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    Clinical Trial Results:
    A two-arm randomised trial of intermittent chemotherapy plus continuous cetuximab and of intermittent chemotherapy plus intermittent cetuximab in first line treatment of patients with K-ras Normal (wild-type) metastatic colorectal cancer

    Summary
    EudraCT number
    		 2006-003049-17
    Trial protocol
    		 GB  
    Global end of trial date
    18 Jan 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Jul 2016
    First version publication date
    29 Jul 2016
    Other versions
    Summary report(s)
    		 Trial Publication
    Summary of results

    Trial information

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    Trial identification
    Sponsor protocol code
    CR11
    Additional study identifiers
    ISRCTN number
    		 ISRCTN38375681
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Medical Research Council
    Sponsor organisation address
    c/o Aviation house, 125 Kingsway , London, United Kingdom, WC2b 6NH
    Public contact
    Dr Angela Meade, Medical Research Council Clinical Trials Unit at UCL, 44 206704761, a.meade@ucl.ac.uk
    Scientific contact
    Dr Angela Meade, Medical Research Council Clinical Trials Unit at UCL, 44 2076704761, a.meade@ucl.ac.uk
    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
    03 Apr 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Apr 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Jan 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary aim of the COIN-B trial is to determine whether adding cetuximab to intermittent OxFp chemotherapy in tumours with K-raswt status, is active, safe and feasible, with the primary outcome measure of failure-free survival at 10 months.
    Protection of trial subjects
    The invitation to participate in the trial will be initiated by the treating clinician who will explain the rationale for the treatment and research, and the alternative (non−trial) standard treatment options available. The patient will then be given the trial Patient Information Sheet and given a period of at least 24 hours (usually one week) to consider their decision. During this period, a telephone contact is provided so that the patient may discuss and clarify any issues with the Research Nurse or clinician. The patient information sheets will be kept by the participant for reference.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Jul 2007
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Safety
    Long term follow-up duration
    		 7 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 168
    Country: Number of subjects enrolled
    Cyprus: 1
    Worldwide total number of subjects
    169
    EEA total number of subjects
    169
    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)
    88
    From 65 to 84 years
    81
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 July 2007 - COIN-B opened recruitment in 8 centres. 7th May 2008 - With 119 patients randomised, trial suspended due to KRAS data from global phase III randomised studies January 2009 - reopened to recruitment following a protocol amendment to introduce KRAS screening 1st June 2010 closed to recruitment with 169 KRAS WT patients randomised

    Pre-assignment
    Screening details
    		 Following protocol amendment in November 2008, pre randomisation screening for KRAS was introduced in protocol version 3

    Pre-assignment period milestones
    Number of subjects started
    		 401 [1]
    Intermediate milestone: Number of subjects
    KRAS wild type patients: 201
    Number of subjects completed
    		 169

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 have KRAS Mutation: 200
    Reason: Number of subjects
    		 patient choice: 9
    Reason: Number of subjects
    		 no longer eligible: 23
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Following the trial reopening in Jan 2009 with a protocol amendment to introduce KRAS screening, a pre-assignment period was brought into being. For consistency, the "overall number enrolled" is given here as the total number randomised, since the screened patients were not enrolled as such.
    Period 1
    Period 1 title
    Initial 12 weeks chemo + cetux
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm D
    Arm description
    		 Intermittent chemotherapy + intermittent cetuximab
    Arm type
    		 Intermittent

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Please refer to protocol

    Arm title
    		 Arm E
    Arm description
    		 Intermittent chemotherapy + cetuximab maintenance
    Arm type
    		 Intermittent

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Please refer to protocol

    Number of subjects in period 1
    		Arm D Arm E
    Started
    78
    91
    Completed
    64
    66
    Not completed
    14
    25
         Left trial in first 12 weeks
    9
    7
         Death in first 12 weeks
    4
    14
         Progression in first 12 weeks
    1
    4
    Period 2
    Period 2 title
    Trial period following initial 12 weeks
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm D
    Arm description
    		 Intermittent chemotherapy + intermittent cetuximab
    Arm type
    		 Intermittent

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Please refer to COIN-B Protocol

    Arm title
    		 Arm E
    Arm description
    		 Intermittent chemotherapy + cetuximab maintenance
    Arm type
    		 Intermittent

