m2 iv. d 1 q3w followed by maintenance treatment until progression: bevacizumab (7.5 mg/kg q3w) ± capecitabine (1000 mg/m2 bid, days 1-14 q3w)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Xeloda
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1000mg/m2 bid d1-14 for 4 months (6 cycles) and optional during maintenance treatment until progression

    Investigational medicinal product name
    Bevcizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    7.5 mg/kg q3w for 6 cycles and during maintenance treatment until progression

    Investigational medicinal product name
    Oxaliplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    130mg/m2 iv. d 1 q3w for 4 months (6 cycles)

    Arm title
    		 Arm B
    Arm description
    		 2nd-line treatment XELIRI+Bevacizumab for 4 months (6 cycles): capecitabine : 800mg/m2 bid d1-14, bevacizumab 7,5 mg/kg given on day 1 q3w combined with irinotecan 200mg/m2 iv. d 1 q3w followed by maintenance treatment until progression: bevacizumab (7.5 mg/kg q3w) ± capecitabine (1000 mg/m2 bid, days 1-14 q3w)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Xeloda
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    800mg/m2 bid d1-14 for 4 months (6 cycles) and 1000 mg/m2 bid, days 1-14 q3w optional during maintenance treatment until progression

    Investigational medicinal product name
    Irinotecan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Irinotecan 200mg/m2 iv. d 1 q3w for 4 months (6 cycles)

    Investigational medicinal product name
    Bevcizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    7.5 mg/kg q3w for 6 cycles and during maintenance treatment until progression

    Number of subjects in period 2
    		Arm A Arm B
    Started
    30
    24
    Completed
    23
    22
    Not completed
    7
    2
         Consent withdrawn by subject
    3
    1
         Adverse event, non-fatal
    4
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 1st-line treatment with XELIRI+Bevacizumab for 6 months (8 cycles): capecitabine : 800mg/m2 bid d1-14, bevacizumab 7,5 mg/kg given on day 1 q3w combined with irinotecan 200mg/m2 iv. d 1 q3w followed by maintenance treatment until progression: bevacizumab (7.5 mg/kg q3w) ± capecitabine (1000 mg/m2 bid, days 1-14 q3w); in case of progression followed by 2nd-line treatment XELOX+Bevacizumab for 4 months (6 cycles).

    Reporting group title
    Arm B
    Reporting group description
    		 1st-line treatment with XELOX+Bevacizumab for 6 months (8 cycles): capecitabine 1000mg/m2 bid d1-14, bevacizumab 7,5 mg/kg given on d1 q3w combined with oxaliplatin 130mg/m2 iv. d 1 q3w followed by maintenance treatment until progression: bevacizumab (7.5 mg/kg q3w) ± capecitabine (1000 mg/m2 bid, days 1-14 q3w); in case of progression followed by 2nd-line treatment XELIRI+Bevacizumab for 4 months (6 cycles)

    Reporting group values
    		 Arm A Arm B Total
    Number of subjects
    		 58 62 120
    Age categorical
    Inclusion criterion: age equal or above 18; no upper limit
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 22 29 51
        From 65-84 years
    		 36 33 69
        85 years and over
    		 0 0 0
    Gender categorical
    not applicable
    Units: Subjects
        Female
    		 19 19 38
        Male
    		 39 43 82

    End points

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    End points reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 1st-line treatment with XELIRI+Bevacizumab for 6 months (8 cycles): capecitabine : 800mg/m2 bid d1-14, bevacizumab 7,5 mg/kg given on day 1 q3w combined with irinotecan 200mg/m2 iv. d 1 q3w followed by maintenance treatment until progression: bevacizumab (7.5 mg/kg q3w) ± capecitabine (1000 mg/m2 bid, days 1-14 q3w); in case of progression followed by 2nd-line treatment XELOX+Bevacizumab for 4 months (6 cycles).

