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    Clinical Trial Results:
    Essai de phase II, randomisé multicentrique, évaluant l'efficacité d'une chimiothérapie standard à base de fluoropyrimidine associée au cétuximab ou au bévacizumab, chez des patients kras sauvage, atteints d'un cancer colorectal métastatique, en progression après une 1ere ligne de traitement avec bévacizumab.

    Summary
    EudraCT number
    		 2009-012942-22
    Trial protocol
    		 FR  
    Global end of trial date
    20 Feb 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Mar 2022
    First version publication date
    01 Mar 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    PRODIGE 18 - ACCORD 22/0906
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01442649
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    UNICANCER
    Sponsor organisation address
    101 rue de Tolbiac, Paris, France, 75013
    Public contact
    Nourredine AIT-RAHMOUNE, UNICANCER, 33 171936704, n.ait-rahmoune@unicancer.fr
    Scientific contact
    Nourredine AIT-RAHMOUNE, UNICANCER, 33 171936704, 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
    01 Mar 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Feb 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to evaluate the efficacy of standard fluoropyrimidine-based chemotherapy associated with either cetuximab or bevacizumab for the treatment of wild-type RAS (KRAS and NRAS) metastatic colorectal cancer after a first-line of treatment with bevacizumab, in terms of progression-free survival (PFS).
    Protection of trial subjects
    This study was conducted in accordance with the Declaration of Helsinki (1964) and subsequent amendments, ICH Good Clinical Practice Guidelines (CPMP/ICH/135/95), the European Directive (2001/20/CE) and the applicable local regulatory requirements and laws. Furthermore, an independent Ethics Committees reviewed and gave a favorable opinion to the study documents, including the initial protocol and all subsequent amendments, and all information and documents provided to subjects/patients.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Dec 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 2 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 132
    Worldwide total number of subjects
    132
    EEA total number of subjects
    132
    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
    56
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Prodige 18 - Accord 22 was a phase II open-label randomized multicenter study, evaluating the efficacy of standard fluoropyrimidine-based chemotherapy associated with either cetuximab or bevacizumab for the treatment of wild-type RAS (KRAS and NRAS) metastatic colorectal cancer after a first-line of treatment with bevacizumab.+

    Pre-assignment
    Screening details
    		 The study consisted of a screening phase before randomization to establish eligibility, a treatment phase, and a long-term follow-up to monitor the progression-free survival, overall response rate, overall survival, and 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
    		 Bevacizumab
    Arm description
    		 Bevacizumab was administered at a dose of 5 mg/kg intravenously (IV) every 14 days associated with standard fluoropyrimidine-based chemotherapy (either mFOLFOX6 or FOLFIRI). * mFOLFOX6: Oxaliplatin at 85 mg/m², IV, over 120 min on D1. Folinic acid at 400 mg/m² if racemic or at 200 mg/m² if enantiomeric (L-folinic acid), simultaneously with oxaliplatin, IV, over 2 h on D1. 5-FU bolus (400 mg/m²) on D1, and then a continuous IV perfusion of 5-FU (2400 mg/m²) over 46 h. The treatment cycle was repeated every 14 days. * FOLFIRI: Irinotecan at 180 mg/m², IV, 90 min on D1. Folinic acid at either 400 mg/m² if racemic or at 200 mg/m² if enantiomeric (L-folinic acid), simultaneously with irinotecan, IV over 2 h on D1. 5-FU bolus (400 mg/m²) on D1, and then a perfusion of 5-fluorouracil of 2400 mg/m² perfusion IV over 46 h. The treatment cycle was repeated every 14 days.
    Arm type
    		 Experimental

    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
    Bevacizumab was dministered at a dose of 5 mg/kg intravenously (IV) every 14 days associated with standard fluoropyrimidine- based chemotherapy (either mFOLFOX6 or FOLFIRI). Initially bevacizumab was administered IV over 90 min (±15 min). If this first perfusion was well tolerated the 2nd perfusion could be administered over 60 min (±15 min). Similarly, if this was well tolerated bevacizumab could subsequently be administered over 30 min (±15 min). If however, the initial administration was not well tolerated subsequent administrations of bevacizumab were to be administrated over 90 min with premedication as per local standards.

