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    Clinical Trial Results:
    Selecting Treatment in Colorectal Cancer: Capecitabine or 5-fluorouracil Selection to be Combined With Oxaliplatin or Irinotecan as First-line Chemotherapy in Advanced Colorectal Cancer (SETICC)

    Summary
    EudraCT number
    		 2009-012562-31
    Trial protocol
    		 ES  
    Global end of trial date
    07 Nov 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Jan 2020
    First version publication date
    26 Jan 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    TTD-09-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01071655
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Grupo de Tratamiento de los Tumores Digestivos (TTD)
    Sponsor organisation address
    Plaza de Castilla, 3, 8º D- 1., Madrid, Spain, 28046
    Public contact
    Inmaculada Ruiz Mena, Grupo de Tratamiento de los Tumores Digestivos (TTD), 0034 913788275, ttd@ttdgroup.org
    Scientific contact
    Inmaculada Ruiz Mena, Grupo de Tratamiento de los Tumores Digestivos (TTD), 0034 913788275, ttd@ttdgroup.org
    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
    30 Apr 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Nov 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Nov 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The aim of the present study was to examine whether assigning first-line chemotherapy based on relevant germline polymorphisms would improve outcomes compared with treating all patients with a standard regimen. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), overall response rate (ORR; assessed using RECIST Version 1.1), proportion of patients whose disease became resectable, adverse events, and evaluation of KRAS exon 2 mutation status as a molecular prognostic marker.
    Protection of trial subjects
    Treatment was assigned depending on TYMS-3'UTR 6 bp ins/del and ERCC1-118C/T polymorphisms. Investigators were informed of treatments by automatically generated e-mails. Polymorphisms were determined for patients assigned to the control group, but these results were not needed before treatment commenced. The investigator still received an automatically generated e-mail. Treatment continued until disease progression, unacceptable toxicity, or patient withdrawal.
    Background therapy
    		 Patients assigned to the control group received bevacizumab 7.5 mg/kg on day 1 with XELOX.
    Evidence for comparator
    		 Our previous study suggested that patients harboring the TYMS-30 untranslated region (UTR) 6 bp ins/ins and ERCC1-118C/T or C/C genotypes might benefit from combining oxaliplatin with capecitabine rather than 5-FU.
    Actual start date of recruitment
    15 Feb 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 195
    Worldwide total number of subjects
    195
    EEA total number of subjects
    195
    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)
    105
    From 65 to 84 years
    88
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 Of 202 patients enrolled, 195 were treated/randomized. There were 7 screening failures (withdrawn consent, n=1; criteria violation, n=6). This was a national study with all patients being included at 31 Spanish sites.

    Pre-assignment
    Screening details
    		 Adult patients (≥18 years) with histologically confirmed colon or rectal adenocarcinoma with measurable metastatic disease, ECOG performance status 0–2, and adequate renal function. Key exclusion criteria: prior systemic treatment of metastatic disease; concomitant CVD; CNS disease, uncontrolled hypertension, bleeding diathesis, or coagulopathy.

    Period 1
    Period 1 title
    Baseline (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not applicable.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Control Group (A) (Bev+XELOX)
    Arm description
    		 Patients were randomized 1 : 2 to the control (A) or experimental (B) group. Patients assigned to the control group received bevacizumab 7.5 mg/kg on day 1 with XELOX (capecitabine 1000 mg/m2/12 h days 1-14, and oxaliplatin 130 mg/m2 on day 1). One cycle corresponds to 3 weeks of treatment.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab 7.5 mg/kg on day 1.

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Capecitabine 1000 mg/m2/12 h on days 1-14

    Investigational medicinal product name
    Oxaliplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Oxaliplatin 130 mg/m2 on day 1

    Arm title
    		 Experimental Group (B)
    Arm description
    		 Patients were randomized 1 : 2 to the control (A) or experimental (B) group. Patients assigned to the experimental group received different schedules according to the number of TYMS-3'UTR 6 bp ins/del and ERCC1-118C/T favorable genotypes: 1) Patients with no favorable genotypes (FG) (Bev+XELIRI); 2) Patients with one FG: TS 3’UTR +6bp/+6bp and ERCC1-118 T/T (Bev+XELOX); TS 3’UTR +6bp/-6bp and ERCC1-118 C/T or C/C (Bev+FUIRI); 3) Patients with two FG (Bev+FUOX).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bev+XELIRI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Bevacizumab 7.5 mg/kg on day 1 with XELIRI (capecitabine 800 mg/m2/12 h days 1-14, and irinotecan 200 mg/m2 on day 1). One cycle corresponds to 3 weeks of treatment.

