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    Clinical Trial Results:
    A two arm phase II study of FOLFIRI in combination with standard or escalating dose of cetuximab as first line treatment of K-Ras wild type metastatic colorectal cancer: Everest 2

    Summary
    EudraCT number
    		 2009-009992-36
    Trial protocol
    		 BE   ES   AT   HU  
    Global end of trial date
    09 Jul 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Aug 2019
    First version publication date
    08 Aug 2019
    Other versions
    Summary report(s)
    		 Synopsis/discussion/conclusions
    CONSORT diagram
    PFS censoring rules
    Deaths on treatment
    Protocol deviations
    References
    Publications
    Abbreviations

    Trial information

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    Trial identification
    Sponsor protocol code
    S51532
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01251536
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    UZ Leuven
    Sponsor organisation address
    Herestraat 49, Leuven, Belgium, 3000
    Public contact
    Prof. Eric Van Cutsem, MD, PhD Gastroenterology/Digestive Oncology Unit, University Hospitals Gasthuisberg Leuven & KU Leuven, Herestraat 49, 3000 Leuven, +32 16344218, Eric.VanCutsem@uzleuven.be
    Scientific contact
    Prof. Eric Van Cutsem, MD, PhD Gastroenterology/Digestive Oncology Unit, University Hospitals Gasthuisberg Leuven & KU Leuven, Herestraat 49, 3000 Leuven, +32 16344218, Eric.VanCutsem@uzleuven.be
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    09 Jul 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Jan 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jul 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To provide an estimate (+/- 15%) of the progression-free survival (PFS) rate at 9 months, in pts without skin toxicity at 3 weeks (according to NCI CTCAE v. 4.0), treated with FOLFIRI + escalating dose of cetuximab (arm A). It is expected that the PFS rate will be similar to that observed after standard cetuximab treatment + FOLFIRI in pts with grade 1-4 skin toxicity in a K-Ras wild type population (CRYSTAL study). Secondary objectives: Safety profile of the combination in both treatment arms Skin toxicity (correlations with outcome were not performed) Response/disease control/duration of response: overall and in patients with liver-limited disease PFS and OS General resection rate and R0 resection rate for metastatic lesions Pharmacokinetic parameters in selected centers only - not performed due to insufficient recruitment Biomarker analyses: proteomics, microarray and PCR studies on plasma and tumour samples Long term follow-up duration: 3 years from DB lock (9 July 2018)
    Protection of trial subjects
    Ethics review and approval, informed consent. Premedication to prevent chemotherapy known adverse events (as per current practice and protocol recommendations), supportive care and routine monitoring.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Jan 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Scientific research
    Long term follow-up duration
    		 3 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 4
    Country: Number of subjects enrolled
    Spain: 51
    Country: Number of subjects enrolled
    Belgium: 24
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Hungary: 22
    Worldwide total number of subjects
    108
    EEA total number of subjects
    108
    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)
    76
    From 65 to 84 years
    32
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 One hundred and eight patients were included. First patient enrolled: 18-Jan-2011. Last patient enrolled: 24-Mar-2014. End of recruitment: 8-Apr-2014. The study was deemed closed as of 30-Jun-2016. Last end of treatment assessment: 25-Jul-2016 and last follow-up data collected 10-Jan-2018. The database was locked on 9 July 2018.

    Pre-assignment
    Screening details
    		 The target population was represented by patients with unresectable metastatic colorectal cancer histologically confirmed, K-Ras wild type tumour, eligible for treatment with cetuximab in combination with irinotecan and 5-FU/LV in a first line setting. Patients were screened as per inclusion and exclusion criteria per protocol.

    Period 1
    Period 1 title
    Full study duration:baseline-> follow-up (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A
    Arm description
    		 Patients with no cetuximab-related skin toxicity or other significant toxicity after first 3 weeks of treatment with cetuximab standard dosing in combination with FOLFIRI, in whom cetuximab doses were increased at day 22.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    Erbitux (TM) Merck
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cetuximab 400 mg/m² (loading at day 1) followed by 250 mg/m² weekly on days 8 and 15. If no skin toxicity occurred at day 22 cetuximab was increased to 350mg/m², then to 500mg/m² at day 36. FOLFIRI (simplified de Gramont) starting at day 1, was given every second week: irinotecan 180mg/m², leucovorin 400 mg/m² (racemic) or 200 mg/m² (L-form), 5-FU 400 mg/m² bolus and 2400 mg/m² infusion over 46 hours. No dose escalation for FOLFIRI.

    Arm title
    		 Arm B
    Arm description
    		 Patients with any grade cetuximab-related skin toxicity or other significant toxicity after first 3 weeks of treatment with cetuximab standard dosing in combination with FOLFIRI, in whom cetuximab doses were maintained at standard levels at day 22.
    Arm type
    		 Standard regimen longer than 3 weeks

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    Erbitux (TM) Merck
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cetuximab 400 mg/m² (loading at day 1) followed by 250 mg/m² weekly from day 8 onwards. FOLFIRI (simplified de Gramont) starting at day 1, was given every second week: irinotecan 180mg/m², leucovorin 400 mg/m² (racemic) or 200 mg/m² (L-form), 5-FU 400 mg/m² bolus and 2400 mg/m² infusion over 46 hours.