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Please refer to protocol

    Number of subjects in period 2
    		Arm D Arm E
    Started
    64
    66
    Completed
    48
    44
    Not completed
    16
    22
         Physician decision
    4
    3
         Treatment delay
    -
    1
         Adverse event, non-fatal
    2
    5
         New evidence of multiple new lesions
    -
    1
         Intercurrent illness
    1
    1
         patient choice
    -
    5
         "Deranged LFT results"
    1
    -
         Neuropathy
    -
    1
         Urgent gynaecological referral
    -
    1
         Lost to follow-up
    5
    1
         Surgical resection
    3
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm D
    Reporting group description
    		 Intermittent chemotherapy + intermittent cetuximab

    Reporting group title
    Arm E
    Reporting group description
    		 Intermittent chemotherapy + cetuximab maintenance

    Reporting group values
    		 Arm D Arm E Total
    Number of subjects
    		 78 91 169
    Age categorical
    Units: Subjects
        <45 years
    		 5 6 11
        45-54 years
    		 11 17 28
        55-64 years
    		 26 23 49
        65-74 years
    		 31 33 64
        75+ years
    		 5 12 17
    Gender categorical
    Units: Subjects
        Female
    		 30 36 66
        Male
    		 48 55 103
    WHO Performance Status
    Units: Subjects
        Normal activity without restriction
    		 38 40 78
        Strenuous activity restricted; can do light work
    		 35 42 77
        Up and about >50% of waking hours, limited self-ca
    		 5 9 14
    Site of primary tumour
    Units: Subjects
        Right colon
    		 19 22 41
        Left colon
    		 12 27 39
        Rectum
    		 25 17 42
        Rectosigmoid junction
    		 18 18 36
        Transverse
    		 4 7 11
    Current status of primary tumour
    Units: Subjects
        Resected
    		 41 48 89
        Unresected/unresectable
    		 34 41 75
        Local recurrence
    		 3 2 5
    Timing of metastases
    Units: Subjects
        Metachronous
    		 23 20 43
        Synchronous
    		 54 70 124
        Missing data
    		 1 1 2
    Distribution of metastases
    Units: Subjects
        Liver only
    		 16 17 33
        Liver + others
    		 39 43 82
        Non-liver
    		 22 30 52
        Missing data
    		 1 1 2
    Number of metastatic sites
    Units: Subjects
        No sites
    		 1 1 2
        One site
    		 28 31 59
        Two sites
    		 22 35 57
        Three or more sites
    		 27 24 51
    Glomerular filtration rate
    Units: Subjects
        ≤80ml/min
    		 32 38 70
        >80ml/min
    		 46 53 99
    Alkaline phosphatase
    Units: Subjects
        ≥300 U/l
    		 9 11 20
        <300 U/l
    		 69 80 149
    White blood cell count
    Units: Subjects
        ≥10,000/l
    		 17 24 41
        <10,000/l
    		 61 67 128
    Platelet count
    Units: Subjects
        ≥400,000/l
    		 17 20 37
        <400,000/l
    		 61 71 132

    End points

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    End points reporting groups
    Reporting group title
    Arm D
    Reporting group description
    		 Intermittent chemotherapy + intermittent cetuximab

    Reporting group title
    Arm E
    Reporting group description
    		 Intermittent chemotherapy + cetuximab maintenance
    Reporting group title
    Arm D
    Reporting group description
    		 Intermittent chemotherapy + intermittent cetuximab

    Reporting group title
    Arm E
    Reporting group description
    		 Intermittent chemotherapy + cetuximab maintenance

    Primary: 10-month failure-free survival rate

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    End point title
    		 10-month failure-free survival rate
    End point description
    End point type
    Primary
    End point timeframe
    The point at which at least half of the randomised patients on the intermittent cetuximab arm (Arm D) with KRAS wild-type tumours can be declared failure-free 10 months after randomisation
    End point values
    		 Arm D Arm E
    Number of subjects analysed
    64
    66
    Units: Failure-free at 10 months
        Failure free at 10 months
    32
    34
        Failed at or before 10 months
    27
    20
        Failure status unknown at or before 10 months
    5
    12
    Statistical analysis title
    		 10-month failure-free survival rate (Arm D)
    Statistical analysis description
    The proportion of randomised patients, with KRAS wild-type tumours and who completed their initial 12 weeks of combination chemo + cetuximab, who did not experience death or disease progression within 10 months of randomisation. N.B. Arm E is *not* involved in this analysis, but the database will not accept single arm analyses within a trial defined as having two arms! Hence, the true number of subjects in this analysis is 64.
    Comparison groups
    Arm D v Arm E
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Percentage
    Point estimate
    50
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 39
         upper limit
    		 -
    Notes
    [1] - An exact binomial test that the observed 10-month failure-free survival rate has a one-sided 95% confidence limit that excludes 35%.
    Statistical analysis title
    		 10-month failure-free survival rate (Arm E)
    Statistical analysis description
    The proportion of randomised patients, with KRAS wild-type tumours and who completed their initial 12 weeks of combination chemo + cetuximab, who did not experience death or disease progression within 10 months of randomisation. N.B. Arm D is *not* involved in this analysis, but the database will not accept single arm analyses within a trial defined as having two arms! Hence, the true number of subjects in this analysis is 66.
    Comparison groups
    Arm E v Arm D
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    Parameter type
    		 Percentage
    Point estimate
    52
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 41
         upper limit
    		 -
    Notes
    [2] - An exact binomial test that the observed 10-month failure-free survival rate has a one-sided 95% confidence limit that excludes 35%.