    Investigational medicinal product name
    Bev+XELOX
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Bevacizumab 7.5 mg/kg on day 1 with XELOX (capecitabine 1000 mg/m2/12 h days 1-14, and oxaliplatin 130 mg/m2 on day 1). One cycle corresponds to 3 weeks of treatment.

    Investigational medicinal product name
    Bev+FUIRI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab 5 mg/kg (days 1, 15 and 29) with FUIRI (5-FU 2.250 mg/m2 in 48h-continuous infusion and irinotecan 80 mg/m2 on days 1, 8, 15, 22, 29 and 36). One cycle corresponds to 6 weeks of treatment.

    Investigational medicinal product name
    Bev+FUOX
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab 5 mg/kg (days 1, 15 and 29) with FUOX (5-FU 2.250 mg/m2 in 48h-continuous infusion on days 1, 8, 15, 22, 29 and 36; and oxaliplatin 85 mg/m2 on days 1, 15 and 29). One cycle corresponds to 6 weeks of treatment.

    Number of subjects in period 1
    		Control Group (A) (Bev+XELOX) Experimental Group (B)
    Started
    65
    130
    Completed
    61
    119
    Not completed
    4
    11
         Adverse event, serious fatal
    4
    3
         Consent withdrawn by subject
    -
    4
         Protocol deviation
    -
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Control Group (A) (Bev+XELOX)
    Reporting group description
    		 Patients were randomized 1 : 2 to the control (A) or experimental (B) group. Patients assigned to the control group received bevacizumab 7.5 mg/kg on day 1 with XELOX (capecitabine 1000 mg/m2/12 h days 1-14, and oxaliplatin 130 mg/m2 on day 1). One cycle corresponds to 3 weeks of treatment.

    Reporting group title
    Experimental Group (B)
    Reporting group description
    		 Patients were randomized 1 : 2 to the control (A) or experimental (B) group. Patients assigned to the experimental group received different schedules according to the number of TYMS-3'UTR 6 bp ins/del and ERCC1-118C/T favorable genotypes: 1) Patients with no favorable genotypes (FG) (Bev+XELIRI); 2) Patients with one FG: TS 3’UTR +6bp/+6bp and ERCC1-118 T/T (Bev+XELOX); TS 3’UTR +6bp/-6bp and ERCC1-118 C/T or C/C (Bev+FUIRI); 3) Patients with two FG (Bev+FUOX).

    Reporting group values
    		 Control Group (A) (Bev+XELOX) Experimental Group (B) Total
    Number of subjects
    		 65 130 195
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Age in years has been calculated the date of signing the informed consent
    Units: years
        arithmetic mean (standard deviation)
    		 64.4 ( 10.1 ) 63.4 ( 10.4 ) -
    Gender categorical
    Units: Subjects
        Female
    		 30 48 78
        Male
    		 35 82 117
    ECOG performance status
    Units: Subjects
        ECOG 0
    		 29 50 79
        ECOG 1
    		 34 79 113
        ECOG 2
    		 2 1 3
    Tumor location
    Units: Subjects
        Colon
    		 41 80 121
        Rectum
    		 18 38 56
        Both
    		 6 12 18
    No. of affected organs
    Units: Subjects
        1 organ
    		 25 55 80
        2 organs
    		 21 52 73
        >2 organs
    		 19 23 42
    Surgery for primary tumor
    Units: Subjects
        Yes
    		 34 73 107
        No
    		 31 57 88
    Prior adjuvant radiotherapy
    With or without prior radiotherapy
    Units: Subjects
        Yes
    		 3 7 10
        No
    		 62 123 185
    KRAS mutation
    Units: Subjects
        Wild-type
    		 31 64 95
        Mutated
    		 27 42 69
        Not available
    		 7 24 31
    Relevant prior and concomitant pathologies
    Units: Subjects
        No
    		 5 15 20
        Yes
    		 60 115 175
    Prior adjuvant chemotherapy
    Units: Subjects
        Yes
    		 9 15 24
        No
    		 56 115 171
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    		 71.4 ( 12.2 ) 71.3 ( 14.8 ) -
    Height
    Units: centimeters
        arithmetic mean (standard deviation)
    		 163.8 ( 8.6 ) 164.2 ( 10.2 ) -
    Body surface
    Units: square meter
        arithmetic mean (standard deviation)
    		 1.8 ( 0.2 ) 1.8 ( 0.2 ) -
    Duration of disease
    Time since diagnosis of primary disease until the date of signing the informed consent.
    Units: months
        arithmetic mean (standard deviation)
    		 10.1 ( 27.2 ) 5.7 ( 11.5 ) -