    Arm title
    		 Cetuximab
    Arm description
    		 Cetuximab was administered at a dose of 500 mg/m² intravenously (IV) every 14 days associated with standard fluoropyrimidine- based chemotherapy (either mFOLFOX6 or FOLFIRI). * mFOLFOX6: Oxaliplatin at 85 mg/m², IV, over 120 min on D1. Folinic acid at 400 mg/m² if racemic or at 200 mg/m² if enantiomeric (L-folinic acid), simultaneously with oxaliplatin, IV, over 2 h on D1. 5-FU bolus (400 mg/m²) on D1, and then a continuous IV perfusion of 5-FU (2400 mg/m²) over 46 h. The treatment cycle was repeated every 14 days. * FOLFIRI: Irinotecan at 180 mg/m², IV, 90 min on D1. Folinic acid at either 400 mg/m² if racemic or at 200 mg/m² if enantiomeric (L-folinic acid), simultaneously with irinotecan, IV over 2 h on D1. 5-FU bolus (400 mg/m²) on D1, and then a perfusion of 5-fluorouracil of 2400 mg/m² perfusion IV over 46 h. The treatment cycle was repeated every 14 days.
    Arm type
    		 Experimental

    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
    Cetuximab was administered at a dose of 500 mg/m² intravenously (IV) every 14 days associated with standard fluoropyrimidine-based chemotherapy (either mFOLFOX6 or FOLFIRI). Allergic reactions and hypersensitivity to cetuximab are known to occur during the perfusion. As a preventative measure all patients received premedication with antihistamines and corticosteroids (methylprednisolone [Solumedrol®] 120 mg and an anti-H1 IV) before the first, second, and third cetuximab administration. The premedication could be stopped at subsequent administrations in absence of a reaction. Preventative treatment with a systemic antibiotherapy (e.g. doxycycline 100 mg/day) could be administered to reduce the frequency and intensity of cutaneous toxicities.

    Number of subjects in period 1
    		Bevacizumab Cetuximab
    Started
    65
    67
    Completed
    26
    18
    Not completed
    39
    49
         Physician decision
    7
    4
         Consent withdrawn by subject
    -
    2
         Disease progression
    31
    35
         Adverse event, non-fatal
    1
    1
         Death
    -
    4
         Hospitalisation
    -
    1
         Second line treatment
    -
    1
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Bevacizumab
    Reporting group description
    		 Bevacizumab was administered at a dose of 5 mg/kg intravenously (IV) every 14 days associated with standard fluoropyrimidine-based chemotherapy (either mFOLFOX6 or FOLFIRI). * mFOLFOX6: Oxaliplatin at 85 mg/m², IV, over 120 min on D1. Folinic acid at 400 mg/m² if racemic or at 200 mg/m² if enantiomeric (L-folinic acid), simultaneously with oxaliplatin, IV, over 2 h on D1. 5-FU bolus (400 mg/m²) on D1, and then a continuous IV perfusion of 5-FU (2400 mg/m²) over 46 h. The treatment cycle was repeated every 14 days. * FOLFIRI: Irinotecan at 180 mg/m², IV, 90 min on D1. Folinic acid at either 400 mg/m² if racemic or at 200 mg/m² if enantiomeric (L-folinic acid), simultaneously with irinotecan, IV over 2 h on D1. 5-FU bolus (400 mg/m²) on D1, and then a perfusion of 5-fluorouracil of 2400 mg/m² perfusion IV over 46 h. The treatment cycle was repeated every 14 days.