    Secondary: Failure-free survival (PPA)

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    End point title
    		 Failure-free survival (PPA)
    End point description
    Median + IQR failure-free survival by arm, among patients with KRAS wild-type tumours who successfully completed their initial 12 weeks of combination chemo + cetuximab. Patients without an event were censored either at the limit of their observed follow-up or at the analysis date of 24th April 2012.
    End point type
    Secondary
    End point timeframe
    Time from randomisation among patients with KRAS wild-type tumours who successfully completed their initial 12 weeks of combination chemo + cetuximab.
    End point values
    		 Arm D Arm E
    Number of subjects analysed
    64
    66
    Units: Months
        median (inter-quartile range (Q1-Q3))
    12.2 (6 to 23.4)
    14.3 (8.7 to 23.3)
    No statistical analyses for this end point

    Secondary: Failure-free survival (ITT)

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    End point title
    		 Failure-free survival (ITT)
    End point description
    Median + IQR failure-free survival by arm, among all randomised patients with KRAS wild-type tumours. Patients without an event were censored either at the limit of their observed follow-up or at the analysis date of 24th April 2012.
    End point type
    Secondary
    End point timeframe
    Time from randomisation among all randomised patients with KRAS wild-type tumours.
    End point values
    		 Arm D Arm E
    Number of subjects analysed
    78
    91
    Units: Months
        median (inter-quartile range (Q1-Q3))
    12.1 (5 to 23.4)
    12 (6.1 to 22)
    No statistical analyses for this end point

    Secondary: Overall survival (ITT)

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    End point title
    		 Overall survival (ITT)
    End point description
    Median + IQR overall survival by arm, among all randomised patients with KRAS wild-type tumours. Patients without an event were censored either at the limit of their observed follow-up or at the analysis date of 24th April 2012.
    End point type
    Secondary
    End point timeframe
    Time from randomisation among all randomised patients with KRAS wild-type tumours.
    End point values
    		 Arm D Arm E
    Number of subjects analysed
    78
    91
    Units: Months
        median (inter-quartile range (Q1-Q3))
    16 (8.9 to 30.9)
    17.5 (6.4 to 29)
    No statistical analyses for this end point

    Secondary: Progression-free survival in the interval

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    End point title
    		 Progression-free survival in the interval
    End point description
    Survival (time-to-event) analysis. For Arm D patients, this is equivalent to time to first progression within the intermittent phase of their treatment.
    End point type
    Secondary
    End point timeframe
    Time from end of initial 12 weeks of continuous chemo + cetuximab to first progression or death.
    End point values
    		 Arm D Arm E
    Number of subjects analysed
    64
    66
    Units: Months
        median (inter-quartile range (Q1-Q3))
    3.1 (2.1 to 8.1)
    5.8 (2.9 to 11.2)
    Statistical analysis title
    		 Cox regression analysis
    Statistical analysis description
    A Cox regression analysis comparing survival between the two arms in the intermittent phase of treatment (i.e. after the initial 12 weeks of continuous treatment in both arms).
    Comparison groups
    Arm E v Arm D
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.059
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 1.01

    Secondary: 12-week response

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    End point title
    		 12-week response
    End point description
    Disease response after 12 weeks of treatment, as measured by RECIST.
    End point type
    Secondary
    End point timeframe
    12 weeks after randomisation (in practice, measurements between 8 and 16 weeks were included)
    End point values
    		 Arm D Arm E
    Number of subjects analysed
    78
    91
    Units: Patients
        Complete response
    1
    1
        Partial response
    48
    38
        Stable disease
    8
    14
        Progressive disease
    7
    7
        Assessment done but result missing
    1
    0
        No assessment done
    13
    31
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAEs occurring from the time of randomisation until 30 days after the last protocol treatment administration. SARs and SUSARs must be notified indefinitely after randomisation.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 NCI CTC
    Dictionary version
    3.0
    Reporting groups
    Reporting group title
    Arm D
    Reporting group description
    		 Intermittent chemotherapy + intermittent cetuximab