    End points

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    End points reporting groups
    Reporting group title
    Control Group (A) (Bev+XELOX)
    Reporting group description
    		 Patients were randomized 1 : 2 to the control (A) or experimental (B) group. Patients assigned to the control group received bevacizumab 7.5 mg/kg on day 1 with XELOX (capecitabine 1000 mg/m2/12 h days 1-14, and oxaliplatin 130 mg/m2 on day 1). One cycle corresponds to 3 weeks of treatment.

    Reporting group title
    Experimental Group (B)
    Reporting group description
    		 Patients were randomized 1 : 2 to the control (A) or experimental (B) group. Patients assigned to the experimental group received different schedules according to the number of TYMS-3'UTR 6 bp ins/del and ERCC1-118C/T favorable genotypes: 1) Patients with no favorable genotypes (FG) (Bev+XELIRI); 2) Patients with one FG: TS 3’UTR +6bp/+6bp and ERCC1-118 T/T (Bev+XELOX); TS 3’UTR +6bp/-6bp and ERCC1-118 C/T or C/C (Bev+FUIRI); 3) Patients with two FG (Bev+FUOX).

    Primary: Progression-free survival

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    End point title
    		 Progression-free survival
    End point description
    Time elapsed from the randomization date until the patient progression or death for any reason (the first that occurred).
    End point type
    Primary
    End point timeframe
    Until patient progression or death for any reason (the first that occurred)
    End point values
    		 Control Group (A) (Bev+XELOX) Experimental Group (B)
    Number of subjects analysed
    65
    130
    Units: months
        median (confidence interval 95%)
    9.4 (6.8 to 12.1)
    10.1 (8.5 to 11.6)
    Attachments
    		 Progression-free survival
    Statistical analysis title
    		 Hazard ratio
    Comparison groups
    Control Group (A) (Bev+XELOX) v Experimental Group (B)
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.745
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.942
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.657
         upper limit
    		 1.351

    Secondary: Overall surival

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    End point title
    		 Overall surival
    End point description
    Time elapsed from the randomization date until the patient death. In other patients the last control was considered the last follow-up available.
    End point type
    Secondary
    End point timeframe
    Until patient death or the last follow-up available.
    End point values
    		 Control Group (A) (Bev+XELOX) Experimental Group (B)
    Number of subjects analysed
    65
    130
    Units: months
        median (confidence interval 95%)
    16.5 (13.7 to 19.4)
    19.1 (15.5 to 22.7)
    Attachments
    		 Overall survival
    Statistical analysis title
    		 Hazard ratio
    Comparison groups
    Control Group (A) (Bev+XELOX) v Experimental Group (B)
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.798
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.956
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.678
         upper limit
    		 1.348

    Secondary: Complete response (CR)

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    End point title
    		 Complete response (CR)
    End point description
    End point type
    Secondary
    End point timeframe
    From treatment start to the decision to end
    End point values
    		 Control Group (A) (Bev+XELOX) Experimental Group (B)
    Number of subjects analysed
    55 [1]
    106 [2]
    Units: Subjects
    2
    4
    Notes
    [1] - Patients of the control group that were evaluable for response.
    [2] - Patients of the experimental group that were evaluable for response.
    No statistical analyses for this end point

