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    Clinical Trial Results:
    Phase II multicentric randomized trial, evaluating the best protocol of chemotherapy, associated with targeted therapy according to the tumor RAS (KRAS and NRAS) status, in Metastatic Colorectal Cancer (MCRC) Patients With Initially Nonresectable Hepatic Metastases (METHEP-2)

    Summary
    EudraCT number
    		 2009-012813-22
    Trial protocol
    		 FR  
    Global end of trial date
    06 Jan 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Jan 2025
    First version publication date
    05 Jan 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    PRODIGE 14 - ACCORD 21/0905
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01442935
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    UNICANCER
    Sponsor organisation address
    101 rue de Tolbiac, Paris, France,
    Public contact
    Nourredine AIT-RAHMOUNE,, UNICANCER, 33 0171936704, n.ait-rahmoune@unicancer.fr
    Scientific contact
    Nourredine AIT-RAHMOUNE,, UNICANCER, 33 0171936704, n.ait-rahmoune@unicancer.fr
    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
    15 Jan 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Dec 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Jan 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Prodige 14 - Accord 21 was a multicenter, open-label, randomized (1:1) phase II study. The primary objective was to assess which of BiCT or TriCT combined with a targeted therapy as conversion therapy would provide the better hepatic metastasis resection rates in colorectal cancer patients with initially non-resectable hepatic metastases. Patients randomized to the BiCT Arm were also randomly allocated BiCT, either FOLFIRI or FOLFOX.
    Protection of trial subjects
    This study was conducted in accordance with the Declaration of Helsinki (1964) and subsequent amendments, ICH Good Clinical Practice (GCP) Guidelines (CPMP/ICH/135/95), the European Directive (2001/20/CE) and the applicable local regulatory requirements and laws. Furthermore, independent Ethics Committees reviewed and gave favorable opinions to the study documents, including the initial protocol and all subsequent amendments, and all information and documents provided to subjects/patients. Written informed consent was obtained from all patients prior to enrollment.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Feb 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 256
    Worldwide total number of subjects
    256
    EEA total number of subjects
    256
    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)
    181
    From 65 to 84 years
    75
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The Prodige 17 – Accord 21 study randomized 256 patients, in 33 centers in France, between 09-Feb-2011 and the 30-Apr-2015. Overall, 126 patients were randomized to bi-chemotherapy (BiCT) and 130 to tri-chemotherapy (TriCT).

    Pre-assignment
    Screening details
    		 The study consisted of screening phase to establish patients' eligibility and document baseline measurements, a treatment phase 12 cycles in both study arms, and a long-term follow-up to monitor the hepatic metastases resection, objestive response rate, complete remission rate, relapse free survival rate, overall survival and the safety.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 BiCT Arm
    Arm description
    		 Patients were randomly allocated either FOLFIRI or FOLFOX chemotherapy every 14 days (2-week cycles) combined with targeted therapy according to the patient tumor RAS status (initially KRAS): cetuximab if wt-RAS (initially wt-KRAS) or bevacizumab if mt-RAS (initially mt-KRAS). *FOLFIRI or FOLFOX chemotherapy: -FOLFOX: oxaliplatin (85 mg/m2), folinic acid (400 mg/m2) or L-folinic acid (200 mg/m2), a bolus dose of fluorouracil (400 mg/m2), and a 46-h infusion of fluorouracil (2400 mg/m2). Or -FOLFIRI: irinotecan (180 mg/m2), folinic acid (400 mg/m2) or L-folinic acid (200 mg/m2), a bolus dose of fluorouracil (400 mg/m2), and a 46-h infusion of fluorouracil (2400 mg/m2). *targeted therapy: mt-RAS (initially mt-KRAS) patients received bevacizumab (5 mg/kg) and wt-RAS (initially wt-KRAS) patients received cetuximab (500 mg/m2) intravenously on day 1 of each chemotherapy cycle.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    oxaliplatin or rinotecan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    85 mg/m² (oxaliplatin) on day 1 every 14 days (2-week cycles) for patients were randomly allocated to FOLFOX chemotherapy every 14 days (2-week cycles). 180 mg/m2 (180 mg/m2) on day 1 every 14 days (2-week cycles) for patients were randomly allocated to FOLFIRI chemotherapy every 14 days (2-week cycles).

