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    Clinical Trial Results:
    Full dose S-1 monotherapy compared to reduced dose S-1/oxaliplatin combination therapy as first-line treatment for older patients with metastatic colorectal cancer.

    Summary
    EudraCT number
    2014-000394-39
    Trial protocol
    DK   NO   FI  
    Global end of trial date
    01 Sep 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    19 Jan 2022
    First version publication date
    19 Jan 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    KFE 14.01
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Odense University Hospital
    Sponsor organisation address
    J. B. Winsløws Vej 4, entrance 140, basemenet, Odense C, Denmark, 5000
    Public contact
    Ida Coordt Elle, Odense University Hospital, +45 29335922, ida.coordt.elle@rsyd.dk
    Scientific contact
    Stine Brændegaard Winther, Odense University Hospital, +45 28601058, stine.winther@rsyd.dk
    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
    01 Sep 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Sep 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Progression-free survival (PFS)
    Protection of trial subjects
    Pre-medication was administered to minmize adverse reactions.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    20 Feb 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 43
    Country: Number of subjects enrolled
    Finland: 9
    Country: Number of subjects enrolled
    Norway: 57
    Country: Number of subjects enrolled
    Sweden: 51
    Worldwide total number of subjects
    160
    EEA total number of subjects
    160
    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)
    0
    From 65 to 84 years
    153
    85 years and over
    7

    Subject disposition

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    Recruitment
    Recruitment details
    Eligible patients were aged 70 years or older and had histopathologically proven colorectal adenocarcinoma, non-resectable metastases, and a WHO performance status of 0–2.

    Pre-assignment
    Screening details
    Participants had received no prior chemotherapy except adjuvant fluoropyrimidine therapy completed more than 180 days before randomisation and had a life expectancy of at least 3 months.

    Period 1
    Period 1 title
    Trial period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    Patients were randomly assigned to sequential full-dose monotherapy (S-1 followed by irinotecan monotherapy at progression) or sequential dose-reduced combination chemotherapy (S-1 and oxaliplatin followed by S-1 and irinotecan at progression). Bevacizumab was optional in first-line therapy at the discretion of the treating physician but the decision had to be made before randomisation.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Full-dose monotherapy
    Arm description
    Patients assigned to full-dose monotherapy were treated with S-1 30 mg/m² orally twice daily on days 1–14 every 3 weeks followed by second-line treatment at progression with irinotecan (250 mg/m² intravenously on day 1 every 3 weeks or 180 mg/m² intravenously on day 1 every 2 weeks). In the absence of toxicity above grade 1 (except alopecia), it was recommended to increase irinotecan in steps to 350 mg/m² intravenously on day 1 every 3 weeks or 250 mg/m² intravenously on day 1 every 2 weeks.
    Arm type
    Active comparator

    Investigational medicinal product name
    S1
    Investigational medicinal product code
    Other name
    Teysuno
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Patients assigned to full-dose monotherapy were treated with S-1 30 mg/m² orally twice daily on days 1–14 every 3 weeks followed by second-line treatment at progression with irinotecan (250 mg/m² intravenously on day 1 every 3 weeks or 180 mg/m² intravenously on day 1 every 2 weeks). In the absence of toxicity above grade 1 (except alopecia), it was recommended to increase irinotecan in steps to 350 mg/m² intravenously on day 1 every 3 weeks or 250 mg/m² intravenously on day 1 every 2 weeks.

    Arm title
    Reduced-dose combination therapy
    Arm description
    Patients assigned to reduced-dose combination chemotherapy received S-1 20 mg/m² orally twice daily on days 1–14 and oxaliplatin 100 mg/m² intravenously on day 1 every 3 weeks followed by second-line treatment at progression with S-1 20 mg/m² orally twice daily on days 1–14 and irinotecan 180 mg/m² intravenously on day 1 every 3 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    S1
    Investigational medicinal product code
    Other name
    Teysuno
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Patients assigned to reduced-dose combination chemotherapy received S-1 20 mg/m² orally twice daily on days 1–14 and oxaliplatin 100 mg/m² intravenously on day 1 every 3 weeks followed by second-line treatment at progression with S-1 20 mg/m² orally twice daily on days 1–14 and irinotecan 180 mg/m² intravenously on day 1 every 3 weeks.