    Reporting group title
    Cetuximab
    Reporting group description
    		 Cetuximab was administered at a dose of 500 mg/m² intravenously (IV) every 14 days associated with standard fluoropyrimidine- based chemotherapy (either mFOLFOX6 or FOLFIRI). * mFOLFOX6: Oxaliplatin at 85 mg/m², IV, over 120 min on D1. Folinic acid at 400 mg/m² if racemic or at 200 mg/m² if enantiomeric (L-folinic acid), simultaneously with oxaliplatin, IV, over 2 h on D1. 5-FU bolus (400 mg/m²) on D1, and then a continuous IV perfusion of 5-FU (2400 mg/m²) over 46 h. The treatment cycle was repeated every 14 days. * FOLFIRI: Irinotecan at 180 mg/m², IV, 90 min on D1. Folinic acid at either 400 mg/m² if racemic or at 200 mg/m² if enantiomeric (L-folinic acid), simultaneously with irinotecan, IV over 2 h on D1. 5-FU bolus (400 mg/m²) on D1, and then a perfusion of 5-fluorouracil of 2400 mg/m² perfusion IV over 46 h. The treatment cycle was repeated every 14 days.

    Reporting group values
    		 Bevacizumab Cetuximab Total
    Number of subjects
    		 65 67 132
    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)
    		 37 39 76
        From 65-84 years
    		 28 28 56
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 61 (33 to 83) 63 (37 to 84) -
    Gender categorical
    Units: Subjects
        Female
    		 24 23 47
        Male
    		 41 44 85
    Eastern Cooperative Oncology Group
    Units: Subjects
        ECOG 0
    		 36 38 74
        ECOG 1
    		 27 27 54
        Missing
    		 2 2 4
    ECG
    Units: Subjects
        Abnormal
    		 8 6 14
        Normal
    		 49 56 105
        Unknown
    		 8 5 13
    Characteristics of the primary tumor
    Units: Subjects
        Right colon
    		 12 7 19
        left colon
    		 11 14 25
        left and right colon
    		 1 1 2
        Colon
    		 0 1 1
        Rectum
    		 18 21 39
        Other
    		 23 23 46
    Systolic blood pressure
    Units: mm Hg
        median (full range (min-max))
    		 82 (39 to 130) 80 (50 to 117) -
    Diastoloic blood pressure
    Units: mm Hg
        median (full range (min-max))
    		 132 (80 to 185) 133 (98 to 181) -

    End points

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    End points reporting groups
    Reporting group title
    Bevacizumab
    Reporting group description
    		 Bevacizumab was administered at a dose of 5 mg/kg intravenously (IV) every 14 days associated with standard fluoropyrimidine-based chemotherapy (either mFOLFOX6 or FOLFIRI). * mFOLFOX6: Oxaliplatin at 85 mg/m², IV, over 120 min on D1. Folinic acid at 400 mg/m² if racemic or at 200 mg/m² if enantiomeric (L-folinic acid), simultaneously with oxaliplatin, IV, over 2 h on D1. 5-FU bolus (400 mg/m²) on D1, and then a continuous IV perfusion of 5-FU (2400 mg/m²) over 46 h. The treatment cycle was repeated every 14 days. * FOLFIRI: Irinotecan at 180 mg/m², IV, 90 min on D1. Folinic acid at either 400 mg/m² if racemic or at 200 mg/m² if enantiomeric (L-folinic acid), simultaneously with irinotecan, IV over 2 h on D1. 5-FU bolus (400 mg/m²) on D1, and then a perfusion of 5-fluorouracil of 2400 mg/m² perfusion IV over 46 h. The treatment cycle was repeated every 14 days.