    Arm title
    		 Not allocated
    Arm description
    		 Patients unable to continue treatment with cetuximab and FOLFIRI at standard or reduced doses, requiring discontinuation before arm allocation at day 22.
    Arm type
    		 Standard regimen less than 3 weeks

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    Erbitux (TM) Merck
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cetuximab 400 mg/m² (loading at day 1) followed by 250 mg/m² weekly from day 8 onwards. FOLFIRI (simplified de Gramont) starting at day 1, was given every second week: irinotecan 180mg/m², leucovorin 400 mg/m² (racemic) or 200 mg/m² (L-form), 5-FU 400 mg/m² bolus and 2400 mg/m² infusion over 46 hours.

    Number of subjects in period 1
    		Arm A Arm B Not allocated
    Started
    8
    93
    7
    Completed
    8
    93
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Patients with no cetuximab-related skin toxicity or other significant toxicity after first 3 weeks of treatment with cetuximab standard dosing in combination with FOLFIRI, in whom cetuximab doses were increased at day 22.

    Reporting group title
    Arm B
    Reporting group description
    		 Patients with any grade cetuximab-related skin toxicity or other significant toxicity after first 3 weeks of treatment with cetuximab standard dosing in combination with FOLFIRI, in whom cetuximab doses were maintained at standard levels at day 22.

    Reporting group title
    Not allocated
    Reporting group description
    		 Patients unable to continue treatment with cetuximab and FOLFIRI at standard or reduced doses, requiring discontinuation before arm allocation at day 22.

    Reporting group values
    		 Arm A Arm B Not allocated Total
    Number of subjects
    		 8 93 7 108
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 2 69 5 76
        From 65-84 years
    		 6 24 2 32
    Age continuous
    Age at first administration of cetuximab was considered. No split per age group was performed.
    Units: years
        median (full range (min-max))
    		 66 (57 to 76) 60 (30 to 79) 64 (58 to 77) -
    Gender categorical
    Units: Subjects
        Female
    		 5 24 1 30
        Male
    		 3 69 6 78
    Primary tumour
    Right colon= caecum, ascending and transversum colon; left colon= descending and sigmoid colon.
    Units: Subjects
        Colon right
    		 2 16 0 18
        Colon left
    		 2 47 5 54
        Rectum
    		 4 30 2 36
    Tumour stage
    Units: Subjects
        T1
    		 0 2 0 2
        T2
    		 0 2 0 2
        T3
    		 2 46 2 50
        T4
    		 4 27 4 35
        Tx
    		 2 16 1 19
    Nodal stage
    Units: Subjects
        N0
    		 2 7 2 11
        N1
    		 0 24 0 24
        N2
    		 3 34 2 39
        Nx
    		 3 28 3 34
    ECOG PS
    Units: Subjects
        PS=0
    		 6 48 1 55
        PS=1
    		 2 45 6 53
    Metastases
    Units: Subjects
        Liver only
    		 4 39 2 45
        Liver + other
    		 4 45 2 51
        Other (no liver)
    		 0 9 3 12
    Index lesions
    Units: Subjects
        1 location
    		 4 44 4 52
        2 locations
    		 2 28 1 31
        >=3 locations
    		 2 21 2 25
    Prior cancer treatment
    Units: Subjects
        Chemotherapy only
    		 0 4 1 5
        Radiotherapy only
    		 0 1 0 1
        Surgery for primary tumour
    		 1 10 0 11
        Other / Combinations
    		 2 5 0 7
        No prior cancer treatment
    		 5 73 6 84
    Heart rate
    Units: Bpm
        arithmetic mean (full range (min-max))
    		 76.7 (58 to 103) 77.7 (44 to 105) 84.5 (64 to 105) -
    Systolic blood pressure
    Units: mmHg
        arithmetic mean (full range (min-max))
    		 120.9 (78 to 145) 129.7 (90 to 194) 126.6 (88 to 180) -
    Diastolic blood pressure
    Units: mmHg
        arithmetic mean (full range (min-max))
    		 68.9 (55 to 79) 78.8 (57 to 107) 78.7 (61 to 105) -
    Subject analysis sets

    Subject analysis set title
    ITT/Safety Set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients for whom there was evidence they were administered any dose of cetuximab or FOLFIRI on study. For this study, the safety set includes all patients and is identical to the intention-to-treat (ITT) set.

    Subject analysis sets values
    		 ITT/Safety Set
    Number of subjects
    108
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    76
        From 65-84 years
    32
    Age continuous
    Age at first administration of cetuximab was considered. No split per age group was performed.
    Units: years
        median (full range (min-max))
    60 (30 to 79)
    Gender categorical
    Units: Subjects
        Female
    30
        Male
    78
    Primary tumour
    Right colon= caecum, ascending and transversum colon; left colon= descending and sigmoid colon.
    Units: Subjects
        Colon right
    18
        Colon left
    54
        Rectum
    36
    Tumour stage
    Units: Subjects
        T1
    2
        T2
    2
        T3
    50
        T4
    35
        Tx
    19
    Nodal stage
    Units: Subjects
        N0
    11
        N1
    24
        N2
    39
        Nx
    34
    ECOG PS
    Units: Subjects
        PS=0
    55
        PS=1
    53
    Metastases
    Units: Subjects
        Liver only
    45
        Liver + other
    51
        Other (no liver)
    12
    Index lesions
    Units: Subjects
        1 location
    52
        2 locations
    31
        >=3 locations
    25
    Prior cancer treatment
    Units: Subjects
        Chemotherapy only
    5
        Radiotherapy only
    1
        Surgery for primary tumour
    11
        Other / Combinations
    7
        No prior cancer treatment
    84
    Heart rate
    Units: Bpm
        arithmetic mean (full range (min-max))
    78.0 (44 to 105)
    Systolic blood pressure
    Units: mmHg
        arithmetic mean (full range (min-max))
    128.9 (78 to 194)
    Diastolic blood pressure
    Units: mmHg
        arithmetic mean (full range (min-max))
    78.1 (55 to 107)

    End points

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    End points reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Patients with no cetuximab-related skin toxicity or other significant toxicity after first 3 weeks of treatment with cetuximab standard dosing in combination with FOLFIRI, in whom cetuximab doses were increased at day 22.