    Reporting group title
    Arm E
    Reporting group description
    		 Intermittent chemotherapy + cetuximab maintenance

    Serious adverse events
    		 Arm D Arm E
    Total subjects affected by serious adverse events
         subjects affected / exposed
    63 / 112 (56.25%)
    63 / 114 (55.26%)
         number of deaths (all causes)
    99
    107
         number of deaths resulting from adverse events
    Vascular disorders
    Thrombosis
         subjects affected / exposed
    1 / 112 (0.89%)
    1 / 114 (0.88%)
         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
    4 / 112 (3.57%)
    3 / 114 (2.63%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Thrombosis in device
    Additional description: Reported as "Thrombosis- venous access device"
         subjects affected / exposed
    0 / 112 (0.00%)
    5 / 114 (4.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SVC obstruction
    Additional description: Reported as "Vascular- other (SVC obstruction)"
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Visceral arterial ischaemia
    Additional description: Reported as "Visceral arterial ischaemia- bowel"
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 112 (2.68%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
    Additional description: Reported as "fever"
         subjects affected / exposed
    2 / 112 (1.79%)
    2 / 114 (1.75%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 112 (0.00%)
    2 / 114 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Pain - abdominal
         subjects affected / exposed
    3 / 112 (2.68%)
    5 / 114 (4.39%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain - other
    Additional description: Back; kidney; headache
         subjects affected / exposed
    3 / 112 (2.68%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    5 / 112 (4.46%)
    2 / 114 (1.75%)
         occurrences causally related to treatment / all
    3 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    2 / 112 (1.79%)
    2 / 114 (1.75%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 112 (0.89%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Supraventricular tachyarrhythmia
    Additional description: Described as "Supraventricular arrhythmia" and as "Supraventricular arrhythmia- atrial fibrilation"
         subjects affected / exposed
    1 / 112 (0.89%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Syncope
    Additional description: Reported as "Vasovagal episode"
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infarction
    Additional description: Reported as "Cardiac ischaemia/ infarction"
         subjects affected / exposed
    1 / 112 (0.89%)
    2 / 114 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    CNS Cerebrovascular Ischaemia
         subjects affected / exposed
    3 / 112 (2.68%)
    2 / 114 (1.75%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Brain metastases
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disorientation
    Additional description: Reported as "Confusion"
         subjects affected / exposed
    1 / 112 (0.89%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Guillen Barre-like syndrome
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Motor dysfunction
    Additional description: Reported as "neuropathy: motor"
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tremor
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cauda equina compression
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    3 / 112 (2.68%)
    2 / 114 (1.75%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    2 / 112 (1.79%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    11 / 112 (9.82%)
    8 / 114 (7.02%)
         occurrences causally related to treatment / all
    5 / 13
    6 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucositis management
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 112 (1.79%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstruction
         subjects affected / exposed
    7 / 112 (6.25%)
    4 / 114 (3.51%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Perforation
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 112 (2.68%)
    2 / 114 (1.75%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injection related reaction
    Additional description: Reported as "Injection site reaction/ extravasation changes"
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 112 (0.00%)
    2 / 114 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound complication
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 114 (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
    Ureteric obstruction
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Fracture
         subjects affected / exposed
    1 / 112 (0.89%)
    2 / 114 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic floor muscle weakness
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Febrile neutropenia
    Additional description: Includes "neutropenic sepsis"
         subjects affected / exposed
    14 / 112 (12.50%)
    10 / 114 (8.77%)
         occurrences causally related to treatment / all
    2 / 15
    4 / 11
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    Metabolism and nutrition disorders
    Hyperglycemia