    Reporting group title
    Cetuximab
    Reporting group description
    		 Cetuximab was administered at a dose of 500 mg/m² intravenously (IV) every 14 days associated with standard fluoropyrimidine- based chemotherapy (either mFOLFOX6 or FOLFIRI). * mFOLFOX6: Oxaliplatin at 85 mg/m², IV, over 120 min on D1. Folinic acid at 400 mg/m² if racemic or at 200 mg/m² if enantiomeric (L-folinic acid), simultaneously with oxaliplatin, IV, over 2 h on D1. 5-FU bolus (400 mg/m²) on D1, and then a continuous IV perfusion of 5-FU (2400 mg/m²) over 46 h. The treatment cycle was repeated every 14 days. * FOLFIRI: Irinotecan at 180 mg/m², IV, 90 min on D1. Folinic acid at either 400 mg/m² if racemic or at 200 mg/m² if enantiomeric (L-folinic acid), simultaneously with irinotecan, IV over 2 h on D1. 5-FU bolus (400 mg/m²) on D1, and then a perfusion of 5-fluorouracil of 2400 mg/m² perfusion IV over 46 h. The treatment cycle was repeated every 14 days.

    Primary: 4-month progression-free survival rate

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    End point title
    		 4-month progression-free survival rate
    End point description
    Progression-free Survival was defined as the time from randomisation to progression (according to RECIST v1.1) or death. Patients alive without progression were censored at the last follow-up
    End point type
    Primary
    End point timeframe
    4 months after randomisation
    End point values
    		 Bevacizumab Cetuximab
    Number of subjects analysed
    65
    67
    Units: Number of subjects
        median (confidence interval 95%)
    80.3 (68.0 to 88.3)
    66.7 (53.6 to 76.8)
    Statistical analysis title
    		 4-month PFS analysis
    Comparison groups
    Bevacizumab v Cetuximab
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.495
         upper limit
    		 1.018
    Variability estimate
    Standard deviation

    Secondary: Objective tumor response rate

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    End point title
    		 Objective tumor response rate
    End point description
    Objective response rate was defined as the rate of occurrence of a complete response or a partial response (according to RECIST v1.1) from the date of randomization until the end of treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 45 months
    End point values
    		 Bevacizumab Cetuximab
    Number of subjects analysed
    65
    67
    Units: Number of subjects
        median (confidence interval 95%)
    24.6 (14.1 to 35.1)
    31.8 (20.3 to 43.2)
    No statistical analyses for this end point

    Secondary: Progression-free survival

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    End point title
    		 Progression-free survival
    End point description
    Progression-free survival was defined as the time from randomization until progression (according to RECIST v1.1) or death. Patients alive without progression were censored at the last follow-up.
    End point type
    Secondary
    End point timeframe
    Up to approximately 45 months
    End point values
    		 Bevacizumab Cetuximab
    Number of subjects analysed
    65
    67
    Units: Number of patients
        median (confidence interval 95%)
    7.1 (5.7 to 8.2)
    5.6 (4.2 to 6.5)
    Statistical analysis title
    		 PFS analysis
    Comparison groups
    Bevacizumab v Cetuximab
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Logrank
    Confidence interval
    Dispersion value
    0.0603

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    Overall survival was defined as the time from randomization until death of any cause or last follow-up (censored data).
    End point type
    Secondary
    End point timeframe
    Up to approximately 45 months
    End point values
    		 Bevacizumab Cetuximab
    Number of subjects analysed
    65
    67
    Units: Number of patients
        median (confidence interval 95%)
    15.8 (9.5 to 22.3)
    10.4 (7.0 to 16.2)
    Statistical analysis title
    		 OS analysis
    Comparison groups
    Bevacizumab v Cetuximab
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Logrank
    Confidence interval
    Dispersion value
    0.0732

    Secondary: Overall survival from the start of first-line chemotherapy for the meatastatic disease

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    End point title
    		 Overall survival from the start of first-line chemotherapy for the meatastatic disease
    End point description
    Overall survival from the start of first-line chemotherapy for mCRC was defined as the time from the start date of first-line chemotherapy for the metastatic disease until death of any cause or last follow-up news (censored data).
    End point type
    Secondary
    End point timeframe
    Up to approximately 45 months
    End point values
    		 Bevacizumab Cetuximab
    Number of subjects analysed
    65
    67
    Units: Number of subjects
        median (confidence interval 95%)
    32.7 (25.4 to 36.6)
    25.5 (21.8 to 34.8)
    Statistical analysis title
    		 OS from first metastasis treatment analysis
    Comparison groups
    Bevacizumab v Cetuximab
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Logrank
    Confidence interval
    Dispersion value
    0.5763