    Reporting group title
    Arm B
    Reporting group description
    		 1st-line treatment with XELOX+Bevacizumab for 6 months (8 cycles): capecitabine 1000mg/m2 bid d1-14, bevacizumab 7,5 mg/kg given on d1 q3w combined with oxaliplatin 130mg/m2 iv. d 1 q3w followed by maintenance treatment until progression: bevacizumab (7.5 mg/kg q3w) ± capecitabine (1000 mg/m2 bid, days 1-14 q3w); in case of progression followed by 2nd-line treatment XELIRI+Bevacizumab for 4 months (6 cycles)
    Reporting group title
    Arm A
    Reporting group description
    		 2nd-line treatment XELOX+Bevacizumab for 4 months (6 cycles): capecitabine 1000mg/m2 bid d1-14, bevacizumab 7,5 mg/kg given on d1 q3w combined with oxaliplatin 130mg/m2 iv. d 1 q3w followed by maintenance treatment until progression: bevacizumab (7.5 mg/kg q3w) ± capecitabine (1000 mg/m2 bid, days 1-14 q3w)

    Reporting group title
    Arm B
    Reporting group description
    		 2nd-line treatment XELIRI+Bevacizumab for 4 months (6 cycles): capecitabine : 800mg/m2 bid d1-14, bevacizumab 7,5 mg/kg given on day 1 q3w combined with irinotecan 200mg/m2 iv. d 1 q3w followed by maintenance treatment until progression: bevacizumab (7.5 mg/kg q3w) ± capecitabine (1000 mg/m2 bid, days 1-14 q3w)

    Subject analysis set title
    Arm A (1st- and 2nd-line treatment)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients randomized were included in the ITT population, if at least one dose of study medication was administered/taken after randomization. Patients were assigned to treatment groups as randomized for analysis purposes. The ITT population is used for the primary efficacy analysis (ITT analysis). For analysis of this population treatment periods 1 and 2 are considered.

    Subject analysis set title
    Arm B (1st- and 2nd-line treatment)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients randomized were included in the ITT population, if at least one dose of study medication was administered/taken after randomization. Patients were assigned to treatment groups as randomized for analysis purposes. The ITT population is used for the primary efficacy analysis (ITT analysis). For analysis of this population treatment periods 1 and 2 are considered.

    Primary: Duration of disease control DDC

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    End point title
    		 Duration of disease control DDC
    End point description
    "Efficacy of modified XELIRI (Capecitabine and Irinotecan) in combination with bevacizumab followed by XELOX (Capecitabine and Oxaliplatin) in combination with bevacizumab at progression in comparison with the reverse sequence based on DDC." The primary variable was duration of disease control (DDC) and was defined as the sum of progression free survival intervals during first line and second line treatment (= time from the beginning of first line treatment until onset of progression during second line treatment). Patients without progression at the last tumor assessment date during their study participation were censored at this last tumor assessment date (exception: availability of validated information about a later onset of progression or a longer progression free interval – in such a case the date of the follow-up assessment was either defined as the onset of progression or replaced the last tumor assessment date).
    End point type
    Primary
    End point timeframe
    From treatment start 1st-line until progression 2nd-line
    End point values
    		 Arm A (1st- and 2nd-line treatment) Arm B (1st- and 2nd-line treatment)
    Number of subjects analysed
    58
    62
    Units: Days
        median (confidence interval 95%)
    373.000 (321.520 to 424.480)
    370.000 (253.255 to 486.745)
    Attachments
    		 Primary Endpoint DDC
    Statistical analysis title
    		 Efficacy analysis DDC
    Statistical analysis description
    DDC between Arm A and Arm B. DDC was calculated by the Kaplan-Meier estimator and compared by using the Mantel-Haenszel-Log-Rank-Test. Power calculation was done too. In case of inhomogeneities of demographic or baseline variables across the arms these variables were examined in an exploratory way (proportional hazard Cox-Regression model, assumption of proportional hazards verified by Schoenfeld-residuals, time dependent Cox-Regression model, two-sided 95%-confidence-intervals for hazards)
    Comparison groups
    Arm B (1st- and 2nd-line treatment) v Arm A (1st- and 2nd-line treatment)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.967
    Method
    		 Mantel-Haenszel
    Confidence interval
    Notes
    [1] - Given the data of the ITT population the study achieved a power of 63.08% for the primary endpoint “DDC (duration of disease control)” based on a sample-size-estimation algorithm for Mantel-Haenszel-Log-Rank-Test. The data resulting from this pilot study can be used for the sample size estimation of a confirmatory trial which is designed either towards superiority or towards non-inferiority.