    Investigational medicinal product name
    folinic acid/L-folinic acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    400 mg/m2 (folinic acid) or 200 mg/m2 (L-folinic acid) on day 1 every 14 days (2-week cycles)

    Investigational medicinal product name
    fluorouracil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    400 mg/m² bolus on day 1 then 2400 mg/m² infusion over 46 h every 14 days.

    Investigational medicinal product name
    bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mg/kg intravenously on day 1 of each chemotherapy cycle for mt-RAS (initially mt-KRAS) patients.

    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
    500 mg/m2 intravenously on day 1 of each chemotherapy cycle for wt-RAS (initially wt-KRAS) patients.

    Arm title
    		 TriCT Arm
    Arm description
    		 Patients were administered FOLFIRINOX chemotherapy every 14 days (2-week cycles) combined with targeted therapy according to the patient tumor RAS status (initially KRAS): cetuximab if wt-RAS (initially wt-KRAS) or bevacizumab if mt-RAS (initially mt-KRAS). *FOLFIRINOX regimen on day 1 of each 2-week cycle as follows: oxaliplatin (85 mg/m2) was administered as an intravenous. infusion for 120 min, followed by irinotecan (150 mg/m2) as an intravenous infusion over 90 min and leucovorin (200 mg/m2) as an intravenous infusion over 120 min. Fluorouracil (400 mg/m2) was delivered as a bolus, followed by a 46-h continuous infusion at 2400 mg/m2. *targeted therapy: mt-RAS patients received bevacizumab (5 mg/kg) and wt-RAS patients received cetuximab (500 mg/m2) intravenously on day 1 of each chemotherapy cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    oxaliplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    85 mg/m² on day 1 every 14 days

    Investigational medicinal product name
    irinotecan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    150 mg/m2 on day 1 every 14 days

    Investigational medicinal product name
    Leucovorin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg/m2 on day 1 evry 14 days

    Investigational medicinal product name
    fluorouracil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    400 mg/m² bolus on day 1 then 2400 mg/m² infusion over 46 h every 14 days.

    Investigational medicinal product name
    bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mg/kg intravenously on day 1 of each chemotherapy cycle for mt-RAS (initially mt-KRAS) patients.

    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
    500 mg/m2 intravenously on day 1 of each chemotherapy cycle for wt-RAS (initially wt-KRAS) patients.

    Number of subjects in period 1
    		BiCT Arm TriCT Arm
    Started
    126
    130
    Completed
    73
    75
    Not completed
    53
    55
         Consent withdrawn by subject
    1
    -
         Physician decision
    18
    23
         Disease progression
    11
    9
         Toxicity
    10
    11
         Death
    5
    4
         Other reason
    7
    7
         Lost to follow-up
    1
    -
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BiCT Arm
    Reporting group description
    		 Patients were randomly allocated either FOLFIRI or FOLFOX chemotherapy every 14 days (2-week cycles) combined with targeted therapy according to the patient tumor RAS status (initially KRAS): cetuximab if wt-RAS (initially wt-KRAS) or bevacizumab if mt-RAS (initially mt-KRAS). *FOLFIRI or FOLFOX chemotherapy: -FOLFOX: oxaliplatin (85 mg/m2), folinic acid (400 mg/m2) or L-folinic acid (200 mg/m2), a bolus dose of fluorouracil (400 mg/m2), and a 46-h infusion of fluorouracil (2400 mg/m2). Or -FOLFIRI: irinotecan (180 mg/m2), folinic acid (400 mg/m2) or L-folinic acid (200 mg/m2), a bolus dose of fluorouracil (400 mg/m2), and a 46-h infusion of fluorouracil (2400 mg/m2). *targeted therapy: mt-RAS (initially mt-KRAS) patients received bevacizumab (5 mg/kg) and wt-RAS (initially wt-KRAS) patients received cetuximab (500 mg/m2) intravenously on day 1 of each chemotherapy cycle.