    Secondary: Partial response (PR)

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    End point title
    		 Partial response (PR)
    End point description
    End point type
    Secondary
    End point timeframe
    From treatment start to the decision to end
    End point values
    		 Control Group (A) (Bev+XELOX) Experimental Group (B)
    Number of subjects analysed
    55 [3]
    106 [4]
    Units: Subjects
    24
    65
    Notes
    [3] - Patients of the control group that were evaluable for response.
    [4] - Patients of the experimental group that were evaluable for response.
    No statistical analyses for this end point

    Secondary: Stable disease

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    End point title
    		 Stable disease
    End point description
    End point type
    Secondary
    End point timeframe
    From treatment start to the decision to end
    End point values
    		 Control Group (A) (Bev+XELOX) Experimental Group (B)
    Number of subjects analysed
    55 [5]
    106 [6]
    Units: Subjects
    22
    30
    Notes
    [5] - Patients of the control group that were evaluable for response.
    [6] - Patients of the experimental group that were evaluable for response.
    No statistical analyses for this end point

    Secondary: Progressive disease

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    End point title
    		 Progressive disease
    End point description
    End point type
    Secondary
    End point timeframe
    From treatment start to the decision to end
    End point values
    		 Control Group (A) (Bev+XELOX) Experimental Group (B)
    Number of subjects analysed
    55 [7]
    106 [8]
    Units: Subjects
    7
    7
    Notes
    [7] - Patients of the control group that were evaluable for response.
    [8] - Patients of the experimental group that were evaluable for response.
    No statistical analyses for this end point

    Secondary: Overall response rate (ORR) (PR+CR)

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    End point title
    		 Overall response rate (ORR) (PR+CR)
    End point description
    Partial response (PR) + Complete response (CR). It was assessed using RECIST Version 1.1
    End point type
    Secondary
    End point timeframe
    From treatment start to the decision to end
    End point values
    		 Control Group (A) (Bev+XELOX) Experimental Group (B)
    Number of subjects analysed
    55 [9]
    106 [10]
    Units: Subjects
    26
    69
    Notes
    [9] - Patients of the control group that were evaluable for response.
    [10] - Patients of the experimental group that were evaluable for response.
    Statistical analysis title
    		 Fisher exact
    Comparison groups
    Control Group (A) (Bev+XELOX) v Experimental Group (B)
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.042
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Disease-control rate (CR+PR+SD)

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    End point title
    		 Disease-control rate (CR+PR+SD)
    End point description
    Complete response (CR) + Partial response (PR) + Stable disease (SD)
    End point type
    Secondary
    End point timeframe
    From treatment start to the decision to end
    End point values
    		 Control Group (A) (Bev+XELOX) Experimental Group (B)
    Number of subjects analysed
    55 [11]
    106 [12]
    Units: Subjects
    48
    99
    Notes
    [11] - Patients of the control group that were evaluable for response.
    [12] - Patients of the experimental group that were evaluable for response.
    Statistical analysis title
    		 Fisher exact
    Comparison groups
    Control Group (A) (Bev+XELOX) v Experimental Group (B)
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.24
    Method
    		 Fisher exact
    Confidence interval

    Secondary: R0 surgery

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    End point title
    		 R0 surgery
    End point description
    End point type
    Secondary
    End point timeframe
    During or after the study
    End point values
    		 Control Group (A) (Bev+XELOX) Experimental Group (B)
    Number of subjects analysed
    16 [13]
    21 [14]
    Units: Subjects
    7
    18
    Notes
    [13] - 16 patients of the control group with surgical resection
    [14] - 21 patients of the experimental group with surgical resection
    Statistical analysis title
    		 Fisher exact
    Comparison groups
    Control Group (A) (Bev+XELOX) v Experimental Group (B)
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.018
    Method
    		 Fisher exact
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Throughout the study period.
    Adverse event reporting additional description
    An adverse event is reported once per patient and treatment period with the highest severity grade according to NCI-CTCAE version 3.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Group A - Safety population
    Reporting group description
    		 Patients who have received at least one administration of study drug in Group A: BVZ+XELOX (Bevacizumab + capecitabine + oxaliplatin).