    Secondary: First line PFS

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    End point title
    		 First line PFS
    End point description
    The first line PFS was defined as the progression free survival interval during first line treatment. Patients without progression at the last tumor assessment date during their study participation were censored at this last tumor assessment date (exception: availability of validated information about a later onset of progression or a longer progression free interval – in such a case the date of the follow-up assessment was either defined as the onset of progression or replaced the last tumor assessment date). Missing onset of progression data because of refusal or because of death was replaced. If several response evaluations for a patient showed progressive disease (PD), the time to PD was assessed by using the first of these measurements.
    End point type
    Secondary
    End point timeframe
    From start until end of 1st-line treatment
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    58
    62
    Units: Days
        median (confidence interval 95%)
    241.000 (203.841 to 278.159)
    280.000 (233.398 to 326.602)
    Attachments
    		 Secondary Endpoint 1st-line PFS
    Statistical analysis title
    		 Efficacy analysis first-line PFS
    Statistical analysis description
    Survival functions were calculated by the Kaplan-Meier estimator and compared by using the Mantel-Haenszel-Log-Rank-Test. For variables representing a proportion of patients achieving a given clinical endpoint, cumulative incidences over time were estimated by the Kaplan-Meier method.
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.474
    Method
    		 Mantel-Haenszel
    Confidence interval

    Secondary: Second-Line PFS

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    End point title
    		 Second-Line PFS
    End point description
    The second line PFS was defined as the progression free survival interval during second line treatment. Patients without progression at the last tumor assessment date during their study participation were censored at this last tumor assessment date (exception: availability of validated information about a later onset of progression or a longer progression free interval – in such a case the date of the follow-up assessment was either defined as the onset of progression or replaced the last tumor assessment date). Missing onset of progression data because of refusal or because of death was replaced. If several response evaluations for a patient showed progressive disease (PD), the time to PD was assessed by using the first of these measurements.
    End point type
    Secondary
    End point timeframe
    Start of 2nd-line treatment until progression
    End point values
    		 Arm A (1st- and 2nd-line treatment) Arm B (1st- and 2nd-line treatment)
    Number of subjects analysed
    32
    24
    Units: Days
        median (confidence interval 95%)
    129.000 (60.340 to 197.660)
    155.000 (108.190 to 201.810)
    Attachments
    		 Secondary Endpoint 2nd-line PFS
    Statistical analysis title
    		 Efficacy analysis second-line PFS
    Statistical analysis description
    Survival functions were calculated by the Kaplan-Meier estimator and compared by using the Mantel-Haenszel-Log-Rank-Test. For variables representing a proportion of patients achieving a given clinical endpoint, cumulative incidences over time were estimated by the Kaplan-Meier method.
    Comparison groups
    Arm A (1st- and 2nd-line treatment) v Arm B (1st- and 2nd-line treatment)
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.464
    Method
    		 Mantel-Haenszel
    Confidence interval