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Overall period of the study (up to 48 months after first study intake)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Bevacizumab
    Reporting group description
    		 Bevacizumab was administered at a dose of 5 mg/kg intravenously (IV) every 14 days associated with standard fluoropyrimidine-based chemotherapy (either mFOLFOX6 or FOLFIRI). * mFOLFOX6: Oxaliplatin at 85 mg/m², IV, over 120 min on D1. Folinic acid at 400 mg/m² if racemic or at 200 mg/m² if enantiomeric (L-folinic acid), simultaneously with oxaliplatin, IV, over 2 h on D1. 5-FU bolus (400 mg/m²) on D1, and then a continuous IV perfusion of 5-FU (2400 mg/m²) over 46 h. The treatment cycle was repeated every 14 days. * FOLFIRI: Irinotecan at 180 mg/m², IV, 90 min on D1. Folinic acid at either 400 mg/m² if racemic or at 200 mg/m² if enantiomeric (L-folinic acid), simultaneously with irinotecan, IV over 2 h on D1. 5-FU bolus (400 mg/m²) on D1, and then a perfusion of 5-fluorouracil of 2400 mg/m² perfusion IV over 46 h. The treatment cycle was repeated every 14 days.

    Reporting group title
    Cetuximab
    Reporting group description
    		 Cetuximab was administered at a dose of 500 mg/m² intravenously (IV) every 14 days associated with standard fluoropyrimidine- based chemotherapy (either mFOLFOX6 or FOLFIRI). * mFOLFOX6: Oxaliplatin at 85 mg/m², IV, over 120 min on D1. Folinic acid at 400 mg/m² if racemic or at 200 mg/m² if enantiomeric (L-folinic acid), simultaneously with oxaliplatin, IV, over 2 h on D1. 5-FU bolus (400 mg/m²) on D1, and then a continuous IV perfusion of 5-FU (2400 mg/m²) over 46 h. The treatment cycle was repeated every 14 days. * FOLFIRI: Irinotecan at 180 mg/m², IV, 90 min on D1. Folinic acid at either 400 mg/m² if racemic or at 200 mg/m² if enantiomeric (L-folinic acid), simultaneously with irinotecan, IV over 2 h on D1. 5-FU bolus (400 mg/m²) on D1, and then a perfusion of 5-fluorouracil of 2400 mg/m² perfusion IV over 46 h. The treatment cycle was repeated every 14 days.