    Reporting group title
    Group B (global) - Safety population
    Reporting group description
    		 Patients who have received at least one administration of study drug in Group B (global). Reported for all Group B subgroups in total (BVZ+XELOX/XELIRI/FUOX/FUIRI).

    Serious adverse events
    		 Group A - Safety population Group B (global) - Safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    27 / 61 (44.26%)
    61 / 119 (51.26%)
         number of deaths (all causes)
    49
    97
         number of deaths resulting from adverse events
    3
    11
    Vascular disorders
    Acute pulmonary edema
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain vascular accident
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 61 (1.64%)
    2 / 119 (1.68%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hematoma
         subjects affected / exposed
    0 / 61 (0.00%)
    2 / 119 (1.68%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary thromboembolism
         subjects affected / exposed
    2 / 61 (3.28%)
    8 / 119 (6.72%)
         occurrences causally related to treatment / all
    2 / 2
    7 / 8
         deaths causally related to treatment / all
    0 / 0
    3 / 3
    Vein thrombosis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Foot ischemia
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Heart failure
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolemic shock
         subjects affected / exposed
    0 / 61 (0.00%)
    2 / 119 (1.68%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vasospastic angina
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cognitive impairment
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusion
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertiginous syndrome
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Abdominal pain
         subjects affected / exposed
    0 / 61 (0.00%)
    3 / 119 (2.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal pain
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epigastralgy
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fever
         subjects affected / exposed
    3 / 61 (4.92%)
    2 / 119 (1.68%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General deterioration
         subjects affected / exposed
    0 / 61 (0.00%)
    3 / 119 (2.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar pain
         subjects affected / exposed
    2 / 61 (3.28%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple myeloma
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 119 (0.84%)
         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 / 61 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 61 (1.64%)
    2 / 119 (1.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Blood and lymphatic system disorders
    Aplasia
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 61 (1.64%)
    4 / 119 (3.36%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal bleeding
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocitopenia
         subjects affected / exposed
    1 / 61 (1.64%)
    3 / 119 (2.52%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal bleeding
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abscess perianal
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bowel obstruction
         subjects affected / exposed
    7 / 61 (11.48%)
    5 / 119 (4.20%)
         occurrences causally related to treatment / all
    0 / 7
    3 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 61 (1.64%)
    12 / 119 (10.08%)
         occurrences causally related to treatment / all
    1 / 1
    14 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal bleeding
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Gastrointestinal perforation
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal toxicity
         subjects affected / exposed
    1 / 61 (1.64%)
    4 / 119 (3.36%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Hematemesis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucositis oral
         subjects affected / exposed
    0 / 61 (0.00%)
    2 / 119 (1.68%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstruction of bile duct anastomotic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parasigmoid abscess
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic duodenitis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 61 (4.92%)
    2 / 119 (1.68%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Hepatobiliary disorders
    Hepatic veno oclusive disease
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic hepatitis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumor fistulization
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 61 (1.64%)
    2 / 119 (1.68%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Infections and infestations
    Bacterial meningitis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Catheter infection
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep infection of intestinal fistula
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 61 (0.00%)
    4 / 119 (3.36%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Fournier Gangrene
         subjects affected / exposed
    0 / 61 (0.00%)
    2 / 119 (1.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peristomal abscess
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 61 (0.00%)
    2 / 119 (1.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory infection
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical wound infection
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycemia
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocapnia
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive ictericia
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Group A - Safety population Group B (global) - Safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    61 / 61 (100.00%)
    118 / 119 (99.16%)
    Cardiac disorders
    Hypertension
         subjects affected / exposed
    14 / 61 (22.95%)
    23 / 119 (19.33%)
         occurrences all number
    20
    24
    Nervous system disorders
    Dysaesthesia
         subjects affected / exposed