    Secondary: Overall response rate

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    End point title
    		 Overall response rate
    End point description
    The rate of overall response was measured as the response rate from randomization until the day of documented complete response (CR) or partial response (PR) (whichever status is recorded first).
    End point type
    Secondary
    End point timeframe
    Start of 1st-line treatment until end of 2nd-line treatment
    End point values
    		 Arm A (1st- and 2nd-line treatment) Arm B (1st- and 2nd-line treatment)
    Number of subjects analysed
    58
    62
    Units: number
        Event
    32
    36
        No Event
    26
    26
    Attachments
    		 Secondary Endpoint Overall response rate
    Statistical analysis title
    		 Efficacy analysis overall response rate
    Statistical analysis description
    For categorical data the Fisher’s Exact Test (2 x 2 tables) or the generalization of the Fisher’s Exact test for n x m tables were used.
    Comparison groups
    Arm A (1st- and 2nd-line treatment) v Arm B (1st- and 2nd-line treatment)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.854
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Time to response

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    End point title
    		 Time to response
    End point description
    Time to overall response was measured from the time of randomization until the day of documented complete response (CR) or partial response (PR) (whichever status is recorded first). Patients without response were censored at the date of the last tumor assessment, the date of death or the date of refusal.
    End point type
    Secondary
    End point timeframe
    From start of 1st-line treatment until end of 2nd-line treatment
    End point values
    		 Arm A (1st- and 2nd-line treatment) Arm B (1st- and 2nd-line treatment)
    Number of subjects analysed
    58
    62
    Units: Days
        median (confidence interval 95%)
    185.000 (97.423 to 272.577)
    178.000 (127.949 to 228.051)
    Attachments
    		 Secondary Endpoint Time to response
    Statistical analysis title
    		 Efficacy analysis time to response
    Statistical analysis description
    Survival functions were calculated by the Kaplan-Meier estimator and compared by using the Mantel-Haenszel-Log-Rank-Test. For variables representing a proportion of patients achieving a given clinical endpoint, cumulative incidences over time were estimated by the Kaplan-Meier method.
    Comparison groups
    Arm A (1st- and 2nd-line treatment) v Arm B (1st- and 2nd-line treatment)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.728
    Method
    		 Mantel-Haenszel
    Confidence interval

    Secondary: Duration of response

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    End point title
    		 Duration of response
    End point description
    Duration of overall response was measured from the time that measurement criteria are met for complete response (CR) or partial response (PR) (whichever status was recorded first) until the onset of progression. Patients without progression at the last tumor assessment date during their study participation were censored at this last tumor assessment date (exception: availability of validated information about a later onset of progression or a longer progression free interval – in such a case the date of the follow-up assessment was either defined as the onset of progression or replaced the last tumor assessment date). Missing onset of progression data because of refusal or because of death was replaced. If several response evaluations for a patient showed progressive disease (PD), the time to PD was assessed by using the first of these measurements.
    End point type
    Secondary
    End point timeframe
    From 1st-line treatment until end of 2nd-line treatment
    End point values
    		 Arm A (1st- and 2nd-line treatment) Arm B (1st- and 2nd-line treatment)
    Number of subjects analysed
    32
    36
    Units: Days
        median (confidence interval 95%)
    244.000 (166.888 to 321.112)
    315.000 (142.297 to 487.703)
    Attachments
    		 Secondary Endpoint Duration of response
    Statistical analysis title
    		 Efficacy analysis duration of response
    Statistical analysis description
    Survival functions were calculated by the Kaplan-Meier estimator and compared by using the Mantel-Haenszel-Log-Rank-Test. For variables representing a proportion of patients achieving a given clinical endpoint, cumulative incidences over time were estimated by the Kaplan-Meier method.
    Comparison groups
    Arm A (1st- and 2nd-line treatment) v Arm B (1st- and 2nd-line treatment)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.668
    Method
    		 Mantel-Haenszel
    Confidence interval