    Reporting group title
    TriCT Arm
    Reporting group description
    		 Patients were administered FOLFIRINOX chemotherapy every 14 days (2-week cycles) combined with targeted therapy according to the patient tumor RAS status (initially KRAS): cetuximab if wt-RAS (initially wt-KRAS) or bevacizumab if mt-RAS (initially mt-KRAS). *FOLFIRINOX regimen on day 1 of each 2-week cycle as follows: oxaliplatin (85 mg/m2) was administered as an intravenous. infusion for 120 min, followed by irinotecan (150 mg/m2) as an intravenous infusion over 90 min and leucovorin (200 mg/m2) as an intravenous infusion over 120 min. Fluorouracil (400 mg/m2) was delivered as a bolus, followed by a 46-h continuous infusion at 2400 mg/m2. *targeted therapy: mt-RAS patients received bevacizumab (5 mg/kg) and wt-RAS patients received cetuximab (500 mg/m2) intravenously on day 1 of each chemotherapy cycle.

    Reporting group values
    		 BiCT Arm TriCT Arm Total
    Number of subjects
    		 126 130 256
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 84 97 181
        From 65-84 years
    		 42 33 75
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 61 (29 to 75) 60 (27 to 78) -
    Gender categorical
    Units: Subjects
        Female
    		 44 47 91
        Male
    		 82 81 163
        Missing data
    		 0 2 2
    ECOG
    Units: Subjects
        ECOG 0
    		 84 82 166
        ECOG 1
    		 42 46 88
        Missing data
    		 0 2 2
    Location of primary tumor
    Units: Subjects
        Right colon
    		 32 28 60
        Left colon
    		 58 63 121
        Rectum
    		 33 34 67
        Multiple sites
    		 3 4 7
        Missing data
    		 0 1 1
    Timing of primary tumor resection
    Units: Subjects
        Not resected
    		 44 35 79
        Before study inclusion
    		 40 43 83
        During the study
    		 42 52 94
    Proportion of liver cancerous
    Units: Subjects
        00-25%
    		 32 40 72
        26-50%
    		 25 17 42
        51-75%
    		 14 12 26
        >75%
    		 6 5 11
        Missing data
    		 49 56 105
    Reason for nonresectability
    Units: Subjects
        Technical
    		 48 40 88
        Oncological
    		 62 64 126
        Both
    		 16 23 39
        Missing data
    		 0 3 3
    Weight
    Units: Kg
        median (full range (min-max))
    		 73 (43 to 140) 75 (43 to 153) -
    Height
    Units: cm
        median (full range (min-max))
    		 171 (148 to 193) 170 (149 to 192) -
    Number of liver metastases
    Units: Median
        median (full range (min-max))
    		 3 (0 to 52) 4 (0 to 31) -

    End points

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    End points reporting groups
    Reporting group title
    BiCT Arm
    Reporting group description
    		 Patients were randomly allocated either FOLFIRI or FOLFOX chemotherapy every 14 days (2-week cycles) combined with targeted therapy according to the patient tumor RAS status (initially KRAS): cetuximab if wt-RAS (initially wt-KRAS) or bevacizumab if mt-RAS (initially mt-KRAS). *FOLFIRI or FOLFOX chemotherapy: -FOLFOX: oxaliplatin (85 mg/m2), folinic acid (400 mg/m2) or L-folinic acid (200 mg/m2), a bolus dose of fluorouracil (400 mg/m2), and a 46-h infusion of fluorouracil (2400 mg/m2). Or -FOLFIRI: irinotecan (180 mg/m2), folinic acid (400 mg/m2) or L-folinic acid (200 mg/m2), a bolus dose of fluorouracil (400 mg/m2), and a 46-h infusion of fluorouracil (2400 mg/m2). *targeted therapy: mt-RAS (initially mt-KRAS) patients received bevacizumab (5 mg/kg) and wt-RAS (initially wt-KRAS) patients received cetuximab (500 mg/m2) intravenously on day 1 of each chemotherapy cycle.