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Magnesium deficiency
    Additional description: Reported as "Magnesium, serum- low"
         subjects affected / exposed
    2 / 112 (1.79%)
    3 / 114 (2.63%)
         occurrences causally related to treatment / all
    2 / 3
    5 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bilirubinuria
    Additional description: Reported as "metabolic/laboratory- bilirubin, AST, ALP"
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm D Arm E
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    111 / 112 (99.11%)
    109 / 114 (95.61%)
    Nervous system disorders
    Peripheral neuropathy
    Additional description: G2+ CTC toxicity
         subjects affected / exposed
    36 / 112 (32.14%)
    28 / 114 (24.56%)
         occurrences all number
    76
    74
    General disorders and administration site conditions
    Pain
    Additional description: G2+ CTC toxicity
         subjects affected / exposed
    50 / 112 (44.64%)
    60 / 114 (52.63%)
         occurrences all number
    110
    131
    Lethargy
    Additional description: G2+ CTC toxicity
         subjects affected / exposed
    72 / 112 (64.29%)
    69 / 114 (60.53%)
         occurrences all number
    240
    212
    Vein pain
    Additional description: G2+ CTC toxicity
         subjects affected / exposed
    3 / 112 (2.68%)
    4 / 114 (3.51%)
         occurrences all number
    3
    5
    Blood and lymphatic system disorders
    Platelet count
    Additional description: G2+ CTC toxicity
         subjects affected / exposed
    12 / 112 (10.71%)
    18 / 114 (15.79%)
         occurrences all number
    28
    21
    Haemoglobin
    Additional description: G2+ CTC toxicity
         subjects affected / exposed
    49 / 112 (43.75%)
    39 / 114 (34.21%)
         occurrences all number
    98
    77
    White blood cell count
    Additional description: G2+ CTC toxicity
         subjects affected / exposed
    39 / 112 (34.82%)
    36 / 114 (31.58%)
         occurrences all number
    96
    57
    Neutrophil count
    Additional description: G2+ CTC toxicity
         subjects affected / exposed
    53 / 112 (47.32%)
    50 / 114 (43.86%)
         occurrences all number
    127
    75
    Hypermagnesaemia
    Additional description: G2+ CTC toxicity
         subjects affected / exposed
    15 / 112 (13.39%)
    19 / 114 (16.67%)
         occurrences all number
    22
    50
    Gastrointestinal disorders
    Nausea
    Additional description: CTC G2+ toxicity
         subjects affected / exposed
    33 / 112 (29.46%)
    30 / 114 (26.32%)
         occurrences all number
    57
    47
    Vomiting
    Additional description: CTC G2+ toxicity
         subjects affected / exposed
    30 / 112 (26.79%)
    24 / 114 (21.05%)
         occurrences all number
    43
    32
    Anorexia
    Additional description: G2+ CTC toxicity
         subjects affected / exposed
    48 / 112 (42.86%)
    37 / 114 (32.46%)
         occurrences all number
    90
    64
    Diarrhoea
    Additional description: G2+ CTC toxicity
         subjects affected / exposed
    51 / 112 (45.54%)
    50 / 114 (43.86%)
         occurrences all number
    123
    92
    Skin and subcutaneous tissue disorders
    Alopecia
    Additional description: G2+ CTC toxicity
         subjects affected / exposed
    1 / 112 (0.89%)
    5 / 114 (4.39%)
         occurrences all number
    2
    7
    Nail disorder
    Additional description: G2+ CTC toxicity "Nail changes"
         subjects affected / exposed
    19 / 112 (16.96%)
    24 / 114 (21.05%)
         occurrences all number
    29
    55
    Rash
    Additional description: G2+ CTC toxicity
         subjects affected / exposed
    77 / 112 (68.75%)
    72 / 114 (63.16%)
         occurrences all number
    236
    253
    Hand-foot syndrome
    Additional description: G2+ CTC toxicity
         subjects affected / exposed
    38 / 112 (33.93%)
    50 / 114 (43.86%)
         occurrences all number
    88
    122
    Infections and infestations
    Stomatitis
    Additional description: G2+ CTC toxicity
         subjects affected / exposed
    56 / 112 (50.00%)
    53 / 114 (46.49%)
         occurrences all number
    135
    129
    Product issues
    Hypersensitivity
    Additional description: G2+ CTC toxicity "Cetuximab hypersensitivity"
         subjects affected / exposed
    6 / 112 (5.36%)
    6 / 114 (5.26%)
         occurrences all number
    10
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Nov 2007
    To become version 2.0 of protocol - Evidence from the main COIN trial that the combination of XELOX plus cetuximab is causing unacceptably high level of GI toxicity. - The introduction of a parallel sub-study to run alongside COIN and COIN-B for any centres who wish to take part. Further information about the sub-study is included in a new Appendix to the main protocol.
    17 Nov 2008
    To become version 3.0 of protocol: Re-opening of the trial following suspension and the introduction of KRAS screening prior to randomisation

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    07 May 2008
    Trial suspended due to KRAS data from global phase III randomised studies.
    05 Jan 2009

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