    Reporting group title
    Arm B
    Reporting group description
    		 Patients with any grade cetuximab-related skin toxicity or other significant toxicity after first 3 weeks of treatment with cetuximab standard dosing in combination with FOLFIRI, in whom cetuximab doses were maintained at standard levels at day 22.

    Reporting group title
    Not allocated
    Reporting group description
    		 Patients unable to continue treatment with cetuximab and FOLFIRI at standard or reduced doses, requiring discontinuation before arm allocation at day 22.

    Subject analysis set title
    ITT/Safety Set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients for whom there was evidence they were administered any dose of cetuximab or FOLFIRI on study. For this study, the safety set includes all patients and is identical to the intention-to-treat (ITT) set.

    Primary: Progression free survival (PFS) rate at 9 months

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    End point title
    		 Progression free survival (PFS) rate at 9 months
    End point description
    The PFS rate at 9 months is defined as the Kaplan-Meier estimate of the probability of being alive and free of progression at 9 months. All patients (ITT).
    End point type
    Primary
    End point timeframe
    Treatment + follow-up (3 years from database lock)
    End point values
    		 Arm A Arm B Not allocated ITT/Safety Set
    Number of subjects analysed
    8
    93
    7
    108
    Units: %
    45
    58
    0
    55
    Statistical analysis title
    		 Progression free survival (PFS) rate at 9 months
    Statistical analysis description
    Proportion estimates from Kaplan-Meier analysis and 95% CI were: Arm A: 45.0 [8.1;81.9]; Arm B: 58.3 [47.3;69.3]; Not allocated: 0.0 [0.0;0.0]; ITT/Safety Set: 55.0 [44.6;65.4]. No formal statistical comparison between groups was performed. Details on PFS definition are provided in attached documents. Detailed data available upon request.
    Comparison groups
    Arm A v Arm B v Not allocated
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    Method
    Parameter type
    		 percentage
    Point estimate
    55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 44.6
         upper limit
    		 65.4
    Variability estimate
    Standard deviation
    Notes
    [1] - Proportion estimates from Kaplan-Meier.

    Secondary: Progression free survival (PFS) median time

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    End point title
    		 Progression free survival (PFS) median time
    End point description
    Progression free survival time was considered from start of treatment until the first observation of disease progression or death from any cause, whichever occurred first. All patients (ITT).
    End point type
    Secondary
    End point timeframe
    Treatment + follow-up (3 years from database lock)
    End point values
    		 Arm A Arm B Not allocated ITT/Safety Set
    Number of subjects analysed
    8
    93
    7
    108
    Units: Months
        median (confidence interval 95%)
    8.8 (6.2 to 25.6)
    11.5 (8.2 to 14.0)
    1.3 (0.9 to 1.5)
    10.7 (8.1 to 13.7)
    Statistical analysis title
    		 PFS median time (all patients)
    Statistical analysis description
    Kaplan-Meier analysis. No formal statistical comparison between groups was performed. Details on PFS definition are provided in attached documents. Detailed data available upon request.
    Comparison groups
    Arm A v Arm B v Not allocated
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    Method
    Parameter type
    		 Months
    Point estimate
    10.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 8.1
         upper limit
    		 13.7
    Variability estimate
    Standard deviation
    Notes
    [2] - Kaplan-Meier.

    Secondary: Progression free survival (PFS) median time for resected patients

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    End point title
    		 Progression free survival (PFS) median time for resected patients [3]
    End point description
    Progression free survival time was considered from start of treatment until the first observation of disease progression or death from any cause, whichever occurred first. This is the subset of resected patients (resection of secondary lesions with curative intent was performed). Patients resected after they started subsequent anti-cancer treatment (600-01-006 and 600-04-006) or after progression on treatment (100-02-002, 200-03-001, and 600-01-038) were not considered as 'resected for metastatic lesions on study'. Patients were not censored at time of surgery. See appendix 3 for definitions of PFS.
    End point type
    Secondary
    End point timeframe
    Treatment + follow-up (3 years from database lock)
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There were no resected patients among the patients in the arm "not allocated". This is a subset analysis.
    End point values
    		 Arm A Arm B ITT/Safety Set
    Number of subjects analysed
    1
    16
    17
    Units: Months
        median (confidence interval 95%)
    11.3 (0 to 999)
    14.5 (12.7 to 17.9)
    14.2 (11.3 to 17.9)
    Statistical analysis title
    		 PFS median time (resected patients)
    Statistical analysis description
    Kaplan-Meier analysis. If median and/or 95% CI was not estimable, code 999 was entered. No formal statistical comparison between groups was performed. Details on PFS definition are provided in attached documents. Detailed data available upon request.
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    Method
    Parameter type
    		 Months
    Point estimate
    14.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 11.3
         upper limit
    		 17.9
    Variability estimate
    Standard deviation
    Notes
    [4] - Kaplan-Meier.