    Reporting group title
    TriCT Arm
    Reporting group description
    		 Patients were administered FOLFIRINOX chemotherapy every 14 days (2-week cycles) combined with targeted therapy according to the patient tumor RAS status (initially KRAS): cetuximab if wt-RAS (initially wt-KRAS) or bevacizumab if mt-RAS (initially mt-KRAS). *FOLFIRINOX regimen on day 1 of each 2-week cycle as follows: oxaliplatin (85 mg/m2) was administered as an intravenous. infusion for 120 min, followed by irinotecan (150 mg/m2) as an intravenous infusion over 90 min and leucovorin (200 mg/m2) as an intravenous infusion over 120 min. Fluorouracil (400 mg/m2) was delivered as a bolus, followed by a 46-h continuous infusion at 2400 mg/m2. *targeted therapy: mt-RAS patients received bevacizumab (5 mg/kg) and wt-RAS patients received cetuximab (500 mg/m2) intravenously on day 1 of each chemotherapy cycle.

    Primary: Hepatic metastases resection rate (R0 or R1)

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    End point title
    		 Hepatic metastases resection rate (R0 or R1)
    End point description
    The primary endpoint was the hepatic metastases resection rate (R0 or R1) in the TriCT/Experimental Arm (tri-chemotherapy with targeted therapy) versus in the BiCT/Control Arm (bi-chemotherapy with targeted therapy).
    End point type
    Primary
    End point timeframe
    at least 4-6 weeks after the end of chemotherapy.
    End point values
    		 BiCT Arm TriCT Arm
    Number of subjects analysed
    126
    130
    Units: percent
        number (confidence interval 95%)
    48.4 (39 to 57)
    56.9 (48 to 66)
    Statistical analysis title
    		 Hepatic metastases resection analysis
    Comparison groups
    BiCT Arm v TriCT Arm
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.016
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.1
         upper limit
    		 2.7

    Secondary: Objective response rate

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    End point title
    		 Objective response rate
    End point description
    The objective response rate (complete response [CR] and partial response [PR]), at the first tumor assessment, after 4 cycles of treatment, according to the RECIST v1.1. Patients with symptoms suggesting disease progression had a tumor evaluation when the symptoms occurred.
    End point type
    Secondary
    End point timeframe
    after 8 weeks
    End point values
    		 BiCT Arm TriCT Arm
    Number of subjects analysed
    126
    130
    Units: percent
    median (confidence interval 95%)
        Objective response rate
    67 (56.7 to 76.2)
    76.5 (66.9 to 84.5)
    No statistical analyses for this end point

    Secondary: Complete remission rate

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    End point title
    		 Complete remission rate
    End point description
    The proportion of patients with remission at 6 months after the last study treatment (hepatic surgery or last chemotherapy cycle)
    End point type
    Secondary
    End point timeframe
    at 6 months after the last study treatment (hepatic surgery or last chemotherapy cycle).
    End point values
    		 BiCT Arm TriCT Arm
    Number of subjects analysed
    126
    130
    Units: percent
        median (confidence interval 95%)
    52.0 (31 to 72)
    41.9 (25 to 61)
    No statistical analyses for this end point

    Secondary: Surgical resection rates (R0, R1, and R2)

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    End point title
    		 Surgical resection rates (R0, R1, and R2)
    End point description
    The surgical resection rates (R0, R1, and R2).
    End point type
    Secondary
    End point timeframe
    24 weeks.
    End point values
    		 BiCT Arm TriCT Arm
    Number of subjects analysed
    126
    130
    Units: Number of patients
        R0
    44
    60
        R1
    17
    14
        R2
    3
    3
    No statistical analyses for this end point

    Secondary: Relapse-free survival rate

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    End point title
    		 Relapse-free survival rate
    End point description
    End point type
    Secondary
    End point timeframe
    Relapse-free Survival was evaluated between randomisation to the date of relapse or death for any cause ( 1 , 2 and 3 years).
    End point values
    		 BiCT Arm TriCT Arm
    Number of subjects analysed
    126
    130
    Units: Months
        median (confidence interval 95%)
    12.5 (11.1 to 13.9)
    13.8 (13.1 to 15.0)
    No statistical analyses for this end point

    Secondary: Response duration in patients not resected

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    End point title
    		 Response duration in patients not resected
    End point description
    End point type
    Secondary
    End point timeframe
    Duration of response is commonly defined as the time from onset of response to progression or death due to any reason.
    End point values
    		 BiCT Arm TriCT Arm
    Number of subjects analysed
    126
    130
    Units: Months
        median (confidence interval 95%)
    10.1 (8.9 to 11.5)
    11.0 (9.5 to 12.0)
    No statistical analyses for this end point