    Serious adverse events
    		 Bevacizumab Cetuximab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    24 / 65 (36.92%)
    24 / 67 (35.82%)
         number of deaths (all causes)
    43
    50
         number of deaths resulting from adverse events
    5
    5
    Vascular disorders
    Pulmonary embolism
         subjects affected / exposed
    2 / 65 (3.08%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Fever
         subjects affected / exposed
    1 / 65 (1.54%)
    2 / 67 (2.99%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    3 / 65 (4.62%)
    2 / 67 (2.99%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Immune system disorders
    Allergic respiratory symptom
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Allergic reaction
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug allergy
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian torsion
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnea
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemoptysis
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumopathy
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary embolism
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alkaline phosphatase increased
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    6 / 65 (9.23%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    2 / 65 (3.08%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    4 / 65 (6.15%)
    5 / 67 (7.46%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Bowel obstruction
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 65 (1.54%)
    3 / 67 (4.48%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucositis oral
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain abdominal
         subjects affected / exposed
    0 / 65 (0.00%)
    2 / 67 (2.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Icterus
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Skin and subcutaneous tissue disorders
    Cellulitis of leg
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hematuria
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethral dilatation
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Diabetes mellitus aggravated
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Femur fracture
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Septicemia
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    2 / 65 (3.08%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Bevacizumab Cetuximab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    65 / 65 (100.00%)
    67 / 67 (100.00%)
    Cardiac disorders
    Epistaxis
         subjects affected / exposed
    12 / 65 (18.46%)
    5 / 67 (7.46%)
         occurrences all number
    12
    5
    Nervous system disorders
    Peripheral sensory neuropathy
         subjects affected / exposed
    26 / 65 (40.00%)
    27 / 67 (40.30%)
         occurrences all number
    26
    27
    Motor neurone disease
         subjects affected / exposed
    6 / 65 (9.23%)
    1 / 67 (1.49%)
         occurrences all number
    6
    1
    Paraesthesia
         subjects affected / exposed
    29 / 65 (44.62%)
    27 / 67 (40.30%)
         occurrences all number
    29
    27
    Taste disorder
         subjects affected / exposed
    5 / 65 (7.69%)
    5 / 67 (7.46%)
         occurrences all number
    5
    5
    Blood and lymphatic system disorders
    Haemoglobin
         subjects affected / exposed
    43 / 65 (66.15%)
    46 / 67 (68.66%)
         occurrences all number
    43
    46
    Neutrophil
         subjects affected / exposed
    40 / 65 (61.54%)
    35 / 67 (52.24%)
         occurrences all number
    40
    35
    Platelet
         subjects affected / exposed
    40 / 65 (61.54%)
    30 / 67 (44.78%)
         occurrences all number
    40
    30
    Leukocyte
         subjects affected / exposed
    37 / 65 (56.92%)
    29 / 67 (43.28%)
         occurrences all number
    37
    29
    Lymphocyte
         subjects affected / exposed
    30 / 65 (46.15%)
    36 / 67 (53.73%)
         occurrences all number
    30
    36
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    55 / 65 (84.62%)
    50 / 67 (74.63%)
         occurrences all number
    55
    50
    Fever
         subjects affected / exposed
    9 / 65 (13.85%)
    4 / 67 (5.97%)
         occurrences all number
    9
    4
    Weight decreased
         subjects affected / exposed
    13 / 65 (20.00%)
    14 / 67 (20.90%)
         occurrences all number
    13
    14
    Pain
         subjects affected / exposed
    21 / 65 (32.31%)
    25 / 67 (37.31%)
         occurrences all number
    21
    25
    Immune system disorders
    Hypersensitivity to oxaliplatin
         subjects affected / exposed
    5 / 65 (7.69%)
    2 / 67 (2.99%)
         occurrences all number
    5
    2
    Gastrointestinal disorders
    Anorexia
         subjects affected / exposed
    21 / 65 (32.31%)
    22 / 67 (32.84%)
         occurrences all number
    21
    22
    Constipation
         subjects affected / exposed