    Secondary: Progression free survival (PFS) time for resected versus non-resected patients (hazard ratio)

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    End point title
    		 Progression free survival (PFS) time for resected versus non-resected patients (hazard ratio)
    End point description
    Progression free survival time was considered from start of treatment until the first observation of disease progression or death from any cause, whichever occurred first. This is the subset of resected patients (resection of secondary lesions with curative intent was performed). Patients resected after they started subsequent anti-cancer treatment (600-01-006 and 600-04-006) or after progression on treatment (100-02-002, 200-03-001, and 600-01-038) were not considered as 'resected for metastatic lesions on study'. Patients were not censored at time of surgery. See appendix 3 for definitions of PFS.
    End point type
    Secondary
    End point timeframe
    Treatment + follow-up (3 years from database lock)
    End point values
    		 Arm A Arm B Not allocated ITT/Safety Set
    Number of subjects analysed
    8
    93
    7
    108
    Units: Hazard ratio
        number (confidence interval 95%)
    1.17 (0.13 to 10.60)
    0.82 (0.48 to 1.42)
    999 (999 to 999)
    0.79 (0.47 to 1.34)
    Statistical analysis title
    		 PFS time resected versus non-resected patients
    Statistical analysis description
    Cox proportional hazard. If Hazard ratio was not available (no resections performed) and 95% CI was not estimable, code 999 was entered. Number of resected patients were: Arm A: 1; Arm B: 16; Not allocated: 0; ITT/Safety Set: 17. Number of not-resected patients were: Arm A: 7; Arm B: 77; Not allocated: 7; ITT/Safety Set: 91. No formal statistical comparison between groups was performed. Details on PFS definition are provided in attached documents. Detailed data available upon request.
    Comparison groups
    Arm A v Arm B v Not allocated
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 1.34
    Variability estimate
    Standard deviation
    Notes
    [5] - Cox proportional hazard.

    Secondary: Death rates by 3 years follow-up

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    End point title
    		 Death rates by 3 years follow-up
    End point description
    Deaths by 3 years follow-up after last cetuximab administration + 30 days. All patients (ITT).
    End point type
    Secondary
    End point timeframe
    Treatment + follow-up (3 years from database lock)
    End point values
    		 Arm A Arm B Not allocated ITT/Safety Set
    Number of subjects analysed
    8
    93
    7
    108
    Units: Number of subjects
        Deceased
    6
    65
    7
    78
        Alive after 3 years follow-up
    2
    16
    0
    18
        Lost to follow-up before 3 years follow-up
    0
    12
    0
    12
    No statistical analyses for this end point

    Secondary: Overall survival (OS) median time

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    End point title
    		 Overall survival (OS) median time
    End point description
    Overall survival was considered from start of treatment to death. All patients (ITT).
    End point type
    Secondary
    End point timeframe
    Treatment + follow-up (3 years from database lock)
    End point values
    		 Arm A Arm B Not allocated ITT/Safety Set
    Number of subjects analysed
    8
    93
    7
    108
    Units: Months
        median (confidence interval 95%)
    28.4 (12.0 to 999)
    31.4 (25.5 to 34.9)
    4.9 (1.0 to 12.5)
    29.8 (22.4 to 33.3)
    Statistical analysis title
    		 OS median time (all patients)
    Statistical analysis description
    Kaplan-Meier analysis. If median and/or 95% CI was not estimable, code 999 was entered. No formal statistical comparison between groups was performed. Detailed data available upon request.
    Comparison groups
    Arm A v Arm B v Not allocated
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    Method
    Parameter type
    		 Months
    Point estimate
    29.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 22.4
         upper limit
    		 33.3
    Variability estimate
    Standard deviation
    Notes
    [6] - Kaplan-Meier.

    Secondary: Overall survival (OS) median time for resected patients

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    End point title
    		 Overall survival (OS) median time for resected patients [7]
    End point description
    Overall survival was considered from start of treatment to death. Subset of resected patients (resection of secondary lesions with curative intent was performed). Patients resected after they started subsequent anti-cancer treatment (600-01-006 and 600-04-006) or after progression (100-02-002, 200-03-001, and 600-01-038) were not considered as 'resected for metastatic lesions on study'.
    End point type
    Secondary
    End point timeframe
    Treatment + follow-up (3 years from database lock)
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There were no resected patients among the patients in the arm "not allocated". This is a subset analysis.
    End point values
    		 Arm A Arm B ITT/Safety Set
    Number of subjects analysed
    1
    16
    17
    Units: Months
        median (confidence interval 95%)
    999 (999 to 999)
    999 (32.7 to 999)
    999 (32.7 to 999)
    Statistical analysis title
    		 OS median time (resected patients)
    Statistical analysis description
    Kaplan-Meier analysis. If median and/or 95% CI was not estimable, code 999 was entered. No formal statistical comparison between groups was performed. Detailed data available upon request.
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    Method
    Parameter type
    		 Counts
    Point estimate
    999
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 32.7
         upper limit
    		 999
    Variability estimate
    Standard deviation
    Notes
    [8] - Kaplan-Meier.