    Secondary: Progression –free survival

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    End point title
    		 Progression –free survival
    End point description
    The progression-free survival (PFS) defined as the time from randomization to progression (RECIST v1.1) or death from any cause (disease relapse was considered as an event). Patients alive without progression were censored at the last follow-up.
    End point type
    Secondary
    End point timeframe
    8 months.
    End point values
    		 BiCT Arm TriCT Arm
    Number of subjects analysed
    126
    130
    Units: Months
        median (confidence interval 95%)
    11.5 (10.2 to 13.0)
    13.0 (11.3 to 13.8)
    Statistical analysis title
    		 PFS Analysis
    Comparison groups
    BiCT Arm v TriCT Arm
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.734
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 1.39

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    The overall survival (OS) was defined as the time from randomization to death due to any cause. Patients lost to follow-up were censored at the date last known to be alive.
    End point type
    Secondary
    End point timeframe
    14 months.
    End point values
    		 BiCT Arm TriCT Arm
    Number of subjects analysed
    126
    130
    Units: Months
        median (confidence interval 95%)
    40.0 (34.4 to 46.5)
    43.4 (36.7 to 49.4)
    Statistical analysis title
    		 OS Analysis
    Comparison groups
    BiCT Arm v TriCT Arm
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7373
    Method
    		 Logrank
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Overall period of the study (up to 5 years after randomization)
    Adverse event reporting additional description
    Informations about the occurences of the non serious Adverse events were not avalaible.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18
    Reporting groups
    Reporting group title
    BiCT Arm
    Reporting group description
    		 -