    22 / 61 (36.07%)
    13 / 119 (10.92%)
         occurrences all number
    53
    18
    Neuropathy
         subjects affected / exposed
    39 / 61 (63.93%)
    36 / 119 (30.25%)
         occurrences all number
    102
    57
    Neurotoxicity
         subjects affected / exposed
    9 / 61 (14.75%)
    8 / 119 (6.72%)
         occurrences all number
    25
    19
    Anxiety
         subjects affected / exposed
    3 / 61 (4.92%)
    7 / 119 (5.88%)
         occurrences all number
    3
    8
    Dizziness
         subjects affected / exposed
    2 / 61 (3.28%)
    10 / 119 (8.40%)
         occurrences all number
    2
    14
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    13 / 61 (21.31%)
    30 / 119 (25.21%)
         occurrences all number
    21
    54
    Neutropenia
         subjects affected / exposed
    14 / 61 (22.95%)
    27 / 119 (22.69%)
         occurrences all number
    40
    72
    Thrombocytopenia
         subjects affected / exposed
    15 / 61 (24.59%)
    10 / 119 (8.40%)
         occurrences all number
    28
    13
    Epistaxis
         subjects affected / exposed
    12 / 61 (19.67%)
    32 / 119 (26.89%)
         occurrences all number
    19
    46
    Rectal bleeding
         subjects affected / exposed
    7 / 61 (11.48%)
    15 / 119 (12.61%)
         occurrences all number
    7
    17
    Oedema
         subjects affected / exposed
    7 / 61 (11.48%)
    8 / 119 (6.72%)
         occurrences all number
    7
    8
    Leukopenia
         subjects affected / exposed
    3 / 61 (4.92%)
    8 / 119 (6.72%)
         occurrences all number
    3
    19
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    46 / 61 (75.41%)
    90 / 119 (75.63%)
         occurrences all number
    117
    280
    Common cold
         subjects affected / exposed
    6 / 61 (9.84%)
    9 / 119 (7.56%)
         occurrences all number
    8
    11
    Fever
         subjects affected / exposed
    12 / 61 (19.67%)
    27 / 119 (22.69%)
         occurrences all number
    16
    33
    Weight decreased
         subjects affected / exposed
    5 / 61 (8.20%)
    3 / 119 (2.52%)
         occurrences all number
    5
    5
    Abdominal pain
         subjects affected / exposed
    24 / 61 (39.34%)
    42 / 119 (35.29%)
         occurrences all number
    38
    54
    Anal pain
         subjects affected / exposed
    4 / 61 (6.56%)
    6 / 119 (5.04%)
         occurrences all number
    5
    9
    Insomnia
         subjects affected / exposed
    3 / 61 (4.92%)
    10 / 119 (8.40%)
         occurrences all number
    3
    10
    Back pain
         subjects affected / exposed
    1 / 61 (1.64%)
    6 / 119 (5.04%)
         occurrences all number
    2
    7
    Lumbar pain
         subjects affected / exposed
    3 / 61 (4.92%)
    6 / 119 (5.04%)
         occurrences all number
    4
    7
    Pain
         subjects affected / exposed
    2 / 61 (3.28%)
    6 / 119 (5.04%)
         occurrences all number
    2
    7
    Gastrointestinal disorders
    Anorexia nervosa
         subjects affected / exposed
    16 / 61 (26.23%)
    32 / 119 (26.89%)
         occurrences all number
    32
    53
    Bowel obstruction
         subjects affected / exposed
    6 / 61 (9.84%)
    3 / 119 (2.52%)
         occurrences all number
    6
    3
    Constipation
         subjects affected / exposed
    19 / 61 (31.15%)
    30 / 119 (25.21%)
         occurrences all number
    30
    46
    Diarrhoea
         subjects affected / exposed
    43 / 61 (70.49%)
    99 / 119 (83.19%)
         occurrences all number
    93
    358
    Dysgeusia
         subjects affected / exposed
    10 / 61 (16.39%)
    18 / 119 (15.13%)
         occurrences all number
    15
    28
    Hyporexia
         subjects affected / exposed
    7 / 61 (11.48%)
    16 / 119 (13.45%)
         occurrences all number
    11
    24
    Mucositis
         subjects affected / exposed
    23 / 61 (37.70%)
    55 / 119 (46.22%)
         occurrences all number
    42
    97
    Nausea
         subjects affected / exposed
    28 / 61 (45.90%)
    56 / 119 (47.06%)
         occurrences all number
    54
    109
    Vomiting
         subjects affected / exposed
    29 / 61 (47.54%)
    51 / 119 (42.86%)
         occurrences all number
    67
    130
    Xerostomy
         subjects affected / exposed
    5 / 61 (8.20%)
    6 / 119 (5.04%)
         occurrences all number
    6
    7
    Gingivitis
         subjects affected / exposed
    3 / 61 (4.92%)
    7 / 119 (5.88%)
         occurrences all number
    3
    10
    Tenesmus
         subjects affected / exposed
    1 / 61 (1.64%)
    6 / 119 (5.04%)
         occurrences all number
    1
    6
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 61 (6.56%)
    11 / 119 (9.24%)
         occurrences all number
    5
    18
    Dyspnoea
         subjects affected / exposed
    4 / 61 (6.56%)
    8 / 119 (6.72%)
         occurrences all number
    6
    9
    Skin and subcutaneous tissue disorders
    Hand-foot syndrome
         subjects affected / exposed
    28 / 61 (45.90%)
    34 / 119 (28.57%)
         occurrences all number
    52
    71
    Hyperpigmentation
         subjects affected / exposed
    6 / 61 (9.84%)
    8 / 119 (6.72%)
         occurrences all number
    8
    9
    Pruritus
         subjects affected / exposed
    4 / 61 (6.56%)
    9 / 119 (7.56%)
         occurrences all number
    5
    9
    Alopecia
         subjects affected / exposed
    2 / 61 (3.28%)
    25 / 119 (21.01%)
         occurrences all number
    2
    31
    Infections and infestations
    Respiratory infection
         subjects affected / exposed
    4 / 61 (6.56%)
    7 / 119 (5.88%)
         occurrences all number
    4
    10
    Urinary tract infection
         subjects affected / exposed
    5 / 61 (8.20%)
    12 / 119 (10.08%)
         occurrences all number
    8
    17
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 61 (1.64%)
    9 / 119 (7.56%)
         occurrences all number
    1
    14
    Hyperglycaemia
         subjects affected / exposed
    0 / 61 (0.00%)
    8 / 119 (6.72%)
         occurrences all number
    0
    14