    Secondary: Overall response

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    End point title
    		 Overall response
    End point description
    Overall response is defined as the best tumor response on treatment of either complete response (CR) or partial response (PR) (CR + PR). Tumor response is based on the assessments (CT/MRI) for target and non-target lesions as well as considering the occurrence of new lesions as per RECIST criteria. All patients (ITT).
    End point type
    Secondary
    End point timeframe
    Treatment
    End point values
    		 Arm A Arm B Not allocated ITT/Safety Set
    Number of subjects analysed
    8
    93
    7
    108
    Units: Number of subjects
        CR or PR
    6
    64
    0
    70
        Other (SD, PD, not evaluable, missing)
    2
    29
    7
    38
    Statistical analysis title
    		 Overall response
    Statistical analysis description
    Descriptive. Rates of overall response (CR or PR) with confidence intervals were calculated per arm: Arm A: 75.0% [34.9%;96.8%]; Arm B: 68.8% [58.4%;78.0%]; Not allocated: 0.0% [0.0%;41.0%]; ITT/Safety Set: 64.8% [55.0%;73.8%]. No formal statistical comparison between arms was performed. Detailed data available upon request.
    Comparison groups
    Arm A v Arm B v Not allocated
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    Method
    Parameter type
    		 percentage
    Point estimate
    64.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 55
         upper limit
    		 73.8
    Variability estimate
    Standard deviation
    Notes
    [9] - Descriptive.

    Secondary: Overall response in patients with liver-limited disease

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    End point title
    		 Overall response in patients with liver-limited disease
    End point description
    Overall response is defined as the best tumor response on treatment of either complete response (CR) or partial response (PR) (CR + PR). Tumor response is based on the assessments (CT/MRI) for target and non-target lesions as well as considering the occurrence of new lesions as per RECIST criteria. Subset of patients with liver-limited disease.
    End point type
    Secondary
    End point timeframe
    Treatment
    End point values
    		 Arm A Arm B Not allocated ITT/Safety Set
    Number of subjects analysed
    4
    39
    2
    45
    Units: Number of subjects
        CR or PR
    2
    30
    0
    32
        Other (SD, PD, missing)
    2
    9
    2
    13
    Statistical analysis title
    		 Overall response (liver-limited disease)
    Statistical analysis description
    Descriptive. Rates of overall response (CR or PR) with confidence intervals were calculated per arm: Arm A: 50.0% [6.8%;93.2%]; Arm B: 76.9% [60.7%;88.9%]; Not allocated: 0.0% [0.0%;84.2%]; ITT/Safety Set: 71.1% [55.7%;83.6%]. No formal statistical comparison between arms was performed. Detailed data available upon request.
    Comparison groups
    Arm A v Arm B v Not allocated
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    Method
    Parameter type
    		 percentage
    Point estimate
    71.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 55.7
         upper limit
    		 83.6
    Variability estimate
    Standard deviation
    Notes
    [10] - Descriptive.

    Secondary: Disease control

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    End point title
    		 Disease control
    End point description
    Disease control is defined as a best response on treatment (e.g. till end of treatment evaluation) of either complete response (CR), partial response (PR), or stable disease (SD) (CR + PR + SD). RECIST criteria (CT/MRI). All patients (ITT).
    End point type
    Secondary
    End point timeframe
    Treatment
    End point values
    		 Arm A Arm B Not allocated ITT/Safety Set
    Number of subjects analysed
    8
    93
    7
    108
    Units: Number of subjects
        CR, PR, or SD
    8
    84
    0
    92
        Other (PD, not evaluable, missing)
    0
    9
    7
    16
    Statistical analysis title
    		 Counts of disease control
    Statistical analysis description
    Descriptive. Rates of disease control (CR, PR, or SD) with confidence intervals were calculated per arm: Arm A: 100% [63.1%;100%]; Arm B: 90.3% [82.4%;95.5%]; Not allocated: 0.0% [0.0%;41.0%]; ITT/Safety Set: 85.2% [77.1%;91.3%] No formal statistical comparison between groups was performed. Detailed data available upon request.
    Comparison groups
    Arm A v Arm B v Not allocated
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    Method
    Parameter type
    		 Counts
    Point estimate
    85.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 77.1
         upper limit
    		 91.3
    Variability estimate
    Standard deviation
    Notes
    [11] - Descriptive.

    Secondary: Disease control in patients with liver-limited disease

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    End point title
    		 Disease control in patients with liver-limited disease
    End point description
    Disease control is defined as a best response on treatment (e.g. till end of treatment evaluation) of either complete response (CR), partial response (PR), or stable disease (SD) (CR + PR + SD). RECIST criteria (CT/MRI). Subset of patients with liver-limited disease.
    End point type
    Secondary
    End point timeframe
    Treatment
    End point values
    		 Arm A Arm B Not allocated ITT/Safety Set
    Number of subjects analysed
    4
    39
    2
    45
    Units: Number of subjects
        CR, PR, or SD
    4
    37
    0
    41
        Other (PD, missing)
    0
    2
    2
    4
    Statistical analysis title
    		 Counts of disease control (liver-limited disease)
    Statistical analysis description
    Descriptive. Rates of disease control (CR, PR, or SD) with confidence intervals were calculated per arm: Arm A: 100% [39.8%;100%]; Arm B: 94.9% [82.7%;99.4%]; Not allocated: 0.0% [0.0%;84.2%]; ITT/Safety Set: 91.1% [78.8%;97.5%]. No formal statistical comparison between groups was performed. Detailed data available upon request.
    Comparison groups
    Arm A v Arm B v Not allocated
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    Method
    Parameter type
    		 Counts
    Point estimate
    91.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 78.8
         upper limit
    		 97.5
    Variability estimate
    Standard deviation
    Notes
    [12] - Descriptive.