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    Overall survival was measured as the time from the randomization date to the date of death. Patients without death date were censored at the date of the last tumor assessment (exception: availability of validated information about a later exitus date or a prolonged survival – in such a case the date of the follow-up assessment was either defined as the exitus date or replaced the last tumor assessment date) or the date of refusal.
    End point type
    Secondary
    End point timeframe
    From 1st-line treatment until end of follow-up period
    End point values
    		 Arm A (1st- and 2nd-line treatment) Arm B (1st- and 2nd-line treatment)
    Number of subjects analysed
    58
    62
    Units: Days
        median (confidence interval 95%)
    593.000 (506.691 to 679.309)
    643.000 (437.227 to 848.773)
    Attachments
    		 Secondary Endpoint Overall survival
    Statistical analysis title
    		 Efficacy analysis overall survival
    Statistical analysis description
    Survival functions were calculated by the Kaplan-Meier estimator and compared by using the Mantel-Haenszel-Log-Rank-Test. For variables representing a proportion of patients achieving a given clinical endpoint, cumulative incidences over time were estimated by the Kaplan-Meier method.
    Comparison groups
    Arm A (1st- and 2nd-line treatment) v Arm B (1st- and 2nd-line treatment)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.618
    Method
    		 Mantel-Haenszel
    Confidence interval

    Secondary: Best response 1st-Line

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    End point title
    		 Best response 1st-Line
    End point description
    Best response in first line was based on the tumor assessments (based on RECIST criteria) using CT scans, MRI scans, X-ray, bone scan and clinical examination.
    End point type
    Secondary
    End point timeframe
    From start of 1st-line treatment until end of 1st-line treatment
    End point values
    		 Arm A (1st- and 2nd-line treatment) Arm B (1st- and 2nd-line treatment)
    Number of subjects analysed
    53
    54
    Units: number
        Progressive Disease (PD)
    4
    1
        Stable Disease (SD)
    21
    23
        Partial Response (PR)
    26
    30
        Complete Response (CR)
    2
    0
    Attachments
    		 Secondary Endpoint Best response 1st-line
    Statistical analysis title
    		 Efficacy Analysis Best Response 1st line
    Statistical analysis description
    For ordinal data the exact Mann-Whitney-U-Test was used.
    Comparison groups
    Arm A (1st- and 2nd-line treatment) v Arm B (1st- and 2nd-line treatment)
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.792
    Method
    		 exact Mann-Whitney-U test
    Confidence interval

    Secondary: Best response 2nd-line

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    End point title
    		 Best response 2nd-line
    End point description
    Best response in second line was based on the tumor assessments (based on RECIST criteria) using CT scans, MRI scans, X-ray, bone scan and clinical examination.
    End point type
    Secondary
    End point timeframe
    From start of 2nd-line treatment until progression during 2nd-line treatment or follow-up
    End point values
    		 Arm A (1st- and 2nd-line treatment) Arm B (1st- and 2nd-line treatment)
    Number of subjects analysed
    24
    23
    Units: number
        Progressive Disease (PD)
    7
    8
        Stable Disease (SD)
    11
    13
        Partial Response (PR)
    6
    2
        Complete Response (CR)
    0
    0
    Attachments
    		 Secondary Endpoint Best response 2nd-line
    Statistical analysis title
    		 Efficacy analysis best response 2nd-line
    Statistical analysis description
    For ordinal data the exact Mann-Whitney-U-Test was used.
    Comparison groups
    Arm A (1st- and 2nd-line treatment) v Arm B (1st- and 2nd-line treatment)
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.371
    Method
    		 exact Mann-Whitney-U test
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From enrollment until 28 days of last study treatment for the individual patient. Adverse events/serious adverse events were collected until last patient last visit (31-Aug-2017); database snapshot was done after data cleaning (28-Nov-2018).
    Adverse event reporting additional description
    Clarification regarding threshold for reporting non-serious adverse events: if more than 5 % of patients within on reporting group were affected, non-serious adverse event was reported (more than 3 patients within Arm A and/or Arm B).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 1st-line treatment with XELIRI+Bevacizumab for 6 months (8 cycles): capecitabine : 800mg/m2 bid d1-14, bevacizumab 7,5 mg/kg given on day 1 q3w combined with irinotecan 200mg/m2 iv. d 1 q3w followed by maintenance treatment until progression: bevacizumab (7.5 mg/kg q3w) ± capecitabine (1000 mg/m2 bid, days 1-14 q3w); in case of progression followed by 2nd-line treatment XELOX+Bevacizumab for 4 months (6 cycles).