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Jul 2009
    Taking into account the suggestions of the research ethics committee to approve the study.
    02 Oct 2009
    Through this amendment 8 new centers have been added: H.San Juan Reus, C.H. Zamora, H. Josep Trueta, H.G.U. Gregorio Marañón, IDOC Corachan, H. Granollers, H. Guadalajara, H. Virgen Arrixaca.
    23 Oct 2009
    Correction of a typographic error regarding the administration regimens of the two drugs administered every 2 weeks (Bevacizumab and Oxaliplatin): arms of treatment with FUIRI and FUOX.
    03 Nov 2009
    Through this amendment one new center has been added (H. Puerta Hierro)
    01 Mar 2010
    Through this amendment some parts of the protocol have been modified /clarified, the biological study has been included and two new centers have been added: ICO and H. Doce de Octubre. Moreover, Dra Sandra Merino Varela replaced Dr Julen Fernandez as the Principal Investigator in H. Sant Joan de Reus.
    01 Apr 2011
    Through this amendment Dra Montserrat Gay Pastor replaced Miquel Nogué Aliguer as the Principal Investigator in Consorci Hospitalari de Vic.
    17 Jan 2013
    Through this amendment Dra Clara Montagut Viladot replaced Dr Manuel Gallén Castillo as the Principal Investigator in Hospital del Mar.
    27 May 2013
    Through this amendment Dr José Luis Manzano Mozo replaced Dr Albert Abad Esteve as the Principal Investigator in Hospital Germans Trias i Pujol.
    16 Jul 2013
    Through this amendment Dr Luis Robles Díaz replaced Dra Cristina Grávalos Castro as the Principal Investigator in Hospital Universitario 12 de Octubre.

    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.
    Serum samples were not analyzed for cell-free tumor DNA. This technique may allow identification of variability in response due to the tumor genome, complementary to information provided by examination of germline polymorphisms.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/29145602
    For support, Contact us.
    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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