    Secondary: Duration of response

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    End point title
    		 Duration of response [13]
    End point description
    The duration of response in responding patients is defined as the time interval from the time measurement criteria are first met for CR/PR during treatment to either the first time disease progression is documented or death. Subset of responders.
    End point type
    Secondary
    End point timeframe
    Treatment + follow-up (3 years from database lock)
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There were no responders among the patients in the arm "not allocated". This is a subset analysis.
    End point values
    		 Arm A Arm B ITT/Safety Set
    Number of subjects analysed
    6
    64
    70
    Units: Months
        median (confidence interval 95%)
    8.3 (3.6 to 24.2)
    11.7 (9.7 to 14.6)
    11.7 (8.6 to 15.4)
    Statistical analysis title
    		 Duration of response
    Statistical analysis description
    Kaplan-Meier analysis of duration of response for the patients with an assessment of CR or PR at any time during the study. No formal statistical comparison between groups was performed. Detailed data available upon request.
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 other [14]
    Method
    Parameter type
    		 Months
    Point estimate
    11.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 8.6
         upper limit
    		 15.4
    Variability estimate
    Standard deviation
    Notes
    [14] - Kaplan-Meier

    Secondary: Duration of response in liver-limited disease patients

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    End point title
    		 Duration of response in liver-limited disease patients [15]
    End point description
    The duration of response in responding patients is defined as the time interval from the time measurement criteria are first met for CR/PR during treatment to either the first time disease progression is documented or death. Subset of responders among patients with liver-limited disease.
    End point type
    Secondary
    End point timeframe
    Treatment + follow-up (3 years from database lock)
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There were no responders among the patients in the arm "not allocated". This is a subset analysis.
    End point values
    		 Arm A Arm B ITT/Safety Set
    Number of subjects analysed
    2
    30
    32
    Units: Months
        median (confidence interval 95%)
    13.9 (3.6 to 24.2)
    11.1 (7.6 to 13.0)
    11.1 (7.6 to 22.5)
    Statistical analysis title
    		 Duration of response (liver-limited disease)
    Statistical analysis description
    Kaplan-Meier analysis of duration of response for the patients with an assessment of CR or PR at any time during the study. No formal statistical comparison between groups was performed. Detailed data available upon request.
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 other [16]
    Method
    Parameter type
    		 Months
    Point estimate
    11.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 7.6
         upper limit
    		 22.5
    Variability estimate
    Standard deviation
    Notes
    [16] - Kaplan-Meier.

    Secondary: Resections for metastatic lesions

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    End point title
    		 Resections for metastatic lesions
    End point description
    All patients were deemed non-resectable at baseline but some became resectable during or post-treatment. All patients (ITT). Only those patients in whom resection of secondary lesions with curative intent was performed were considered as 'resected'. Patients resected after they started subsequent anti-cancer treatment (600-01-006 and 600-04-006) or after progression (100-02-002, 200-03-001, and 600-01-038) were not considered as 'resected for metastatic lesions on study'.
    End point type
    Secondary
    End point timeframe
    Treatment + follow-up (3 years from database lock)
    End point values
    		 Arm A Arm B Not allocated ITT/Safety Set
    Number of subjects analysed
    8
    93
    7
    108
    Units: Number of subjects
        Resected (surgery with curative intent performed)
    1
    16
    0
    17
        Non-resected
    7
    77
    7
    91
    No statistical analyses for this end point

    Secondary: R0 rate (free of tumor after resection for metastatic lesions)

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    End point title
    		 R0 rate (free of tumor after resection for metastatic lesions) [17]
    End point description
    Rate of patients free of tumor after surgery. Subset of resected patients (resection of secondary lesions with curative intent was performed). Patients resected after they started subsequent anti-cancer treatment (600-01-006 and 600-04-006) or after progression (100-02-002, 200-03-001, and 600-01-038) were not considered as 'resected for metastatic lesions on study'.
    End point type
    Secondary
    End point timeframe
    Treatment + follow-up (3 years from database lock)
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There were no resected patients among the patients in the arm "not allocated". This is a subset analysis.
    End point values
    		 Arm A Arm B ITT/Safety Set
    Number of subjects analysed
    1
    16
    17
    Units: Number of subjects
        Free of tumor
    1
    12
    13
        Not free of tumor
    0
    4
    4
    No statistical analyses for this end point

    Secondary: Skin toxicity (safety)

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    End point title
    		 Skin toxicity (safety)
    End point description
    Treatment-emergent adverse events identified by the investigator as skin reaction or events with description skin infection or nail infection. These events were not always considered by the investigator for arm allocation: Arm A: Patient 100-09-002 - Rash acneiform (Minimal redness of skin of the forehead) unrelated to cetuximab and patient 100-11-001 - Rash acneiform (only on the chin) lasting 5 days during the first 3 weeks, possibly related to cetuximab: These patients were escalated notwithstanding these events. Arm B: Patient 300-07-001 was not escalated though at Infusion visit 4, no skin reaction grade 1 or higher had appeared. Worst grade per patient. All patients treated (Safety).
    End point type
    Secondary
    End point timeframe
    From signature of informed consent to end of treatment visit plus 30 days.
    End point values
    		 Arm A Arm B Not allocated
    Number of subjects analysed
    8
    93
    7
    Units: Number of subjects
        Any (onset prior to arm allocation)
    2
    92
    3
        Any (all times)
    7
    93
    3
        Grade 1
    0
    19
    2
        Grade 2
    5
    44
    1
        Grade 3
    2
    30
    0
    No statistical analyses for this end point