    Reporting group title
    TriCT Arm
    Reporting group description
    		 -

    Serious adverse events
    		 BiCT Arm TriCT Arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    72 / 126 (57.14%)
    81 / 128 (63.28%)
         number of deaths (all causes)
    76
    78
         number of deaths resulting from adverse events
    5
    5
    Investigations
    GGT increased
         subjects affected / exposed
    1 / 126 (0.79%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Biloma
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical procedure repeated
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac disorders
    Atrial fibrillation paroxysmal
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary spastic angina
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decompensation cardiac
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Aplasia bone marrow
    alternative dictionary used: MedDRA 1
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile aplasia
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 126 (0.79%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Neutropenia
         subjects affected / exposed
    3 / 126 (2.38%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    5 / 5
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device complication
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device malfunction
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fever
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 126 (0.00%)
    3 / 128 (2.34%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperthermia
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion associated discomfort
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiorgan failure
         subjects affected / exposed
    0 / 126 (0.00%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    Multi-organ failure
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Sudden death
         subjects affected / exposed
    1 / 126 (0.79%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    Unknown cause of death
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Immune system disorders
    Allergic reaction
         subjects affected / exposed
    1 / 126 (0.79%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaphylactic shock
         subjects affected / exposed
    1 / 126 (0.79%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug allergy
         subjects affected / exposed
    3 / 126 (2.38%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal abscess
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 126 (0.79%)
    4 / 128 (3.13%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal wall abscess
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bowel obstruction
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon obstruction
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colostomy prolapse
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhea
         subjects affected / exposed
    5 / 126 (3.97%)
    9 / 128 (7.03%)
         occurrences causally related to treatment / all
    4 / 5
    9 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhea bloody
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fecal peritonitis
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 126 (0.79%)
    4 / 128 (3.13%)
         occurrences causally related to treatment / all
    1 / 1
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Gastrointestinal obstruction
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal toxicity
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucositis oral
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstruction intestinal
         subjects affected / exposed
    0 / 126 (0.00%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstruction small intestine
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    3 / 126 (2.38%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small bowel obstruction
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subacute intestinal obstruction
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subocclusive syndrome
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Watery diarrhea
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VOMITING GRADE 2 AND NAUSEA GRADE 3
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute cholecystitis
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary fistula
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cytolysis
         subjects affected / exposed
    1 / 126 (0.79%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver cholestasis
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver failure
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperosmolar (non-ketotic) coma
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Catheter infection
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parotitis
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 126 (0.79%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septicemia
         subjects affected / exposed
    1 / 126 (0.79%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Serratia sepsis
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcus aureus bacteraemia
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary infection
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 BiCT Arm TriCT Arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    126 / 126 (100.00%)
    128 / 128 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    9 / 126 (7.14%)
    10 / 128 (7.81%)
         occurrences all number
    9
    10
    Thromboembolic events
         subjects affected / exposed
    19 / 126 (15.08%)
    15 / 128 (11.72%)
         occurrences all number
    19
    15
    Edema
         subjects affected / exposed
    6 / 126 (4.76%)
    3 / 128 (2.34%)
         occurrences all number
    6
    3
    General disorders and administration site conditions
    Mucositis
         subjects affected / exposed
    40 / 126 (31.75%)
    37 / 128 (28.91%)
         occurrences all number
    40
    37
    Pain
         subjects affected / exposed
    43 / 126 (34.13%)
    46 / 128 (35.94%)
         occurrences all number
    43
    46
    Weakness
         subjects affected / exposed
    3 / 126 (2.38%)
    2 / 128 (1.56%)
         occurrences all number
    3
    2
    Fatigue
         subjects affected / exposed
    89 / 126 (70.63%)
    108 / 128 (84.38%)
         occurrences all number
    89
    108
    Fever
         subjects affected / exposed
    17 / 126 (13.49%)
    17 / 128 (13.28%)
         occurrences all number
    17
    17
    Weight loss
         subjects affected / exposed
    29 / 126 (23.02%)
    47 / 128 (36.72%)
         occurrences all number
    29
    47
    Immune system disorders
    Hypersensitivity reaction to oxaliplatin
         subjects affected / exposed
    3 / 126 (2.38%)
    8 / 128 (6.25%)
         occurrences all number
    3
    8
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    34 / 126 (26.98%)
    27 / 128 (21.09%)
         occurrences all number
    34
    27
    Bronchospasm
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 128 (0.78%)
         occurrences all number
    0
    1
    Thoracic pain
         subjects affected / exposed
    3 / 126 (2.38%)
    5 / 128 (3.91%)
         occurrences all number
    3
    5
    Dyspnea
         subjects affected / exposed
    13 / 126 (10.32%)
    18 / 128 (14.06%)
         occurrences all number
    13
    18
    Cough
         subjects affected / exposed
    14 / 126 (11.11%)
    8 / 128 (6.25%)
         occurrences all number
    14
    8
    Pulmonary edema
         subjects affected / exposed
    2 / 126 (1.59%)
    2 / 128 (1.56%)
         occurrences all number
    2
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    10 / 126 (7.94%)
    12 / 128 (9.38%)
         occurrences all number
    10
    12
    Investigations
    ALAT/SGPT abnormal
         subjects affected / exposed
    71 / 126 (56.35%)