    Reporting group title
    Arm B
    Reporting group description
    		 1st-line treatment with XELOX+Bevacizumab for 6 months (8 cycles): capecitabine 1000mg/m2 bid d1-14, bevacizumab 7,5 mg/kg given on d1 q3w combined with oxaliplatin 130mg/m2 iv. d 1 q3w followed by maintenance treatment until progression: bevacizumab (7.5 mg/kg q3w) ± capecitabine (1000 mg/m2 bid, days 1-14 q3w); in case of progression followed by 2nd-line treatment XELIRI+Bevacizumab for 4 months (6 cycles)

    Serious adverse events
    		 Arm A Arm B
    Total subjects affected by serious adverse events
         subjects affected / exposed
    43 / 58 (74.14%)
    51 / 62 (82.26%)
         number of deaths (all causes)
    4
    8
         number of deaths resulting from adverse events
    3
    7
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Laryngeal cancer
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to abdominal wall
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Colectomy
    Additional description: Curative surgery for residual primary tumor of metastatic colorectal cancer (mCRC)
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colostomy
    Additional description: Curative surgery for residual primary tumor of metastatic colorectal cancer (mCRC)
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatectomy
    Additional description: Unplanned curative surgery of hepatic metastases of colorectal cancer (mCRC)
         subjects affected / exposed
    6 / 58 (10.34%)
    8 / 62 (12.90%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung lobectomy
    Additional description: Unplanned curative surgery of lung metastases of colorectal cancer (mCRC)
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctectomy
    Additional description: Curative surgery for residual primary tumor of metastatic colorectal cancer (mCRC)
         subjects affected / exposed
    2 / 58 (3.45%)
    2 / 62 (3.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctocolectomy
    Additional description: Curative surgery for residual primary tumor of metastatic colorectal cancer (mCRC)
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary resection
    Additional description: Unplanned curative surgery of lung metastases of colorectal cancer (mCRC)
         subjects affected / exposed
    2 / 58 (3.45%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salpingo-oophorectomy bilateral
    Additional description: Surgery of metastasis of colorectal cancer
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sigmoidectomy
    Additional description: Curative surgery for residual primary tumor of metastatic colorectal cancer (mCRC)
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thermal ablation
    Additional description: Unplanned curative surgery of lung metastases of colorectal cancer (mCRC)
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    2 / 58 (3.45%)
    5 / 62 (8.06%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Performance status decreased
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 58 (1.72%)
    4 / 62 (6.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulcer
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Allergic reaction
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dysphonia
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hiccups
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    6 / 58 (10.34%)
    8 / 62 (12.90%)
         occurrences causally related to treatment / all
    7 / 7
    6 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Psychiatric disorders
    Completed suicide
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Confusional state
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Panic attack
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Body temperature increased
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical condition
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight increased
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         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
    Gastrointestinal stoma necrosis
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Scapula fracture
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stoma site inflammation
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Intestinal atresia
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 58 (1.72%)
    2 / 62 (3.23%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiplegia
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Restless legs syndrome
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    3 / 58 (5.17%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemolytic anaemia
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 58 (3.45%)