    18 / 65 (27.69%)
    19 / 67 (28.36%)
         occurrences all number
    18
    19
    Diarrhoea
         subjects affected / exposed
    42 / 65 (64.62%)
    25 / 67 (37.31%)
         occurrences all number
    42
    25
    Nausea
         subjects affected / exposed
    38 / 65 (58.46%)
    25 / 67 (37.31%)
         occurrences all number
    38
    25
    Vomiting
         subjects affected / exposed
    15 / 65 (23.08%)
    14 / 67 (20.90%)
         occurrences all number
    15
    14
    Stomatitis
         subjects affected / exposed
    20 / 65 (30.77%)
    24 / 67 (35.82%)
         occurrences all number
    20
    24
    Abdominal pain
         subjects affected / exposed
    13 / 65 (20.00%)
    9 / 67 (13.43%)
         occurrences all number
    13
    9
    Hepatobiliary disorders
    Bilirubin
         subjects affected / exposed
    13 / 65 (20.00%)
    14 / 67 (20.90%)
         occurrences all number
    13
    14
    alkaline phophatase
         subjects affected / exposed
    47 / 65 (72.31%)
    46 / 67 (68.66%)
         occurrences all number
    47
    46
    Alanine aminotransferase
         subjects affected / exposed
    39 / 65 (60.00%)
    37 / 67 (55.22%)
         occurrences all number
    39
    37
    Aspartate aminotransferase
         subjects affected / exposed
    43 / 65 (66.15%)
    42 / 67 (62.69%)
         occurrences all number
    43
    42
    Gamma-glutamyltransferase
         subjects affected / exposed
    59 / 65 (90.77%)
    56 / 67 (83.58%)
         occurrences all number
    59
    56
    Lactate dehydrogenase
         subjects affected / exposed
    40 / 65 (61.54%)
    41 / 67 (61.19%)
         occurrences all number
    40
    41
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    7 / 65 (10.77%)
    5 / 67 (7.46%)
         occurrences all number
    7
    5
    Rash
         subjects affected / exposed
    3 / 65 (4.62%)
    30 / 67 (44.78%)
         occurrences all number
    3
    30
    Hand and foot skin reaction
         subjects affected / exposed
    7 / 65 (10.77%)
    11 / 67 (16.42%)
         occurrences all number
    7
    11
    Paronychia
         subjects affected / exposed
    0 / 65 (0.00%)
    13 / 67 (19.40%)
         occurrences all number
    0
    13
    Skin fissures
         subjects affected / exposed
    2 / 65 (3.08%)
    19 / 67 (28.36%)
         occurrences all number
    2
    19
    Pruritus
         subjects affected / exposed
    3 / 65 (4.62%)
    11 / 67 (16.42%)
         occurrences all number
    3
    11
    Dermatitis acneiform
         subjects affected / exposed
    1 / 65 (1.54%)
    46 / 67 (68.66%)
         occurrences all number
    1
    46
    Skin hyperpigmentation
         subjects affected / exposed
    0 / 65 (0.00%)
    4 / 67 (5.97%)
         occurrences all number
    0
    4
    Dry skin
         subjects affected / exposed
    7 / 65 (10.77%)
    27 / 67 (40.30%)
         occurrences all number
    7
    27
    Renal and urinary disorders
    Creatinine
         subjects affected / exposed
    24 / 65 (36.92%)
    16 / 67 (23.88%)
         occurrences all number
    24
    16
    Haematuria
         subjects affected / exposed
    4 / 65 (6.15%)
    6 / 67 (8.96%)
         occurrences all number
    4
    6
    Proteinuria
         subjects affected / exposed
    18 / 65 (27.69%)
    6 / 67 (8.96%)
         occurrences all number
    18
    6
    Infections and infestations
    Infection
         subjects affected / exposed
    3 / 65 (4.62%)
    4 / 67 (5.97%)
         occurrences all number
    3
    4
    Localised infection
         subjects affected / exposed
    4 / 65 (6.15%)
    6 / 67 (8.96%)
         occurrences all number
    4
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Mar 2011
    The cetuximab infusion duration was modified. It was calculated for a body surface of 1.20 m² in the amended version of the protocol.
    19 Sep 2014
    - Results from other studies (N Engl J Med, 2013. 369(11): p. 1023-34 and EJC, Vol. 49. 2013. Abstract 17) published during the recruitment period of this clinical trial demonstrated that treatment with anti-EGFR plus FOLFOX or FOLFIRI as no benefits for patients with rare KRAS or NRAS mutations. Inclusion criteria were modified to exclude these patients from the study. - During the recruitment period of the Prodige 18 - Accord 22 trial, results of a clinical trial published by Loprinzi et al (J Clin Oncol, 2014. 32(10): p. 997-1005), demonstrated that calcium gluconate and magnesium sulfate do not prevent oxaliplatin-induced neurotoxicity. Thus, the recommendation to perfuse patients with a solution of gluconate calcium and sulfate magnesium before and after each oxaliplatin injection was removed from the protocol.

    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.
    The results must be interpreted with caution owing to the low number of patients included and the phase II study design.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30422156
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