    89 / 128 (69.53%)
         occurrences all number
    71
    89
    ASAT/SGOT abnormal
         subjects affected / exposed
    70 / 126 (55.56%)
    82 / 128 (64.06%)
         occurrences all number
    70
    82
    GGT abnormal
         subjects affected / exposed
    86 / 126 (68.25%)
    91 / 128 (71.09%)
         occurrences all number
    86
    91
    Phosphatase alkaline abnormal
         subjects affected / exposed
    89 / 126 (70.63%)
    114 / 128 (89.06%)
         occurrences all number
    89
    114
    Prothrombin time
         subjects affected / exposed
    8 / 126 (6.35%)
    13 / 128 (10.16%)
         occurrences all number
    8
    13
    Creatinine abnormal
         subjects affected / exposed
    24 / 126 (19.05%)
    28 / 128 (21.88%)
         occurrences all number
    24
    28
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    1 / 126 (0.79%)
    3 / 128 (2.34%)
         occurrences all number
    1
    3
    Ischemic cardiac event/infarction
         subjects affected / exposed
    2 / 126 (1.59%)
    0 / 128 (0.00%)
         occurrences all number
    2
    0
    Nervous system disorders
    Dysgeusia (altered taste)
         subjects affected / exposed
    26 / 126 (20.63%)
    27 / 128 (21.09%)
         occurrences all number
    26
    27
    Encephalopathy
         subjects affected / exposed
    22 / 126 (17.46%)
    17 / 128 (13.28%)
         occurrences all number
    22
    17
    Pripheral sensory neuropathy
         subjects affected / exposed
    66 / 126 (52.38%)
    107 / 128 (83.59%)
         occurrences all number
    66
    107
    Somnolence
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 128 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Hemoglobin level disorder
         subjects affected / exposed
    85 / 126 (67.46%)
    106 / 128 (82.81%)
         occurrences all number
    85
    106
    Leucopenia
         subjects affected / exposed
    67 / 126 (53.17%)
    60 / 128 (46.88%)
         occurrences all number
    67
    60
    Lymphopenia
         subjects affected / exposed
    55 / 126 (43.65%)
    55 / 128 (42.97%)
         occurrences all number
    55
    55
    Neutrophils/granulocytes disorder
         subjects affected / exposed
    82 / 126 (65.08%)
    78 / 128 (60.94%)
         occurrences all number
    82
    78
    Platelets disorder
         subjects affected / exposed
    46 / 126 (36.51%)
    88 / 128 (68.75%)
         occurrences all number
    46
    88
    Febrile neutropenia
         subjects affected / exposed
    5 / 126 (3.97%)
    6 / 128 (4.69%)
         occurrences all number
    5
    6
    Ear and labyrinth disorders
    Hearing impaired
         subjects affected / exposed
    5 / 126 (3.97%)
    2 / 128 (1.56%)
         occurrences all number
    5
    2
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    5 / 126 (3.97%)
    7 / 128 (5.47%)
         occurrences all number
    5
    7
    Visual problems
         subjects affected / exposed
    2 / 126 (1.59%)
    3 / 128 (2.34%)
         occurrences all number
    2
    3
    Gastrointestinal disorders
    Anorexia
         subjects affected / exposed
    26 / 126 (20.63%)
    50 / 128 (39.06%)
         occurrences all number
    26
    50
    Ascites
         subjects affected / exposed
    1 / 126 (0.79%)
    2 / 128 (1.56%)
         occurrences all number
    1
    2
    Constipation
         subjects affected / exposed
    46 / 126 (36.51%)
    47 / 128 (36.72%)
         occurrences all number
    46
    47
    Diarrhea
         subjects affected / exposed
    64 / 126 (50.79%)
    96 / 128 (75.00%)
         occurrences all number
    64
    96
    Abdominal pain
         subjects affected / exposed
    50 / 126 (39.68%)
    58 / 128 (45.31%)
         occurrences all number
    50
    58
    Digestive hemorrhage
         subjects affected / exposed
    8 / 126 (6.35%)
    10 / 128 (7.81%)
         occurrences all number
    8
    10
    Nausea
         subjects affected / exposed
    66 / 126 (52.38%)
    94 / 128 (73.44%)
         occurrences all number
    66
    94
    Pancreatitis
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 128 (0.78%)
         occurrences all number
    0
    1
    Stomatitis
         subjects affected / exposed
    17 / 126 (13.49%)
    21 / 128 (16.41%)
         occurrences all number
    17
    21
    Vomiting
         subjects affected / exposed
    28 / 126 (22.22%)
    48 / 128 (37.50%)
         occurrences all number
    28
    48
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 128 (0.78%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 126 (0.79%)
    1 / 128 (0.78%)
         occurrences all number
    1
    1
    Alopecia
         subjects affected / exposed
    18 / 126 (14.29%)
    38 / 128 (29.69%)
         occurrences all number
    18
    38
    Nail disorder
         subjects affected / exposed
    15 / 126 (11.90%)
    8 / 128 (6.25%)
         occurrences all number
    15
    8
    Eruptions/desquamation
         subjects affected / exposed
    51 / 126 (40.48%)
    38 / 128 (29.69%)
         occurrences all number
    51
    38
    Erythroderma
         subjects affected / exposed
    10 / 126 (7.94%)
    6 / 128 (4.69%)
         occurrences all number
    10
    6
    Pruritus
         subjects affected / exposed
    23 / 126 (18.25%)
    10 / 128 (7.81%)
         occurrences all number
    23
    10
    Rash
         subjects affected / exposed
    41 / 126 (32.54%)
    29 / 128 (22.66%)
         occurrences all number
    41
    29
    Hands and feet skin reaction
         subjects affected / exposed
    39 / 126 (30.95%)
    33 / 128 (25.78%)
         occurrences all number
    39
    33
    Injection site reaction
         subjects affected / exposed
    2 / 126 (1.59%)
    1 / 128 (0.78%)
         occurrences all number
    2
    1
    Dry skin
         subjects affected / exposed
    43 / 126 (34.13%)
    32 / 128 (25.00%)
         occurrences all number
    43
    32
    Wound healing disorder
         subjects affected / exposed
    5 / 126 (3.97%)
    2 / 128 (1.56%)
         occurrences all number
    5
    2
    Urticaria
         subjects affected / exposed
    3 / 126 (2.38%)
    4 / 128 (3.13%)
         occurrences all number
    3
    4
    Skin edema
         subjects affected / exposed
    4 / 126 (3.17%)
    1 / 128 (0.78%)
         occurrences all number
    4
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    3 / 126 (2.38%)
    1 / 128 (0.78%)
         occurrences all number
    3
    1
    Abnormal urination/urinary frequency
         subjects affected / exposed
    1 / 126 (0.79%)
    1 / 128 (0.78%)
         occurrences all number
    1
    1
    Hematuria
         subjects affected / exposed
    6 / 126 (4.76%)
    5 / 128 (3.91%)
         occurrences all number
    6
    5
    Proteinuria
         subjects affected / exposed
    13 / 126 (10.32%)
    15 / 128 (11.72%)
         occurrences all number
    13
    15
    Urinary retention
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 128 (0.78%)
         occurrences all number
    0
    1
    Infections and infestations
    Infection with neutropenia
         subjects affected / exposed
    2 / 126 (1.59%)
    2 / 128 (1.56%)
         occurrences all number
    2
    2
    Infection without neutropenia
         subjects affected / exposed
    7 / 126 (5.56%)
    11 / 128 (8.59%)
         occurrences all number
    7
    11
    Local infections
         subjects affected / exposed
    27 / 126 (21.43%)
    27 / 128 (21.09%)
         occurrences all number
    27
    27
    Septicemia
         subjects affected / exposed
    3 / 126 (2.38%)
    2 / 128 (1.56%)
         occurrences all number
    3
    2
    Bilirubin
         subjects affected / exposed
    14 / 126 (11.11%)
    17 / 128 (13.28%)
         occurrences all number
    14
    17
    Paronychia
         subjects affected / exposed
    17 / 126 (13.49%)
    8 / 128 (6.25%)
         occurrences all number
    17
    8