    Investigational medicinal product name
    Oxaliplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients assigned to reduced-dose combination chemotherapy received S-1 20 mg/m² orally twice daily on days 1–14 and oxaliplatin 100 mg/m² intravenously on day 1 every 3 weeks followed by second-line treatment at progression with S-1 20 mg/m² orally twice daily on days 1–14 and irinotecan 180 mg/m² intravenously on day 1 every 3 weeks.

    Investigational medicinal product name
    Irinotecan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients assigned to reduced-dose combination chemotherapy received S-1 20 mg/m² orally twice daily on days 1–14 and oxaliplatin 100 mg/m² intravenously on day 1 every 3 weeks followed by second-line treatment at progression with S-1 20 mg/m² orally twice daily on days 1–14 and irinotecan 180 mg/m² intravenously on day 1 every 3 weeks.

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Because bevacizumab was not standard of care in most Nordic countries at the time of study design, the addition of bevacizumab to first-line chemotherapy was optional and given at the discretion of the treating physician. When used, bevacizumab was given at 7.5 mg/kg intravenously on day 1 every 3 weeks.

    Number of subjects in period 1
    Full-dose monotherapy Reduced-dose combination therapy
    Started
    83
    77
    Completed
    83
    77

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Full-dose monotherapy
    Reporting group description
    Patients assigned to full-dose monotherapy were treated with S-1 30 mg/m² orally twice daily on days 1–14 every 3 weeks followed by second-line treatment at progression with irinotecan (250 mg/m² intravenously on day 1 every 3 weeks or 180 mg/m² intravenously on day 1 every 2 weeks). In the absence of toxicity above grade 1 (except alopecia), it was recommended to increase irinotecan in steps to 350 mg/m² intravenously on day 1 every 3 weeks or 250 mg/m² intravenously on day 1 every 2 weeks.

    Reporting group title
    Reduced-dose combination therapy
    Reporting group description
    Patients assigned to reduced-dose combination chemotherapy received S-1 20 mg/m² orally twice daily on days 1–14 and oxaliplatin 100 mg/m² intravenously on day 1 every 3 weeks followed by second-line treatment at progression with S-1 20 mg/m² orally twice daily on days 1–14 and irinotecan 180 mg/m² intravenously on day 1 every 3 weeks.

    Reporting group values
    Full-dose monotherapy Reduced-dose combination therapy Total
    Number of subjects
    83 77 160
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    78 (76 to 81) 78 (75 to 80) -
    Gender categorical
    Units: Subjects
        Female
    40 38 78
        Male
    43 39 82

    End points

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    End points reporting groups
    Reporting group title
    Full-dose monotherapy
    Reporting group description
    Patients assigned to full-dose monotherapy were treated with S-1 30 mg/m² orally twice daily on days 1–14 every 3 weeks followed by second-line treatment at progression with irinotecan (250 mg/m² intravenously on day 1 every 3 weeks or 180 mg/m² intravenously on day 1 every 2 weeks). In the absence of toxicity above grade 1 (except alopecia), it was recommended to increase irinotecan in steps to 350 mg/m² intravenously on day 1 every 3 weeks or 250 mg/m² intravenously on day 1 every 2 weeks.

    Reporting group title
    Reduced-dose combination therapy
    Reporting group description
    Patients assigned to reduced-dose combination chemotherapy received S-1 20 mg/m² orally twice daily on days 1–14 and oxaliplatin 100 mg/m² intravenously on day 1 every 3 weeks followed by second-line treatment at progression with S-1 20 mg/m² orally twice daily on days 1–14 and irinotecan 180 mg/m² intravenously on day 1 every 3 weeks.