    3 / 62 (4.84%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 58 (3.45%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    4 / 58 (6.90%)
    5 / 62 (8.06%)
         occurrences causally related to treatment / all
    4 / 4
    5 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer perforation
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    2 / 58 (3.45%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incarcerated inguinal hernia
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 58 (0.00%)
    3 / 62 (4.84%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal perforation
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Subileus
         subjects affected / exposed
    1 / 58 (1.72%)
    2 / 62 (3.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallbladder fistula
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder perforation
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 58 (1.72%)
    2 / 62 (3.23%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bursitis
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (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
    Abdominal abscess
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Medical device site infection
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 58 (0.00%)
    2 / 62 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal abscess
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Sinusitis
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestine gangrene
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic infection
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dehydration
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm A Arm B
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    55 / 58 (94.83%)
    61 / 62 (98.39%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    13 / 58 (22.41%)
    14 / 62 (22.58%)
         occurrences all number
    23
    19
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    21 / 58 (36.21%)
    27 / 62 (43.55%)
         occurrences all number
    43
    63
    General physical health deterioration
         subjects affected / exposed
    4 / 58 (6.90%)
    3 / 62 (4.84%)
         occurrences all number
    6
    3
    Mucosal inflammation
         subjects affected / exposed
    7 / 58 (12.07%)
    6 / 62 (9.68%)
         occurrences all number
    9
    9
    Oedema
         subjects affected / exposed
    1 / 58 (1.72%)
    4 / 62 (6.45%)
         occurrences all number
    1
    8
    Pain
         subjects affected / exposed
    0 / 58 (0.00%)
    4 / 62 (6.45%)
         occurrences all number
    0
    4
    Pyrexia
         subjects affected / exposed
    3 / 58 (5.17%)
    5 / 62 (8.06%)
         occurrences all number
    5
    9
    Respiratory, thoracic and mediastinal disorders
    Dysphonia
         subjects affected / exposed
    5 / 58 (8.62%)
    5 / 62 (8.06%)
         occurrences all number
    5
    5
    Dyspnoea
         subjects affected / exposed
    6 / 58 (10.34%)
    5 / 62 (8.06%)
         occurrences all number
    7
    7
    Epistaxis
         subjects affected / exposed
    1 / 58 (1.72%)
    6 / 62 (9.68%)
         occurrences all number
    1
    7
    Psychiatric disorders
    Depression
         subjects affected / exposed
    3 / 58 (5.17%)
    4 / 62 (6.45%)
         occurrences all number
    3
    11
    Insomnia
         subjects affected / exposed
    5 / 58 (8.62%)
    3 / 62 (4.84%)
         occurrences all number
    7
    3
    Investigations
    Blood pressure increased
         subjects affected / exposed
    3 / 58 (5.17%)
    3 / 62 (4.84%)
         occurrences all number
    4
    5
    Body temperature increased
         subjects affected / exposed
    1 / 58 (1.72%)
    4 / 62 (6.45%)
         occurrences all number
    1
    4
    C-reactive protein increased
         subjects affected / exposed
    4 / 58 (6.90%)
    10 / 62 (16.13%)
         occurrences all number
    5
    15
    Weight decreased
         subjects affected / exposed
    7 / 58 (12.07%)
    14 / 62 (22.58%)
         occurrences all number
    7
    19
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    6 / 58 (10.34%)
    7 / 62 (11.29%)
         occurrences all number
    8
    9
    Headache
         subjects affected / exposed
    7 / 58 (12.07%)
    1 / 62 (1.61%)
         occurrences all number
    8
    2
    Neuropathy peripheral
         subjects affected / exposed
    6 / 58 (10.34%)
    4 / 62 (6.45%)
         occurrences all number
    7
    4
    Paraesthesia
         subjects affected / exposed
    5 / 58 (8.62%)
    7 / 62 (11.29%)
         occurrences all number
    9
    10
    Polyneuropathy
         subjects affected / exposed
    21 / 58 (36.21%)
    37 / 62 (59.68%)
         occurrences all number
    32
    90
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    8 / 58 (13.79%)