    Secondary: Laboratory safety assessments

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    End point title
    		 Laboratory safety assessments
    End point description
    Severe laboratory abnormalities (hematology and biochemistry grade 3 and higher). Worst grade per patient. All patients treated (Safety).
    End point type
    Secondary
    End point timeframe
    From signature of informed consent to end of treatment visit plus 30 days.
    End point values
    		 Arm A Arm B Not allocated
    Number of subjects analysed
    8
    93
    7
    Units: Number of subjects
        Hemoglobin decreased
    0
    3
    0
        White blood cell count decreased
    3
    8
    0
        Neutrophils decreased
    3
    19
    0
        Lymphocytes decreased
    2
    6
    0
        Platelet count decreased
    0
    2
    0
        Bilirubin increased
    0
    3
    0
        ALAT increased
    0
    2
    0
        ASAT increased
    0
    1
    0
        ALP increased
    2
    4
    0
        Sodium decreased
    1
    3
    1
        Potassium decreased
    2
    7
    0
        Magnesium decreased
    1
    2
    0
        Magnesium increased
    0
    1
    0
        Serum calcium decreased
    0
    2
    0
    No statistical analyses for this end point

    Secondary: Deaths till 30 days from last cetuximab administration

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    End point title
    		 Deaths till 30 days from last cetuximab administration
    End point description
    Deaths of all causes occuring between the signature of consent and the date of last cetuximab administration + 30 days are listed per arm. None of these fatalities were deemed related to the investigational drug. Details are provided in attached documents.
    End point type
    Secondary
    End point timeframe
    From signature of informed consent to last cetuximab administration plus 30 days.
    End point values
    		 Arm A Arm B Not allocated ITT/Safety Set
    Number of subjects analysed
    8
    93
    7
    108
    Units: Number of subjects
        All causes
    1
    6
    2
    9
        Colonic perforation
    1
    0
    0
    1
        Malaise
    0
    1
    0
    1
        Bronchial infection
    0
    1
    0
    1
        Lung infection
    0
    1
    0
    1
        Circulatory failure
    0
    1
    0
    1
        Cardiac arrest
    0
    1
    0
    1
        Colonic obstruction
    0
    1
    0
    1
        Peritoneal infection
    0
    0
    1
    1
        Ileus
    0
    0
    1
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From signature of informed consent to end of treatment visit plus 30 days.
    Adverse event reporting additional description
    SAEs occurring between ICF signature and EOT+30 days are listed. Fatalities are entered if occurred within 30 days from last drug administration. All severe AEs (grade 3-5) including SAEs, are listed in the non-serious AE table. Skin toxicity and severe lab abnormalities are further detailed in section End points.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 NCI-CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Patients with no cetuximab-related skin toxicity or other significant toxicity after first 3 weeks of treatment with cetuximab standard dosing in combination with FOLFIRI, in whom cetuximab doses were increased at day 22.

    Reporting group title
    Arm B
    Reporting group description
    		 Patients with any grade cetuximab-related skin toxicity or other significant toxicity after first 3 weeks of treatment with cetuximab standard dosing in combination with FOLFIRI, in whom cetuximab doses were maintained at standard levels at day 22.

    Reporting group title
    Not allocated
    Reporting group description
    		 Patients unable to continue treatment with cetuximab and FOLFIRI at standard or reduced doses, requiring discontinuation before arm allocation at day 22.