    Primary: Progression-free survival

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    End point title
    Progression-free survival [1]
    End point description
    End point type
    Primary
    End point timeframe
    Data-cut-off was 36 months.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Please see the original publication for statistical analysis.
    End point values
    Full-dose monotherapy Reduced-dose combination therapy
    Number of subjects analysed
    83
    77
    Units: months
        median (confidence interval 95%)
    5.3 (4.1 to 6.8)
    6.2 (5.3 to 8.3)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Last treatment + 30 days.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Full-dose monotherapy
    Reporting group description
    -

    Reporting group title
    Reduced-dose combination therapy
    Reporting group description
    -

    Serious adverse events
    Full-dose monotherapy Reduced-dose combination therapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    33 / 83 (39.76%)
    13 / 77 (16.88%)
         number of deaths (all causes)
    2
    0
         number of deaths resulting from adverse events
    2
    0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 77 (1.30%)
         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
    Dehydration
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ileus
         subjects affected / exposed
    4 / 83 (4.82%)
    2 / 77 (2.60%)
         occurrences causally related to treatment / all
    4 / 4
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    12 / 83 (14.46%)
    2 / 77 (2.60%)
         occurrences causally related to treatment / all
    12 / 12
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infection
         subjects affected / exposed
    15 / 83 (18.07%)
    8 / 77 (10.39%)
         occurrences causally related to treatment / all
    15 / 15
    8 / 8
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    Mucositis management
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    Full-dose monotherapy Reduced-dose combination therapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    83 / 83 (100.00%)
    77 / 77 (100.00%)
    Vascular disorders
    Embolism
         subjects affected / exposed
    7 / 83 (8.43%)
    3 / 77 (3.90%)
         occurrences all number
    7
    3
    Investigations
    Hyponatraemia
         subjects affected / exposed
    5 / 83 (6.02%)
    1 / 77 (1.30%)
         occurrences all number
    5
    1
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    14 / 83 (16.87%)
    16 / 77 (20.78%)
         occurrences all number
    14
    16
    Anaemia
         subjects affected / exposed
    54 / 83 (65.06%)
    46 / 77 (59.74%)
         occurrences all number
    54
    46
    Thrombocytopenia
         subjects affected / exposed
    13 / 83 (15.66%)
    20 / 77 (25.97%)
         occurrences all number
    13
    20
    Nervous system disorders
    Neuropathy peripheral
         subjects affected / exposed
    18 / 83 (21.69%)
    55 / 77 (71.43%)
         occurrences all number
    18
    55
    General disorders and administration site conditions
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    13 / 83 (15.66%)
    15 / 77 (19.48%)
         occurrences all number
    13
    15
    Fatigue
         subjects affected / exposed
    60 / 83 (72.29%)
    60 / 77 (77.92%)
         occurrences all number
    60
    60
    Dehydration
         subjects affected / exposed
    4 / 83 (4.82%)
    0 / 77 (0.00%)
         occurrences all number
    4
    0
    Pain
         subjects affected / exposed
    32 / 83 (38.55%)
    25 / 77 (32.47%)
         occurrences all number
    32
    25
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    37 / 83 (44.58%)
    42 / 77 (54.55%)
         occurrences all number
    37
    42
    Diarrhoea
         subjects affected / exposed
    31 / 83 (37.35%)
    30 / 77 (38.96%)
         occurrences all number
    31
    30
    Vomiting
         subjects affected / exposed
    24 / 83 (28.92%)
    13 / 77 (16.88%)
         occurrences all number
    24
    13
    Constipation
         subjects affected / exposed
    10 / 83 (12.05%)
    9 / 77 (11.69%)
         occurrences all number
    10
    9
    Infections and infestations
    Mucositis management
         subjects affected / exposed
    9 / 83 (10.84%)
    8 / 77 (10.39%)
         occurrences all number
    9
    8
    Infection
         subjects affected / exposed
    11 / 83 (13.25%)
    6 / 77 (7.79%)
         occurrences all number
    11
    6

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Jan 2014
    Questionnaire VES13 added, Barthel deleted. GFR clarified in relation to treatment.
    17 Feb 2014
    Corrections and comments from authorities.
    14 Apr 2014
    Elaboration of Safety section. Corrections in patient information.
    03 Nov 2014
    Author added to the protocol committee. General changes to protocol.
    24 Apr 2017
    Number of patients increased from 150 to 160. Number of sites changed, as Finland entered the study.
    08 Sep 2017
    Extension of inclusion period until Nov. 1st 2017. Extension of study period until LPLV May 1st 2019. Change of PI in Herning from Nina Keldsen to Halla Skuladottir.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/30852136
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