    7 / 62 (11.29%)
         occurrences all number
    14
    18
    Neutropenia
         subjects affected / exposed
    9 / 58 (15.52%)
    5 / 62 (8.06%)
         occurrences all number
    22
    8
    Thrombocytopenia
         subjects affected / exposed
    10 / 58 (17.24%)
    3 / 62 (4.84%)
         occurrences all number
    15
    3
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    8 / 58 (13.79%)
    11 / 62 (17.74%)
         occurrences all number
    9
    16
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    15 / 58 (25.86%)
    11 / 62 (17.74%)
         occurrences all number
    21
    15
    Abdominal pain upper
         subjects affected / exposed
    6 / 58 (10.34%)
    5 / 62 (8.06%)
         occurrences all number
    8
    10
    Constipation
         subjects affected / exposed
    16 / 58 (27.59%)
    14 / 62 (22.58%)
         occurrences all number
    27
    18
    Diarrhoea
         subjects affected / exposed
    32 / 58 (55.17%)
    24 / 62 (38.71%)
         occurrences all number
    64
    59
    Flatulence
         subjects affected / exposed
    2 / 58 (3.45%)
    7 / 62 (11.29%)
         occurrences all number
    2
    8
    Nausea
         subjects affected / exposed
    21 / 58 (36.21%)
    13 / 62 (20.97%)
         occurrences all number
    38
    37
    Stomatitis
         subjects affected / exposed
    3 / 58 (5.17%)
    4 / 62 (6.45%)
         occurrences all number
    4
    7
    Vomiting
         subjects affected / exposed
    5 / 58 (8.62%)
    8 / 62 (12.90%)
         occurrences all number
    6
    8
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    18 / 58 (31.03%)
    5 / 62 (8.06%)
         occurrences all number
    25
    5
    Dry skin
         subjects affected / exposed
    2 / 58 (3.45%)
    7 / 62 (11.29%)
         occurrences all number
    2
    11
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    20 / 58 (34.48%)
    22 / 62 (35.48%)
         occurrences all number
    46
    53
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 58 (5.17%)
    3 / 62 (4.84%)
         occurrences all number
    4
    4
    Back pain
         subjects affected / exposed
    4 / 58 (6.90%)
    5 / 62 (8.06%)
         occurrences all number
    4
    6
    Pain in extremity
         subjects affected / exposed
    5 / 58 (8.62%)
    1 / 62 (1.61%)
         occurrences all number
    5
    1
    Infections and infestations
    Gastrointestinal infection
         subjects affected / exposed
    4 / 58 (6.90%)
    0 / 62 (0.00%)
         occurrences all number
    4
    0
    Nasopharyngitis
         subjects affected / exposed
    5 / 58 (8.62%)
    8 / 62 (12.90%)
         occurrences all number
    6
    10
    Rhinitis
         subjects affected / exposed
    3 / 58 (5.17%)
    4 / 62 (6.45%)
         occurrences all number
    3
    7
    Urinary tract infection
         subjects affected / exposed
    11 / 58 (18.97%)
    5 / 62 (8.06%)
         occurrences all number
    13
    5
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    15 / 58 (25.86%)
    11 / 62 (17.74%)
         occurrences all number
    26
    23
    Hypokalaemia
         subjects affected / exposed
    5 / 58 (8.62%)
    12 / 62 (19.35%)
         occurrences all number
    7
    20

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Jun 2013
    This change was done to clarify that first-line treatment of 6 months is corresponding with 8 cycles of chemotherapy and second-line treatment of 4 months is corresponding with 6 cycles of chemotherapy. All patients should receive the same number of cycles if tolerated. Furthermore advice was given in case of not previously done resection of colorectal tumor or if subjects become resectable regarding tumor metastases. In case of surgery of primary colorectal tumor or resection of metastases bevacizumab treatment should be interrupted 6 to 8 weeks prior to planned surgery and restarted 4 weeks after surgery. Chemotherapy treatment with oxaliplatin, irinotecan and/or capecitabine should be interrupted at least 4 weeks prior to surgery and restarted 4 weeks after surgery. Interruption of protocol treatment due to surgery of primary colorectal tumor or metastases will not result in withdrawal of subjects or change of protocol treatment dosing.
    10 Dec 2015
    Recruitment period was longer than expected (33 instead of 24 months expected) and successful treatment of patients within the different phases of the study is also longer than expected. Therefore, duration of study has to be adapted.

    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.
    not applicable
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    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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