    Serious adverse events
    		 Arm A Arm B Not allocated
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 8 (75.00%)
    39 / 93 (41.94%)
    6 / 7 (85.71%)
         number of deaths (all causes)
    1
    6
    2
         number of deaths resulting from adverse events
    1
    6
    2
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 6
    0 / 2
    White blood cell decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 6
    0 / 2
    Vascular disorders
    Circulatory failure
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 6
    0 / 2
    Thromboembolic event
         subjects affected / exposed
    0 / 8 (0.00%)
    8 / 93 (8.60%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 8
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 6
    0 / 2
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 6
    0 / 2
    Ventricular fibrillation
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 6
    0 / 2
    Nervous system disorders
    Ischemia cerebrovascular
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 93 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 6
    0 / 2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 6
    0 / 2
    Fever
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 93 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 6
    0 / 2
    Malaise
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 6
    0 / 2
    Immune system disorders
    Anaphylaxis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 6
    0 / 2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 93 (3.23%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 6
    0 / 2
    Colonic hemorrhage
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 6
    0 / 2
    Colonic obstruction
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 93 (3.23%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 6
    0 / 2
    Colonic perforation
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 93 (1.08%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 6
    0 / 2
    Diarrhea
         subjects affected / exposed
    2 / 8 (25.00%)
    2 / 93 (2.15%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 6
    0 / 2
    Enterocolitis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 6
    0 / 2
    Ileus
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 6
    0 / 2
    Jejunal obstruction
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 93 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 6
    0 / 2
    Rectal hemorrhage
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 6
    0 / 2
    Small intestinal obstruction
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 93 (3.23%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 6
    0 / 2
    Hepatobiliary disorders
    Gallbladder obstruction
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 93 (2.15%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 6
    0 / 2
    Hepatic hematoma
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 93 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 6
    0 / 2
    Portal vein thrombosis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 6
    0 / 2
    Respiratory, thoracic and mediastinal disorders
    Respiratory insufficiency
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 6
    0 / 2
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 6
    0 / 2
    Infections and infestations
    Bronchial infection
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 93 (2.15%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 6
    0 / 2
    Catheter related infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 6
    0 / 2
    Enterocolitis infectious
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 6
    0 / 2
    Erysipelas
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 6
    0 / 2
    Kidney infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 6
    0 / 2
    Lung infection
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 93 (3.23%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 6
    0 / 2
    Pelvic infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 6
    0 / 2
    Peritoneal infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 93 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 6
    0 / 2
    Sepsis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 6
    0 / 2
    Urinary tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 6
    0 / 2
    Yersinia enterocolitica gastroenteritis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 6
    0 / 2
    Metabolism and nutrition disorders
    Diabetes angiopathy
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 6
    0 / 2
    Severe undernutrition
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 6
    0 / 2
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Arm A Arm B Not allocated
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 8 (75.00%)
    66 / 93 (70.97%)
    3 / 7 (42.86%)
    Vascular disorders
    Circulatory failure
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Thromboembolic event
         subjects affected / exposed
    0 / 8 (0.00%)
    11 / 93 (11.83%)
    0 / 7 (0.00%)
         occurrences all number
    0
    11
    0
    General disorders and administration site conditions
    General deterioration
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Fatigue
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 93 (3.23%)
    0 / 7 (0.00%)
         occurrences all number
    0
    5
    0
    Immune system disorders
    Anaphylaxis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary edema
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory failure
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Dyspnea
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory insufficiency
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Investigations
    Weight gain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 93 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Syncope
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 93 (3.23%)
    0 / 7 (0.00%)
         occurrences all number
    0
    5
    0
    Febrile neutropenia
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 93 (2.15%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    Leukocytosis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    1
    Colonic haemorrhage
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Hemorrhoids
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 93 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Colonic obstruction
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 93 (3.23%)
    0 / 7 (0.00%)
         occurrences all number
    0
    4
    0
    Diarrhea
         subjects affected / exposed
    2 / 8 (25.00%)
    14 / 93 (15.05%)
    0 / 7 (0.00%)
         occurrences all number
    2
    20
    0
    Ileus
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Colonic perforation
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 93 (1.08%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    1
    Small intestinal obstruction
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 93 (2.15%)
    1 / 7 (14.29%)
         occurrences all number
    0
    2
    1
    Jejunal obstruction
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 93 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Mucositis oral
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 93 (3.23%)
    0 / 7 (0.00%)
         occurrences all number
    0
    3
    0
    Vomiting
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 93 (2.15%)
    1 / 7 (14.29%)
         occurrences all number
    0
    2
    1
    Hepatobiliary disorders
    Gallbladder obstruction
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 93 (2.15%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    Hepatic hematoma
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 93 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Portal vein thrombosis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Hepatic pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Hypertrichosis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 93 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Fissure/feet
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Fissure/fingers
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Pruritus
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 93 (2.15%)
    0 / 7 (0.00%)
         occurrences all number
    0
    3
    0
    Rash maculo-papular
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 93 (2.15%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    Rash acneiform
         subjects affected / exposed
    0 / 8 (0.00%)
    17 / 93 (18.28%)
    0 / 7 (0.00%)
         occurrences all number
    0
    25
    0
    Skin hyperpigmentation
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 93 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    Bronchial infection
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 93 (2.15%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    Enterocolitis infectious
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Acute cytolysis due to viral infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Erysipelas
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Lung infection
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 93 (3.23%)
    0 / 7 (0.00%)
         occurrences all number
    0
    3
    0
    Paronychia
         subjects affected / exposed
    2 / 8 (25.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences all number
    2
    3
    0
    Catheter related infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    Kidney infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Papulopustular rash
         subjects affected / exposed
    0 / 8 (0.00%)
    7 / 93 (7.53%)
    0 / 7 (0.00%)
         occurrences all number
    0
    16
    0
    Skin infection
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences all number
    1
    1
    0
    Pelvic infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Peritoneal infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 93 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Yersinia enterocolitica gastroenteritis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Sepsis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 93 (2.15%)
    0 / 7 (0.00%)
         occurrences all number
    1
    3
    0
    Diabetes angiopathy
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Hypokalemia
         subjects affected / exposed
    2 / 8 (25.00%)
    2 / 93 (2.15%)
    0 / 7 (0.00%)
         occurrences all number
    4
    7
    0
    Dehydration
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Hyperglycemia
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 93 (2.15%)
    0 / 7 (0.00%)
         occurrences all number
    0
    4
    0
    Hypophosphatemia
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 93 (2.15%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    Hyponatremia
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences all number
    2
    1
    0
    Hypomagnesemia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 93 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Severe undernutrition
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 93 (1.08%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 May 2013
    The amendment consisted mainly of reducing the total sample size from the initially planned 375 patients to 130 patients in two study arms due to general slow accrual. The amended protocol and amended ICF have been approved in all participating countries during the year 2013.
    01 Apr 2016
    Recruitment was stopped at 108 patients in April 2014 due to slow accrual that determined a much longer duration than limited academic financial resources could sustain. In March 2016, there were 2 patients in Spain still receiving treatment. The amendment of April 2016, submitted in Spain only, was necessary to early terminate the trial while these patients were actively receiving study medication. Arrangements had been made for them to continue treatment outside of trial.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    07 Jan 2013
    Temporary interruption due to administrative reasons (change of CRO in charge for project management and pharmacovigilance).
    05 Feb 2013

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Insufficient population in escalation arm A as early skin toxicity in most patients; study not powered for formal comparison between arms. Systematic error sources: some AEs re-coded by sponsor, misclassification bias (local response assessment).
    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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