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Feb 2011
    · Change of study contact, as project leader from Christine Montoto-Grillot to Beata Juzyna. · Correction of errors in the protocol: inconsistencies and spelling errors. · Modification of the Investigator’s list.
    12 Apr 2011
    · Modification and clarification of the dose adaption. · Modification of the SAE declaration document/form. · Correction of errors in the protocol: inconsistencies and spelling errors. · Modification of the investigators list.
    05 Jul 2011
    · Modification of the investigators list.
    02 Aug 2011
    · Updating of the abbreviation list. · Addition of an upper age limit of 75 years old to the Inclusion criterion N°10. · Modification of the study rational. · Addition of calcium testing during the study treatment phase. · Addition of a translational research concerning circulating DNA. · Modification of the investigators list.
    13 Dec 2011
    · Change of the trial sponsor from the Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC) to UNICANCER.
    20 Mar 2012
    · Modification of the investigators list. · Modification of the statistical analysis.
    10 Sep 2013
    examined by the EC on the 29-Jul-2013, with EC approval letter dated the 10-Sep-2013) · Prolongation of the inclusion period by 2 years. · Updating of the study contacts. · Correction of the logistics concerning the blood sampling. · Correction of the numbering of the annexes in the study protocol. · Modification of the investigators list.
    08 Jul 2014
    · Modification of the protocol following the publication by Douillard et.al. showing a diminished survival in patients with mt-NRAS tumours treated with the anti-EGFR - panitumumab [20]. Obligation to verify the NRAS status of tumors. Only patients with wt-RAS tumors were eligible for cetuximab. · Updating of the study contacts: a new fax number. · Clarification of the non-inclusion criterion N°9. · Correction of the statistical analysis. · Modification of the investigators list.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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