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    Clinical Trial Results:
    Randomized phase II trial evaluating the efficacy of FOLFOX alone, FOLFOX plus bevacizumab and FOLFOX plus panitumumab as perioperative treatment in patients with resectable liver metastases from wild type KRAS and NRAS colorectal cancer

    Summary
    EudraCT number
    		 2010-019238-29
    Trial protocol
    		 BE   AT   GB   DE   NL   ES  
    Global end of trial date
    25 Jul 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Aug 2019
    First version publication date
    28 Aug 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    40091
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01508000
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    European Organisation for Research and Treatment of Cancer
    Sponsor organisation address
    Avenue E. Mounier 83/11, Brussels, Belgium, 1200
    Public contact
    Project, Budget& Regulatory Dept, European Organisation for Research and Treatment of Cancer, 32 2774 1654, regulatory@eortc.be
    Scientific contact
    Project, Budget& Regulatory Dept, European Organisation for Research and Treatment of Cancer, 32 2774 1654, regulatory@eortc.be
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    25 Jul 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Jul 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Jul 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective is to detect an increase in progression free survival (PFS*) rate at 1 year in each experimental arm (mFOLFOX6 + bevacizumab or panitumumab) compared to mFOLFOX6 alone arm as perioperative treatment for resectable liver metastasis from wild type Kirsten rat sarcoma viral oncogene homolog (KRAS) and NRAS colorectal cancer (CRC).
    Protection of trial subjects
    The responsible investigator ensured that this study was conducted in agreement with either the Declaration of Helsinki (available on the World Medical Association web site (http://www.wma.net)) and/or the laws and regulations of the country, whichever provides the greatest protection of the patient. The protocol has been written, and the study was conducted according to the ICH Harmonized Tripartite Guideline on Good Clinical Practice (ICH-GCP, available online at http://www.ema.europa.eu/pdfs/human/ich/013595en.pdf). The protocol was approved by the competent ethics committee(s) as required by the applicable national legislation.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Jun 2013
    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
    Netherlands: 2
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    Austria: 4
    Country: Number of subjects enrolled
    France: 34
    Country: Number of subjects enrolled
    Germany: 1
    Worldwide total number of subjects
    44
    EEA total number of subjects
    44
    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)
    26
    From 65 to 84 years
    18
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study opened for recruitment in June 2013 and despite many efforts from all the parties involved, only few patients (44 patients in total) were recruited. The study was closed for recruitment on 14/12/2015 for poor accrual.

    Pre-assignment
    Screening details
    		 Each patient considered by the Investigator to be a potential patient for the study underwent the informed consent process. If the patient agreed to participate in the study and an informed consent form was duly completed, dated and signed, then the Investigator assessed the patient’s eligibility for the study.

    Period 1
    Period 1 title
    Randomization (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
    		 modified FOLFOX6 + Surgery
    Arm description
    		 Day 1 of a 14 day cycle: Hour 0: Oxaliplatin 85 mg/m² IV 2-h infusion Hour 0: Folinic Acid 400 mg/m² (DL form) or 200 mg/m2 (L form) IV 2-h infusion Hour 2: 5-FU 400 mg/m² IV bolus over 2-4 minutes Hour 2: 5-FU 2400 mg/m² given as a continuous infusion over 46h. Six cycles pre and six cycles post surgery
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Oxaliplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    85 mg/m² IV 2-h infusion

    Investigational medicinal product name
    Folinic Acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    400 mg/m² (DL form) or 200 mg/m2 (L form) IV 2-h infusion

    Investigational medicinal product name
    5-FU
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5-FU 400 mg/m² IV bolus over 2-4 minutes 5-FU 2400 mg/m² given as a continuous infusion over 46h.

    Arm title
    		 modified FOLFOX6 + Bevacizumab + Surgery
    Arm description
    		 Day 1 of a 14 day cycle Hour 0: Oxaliplatin 85 mg/m2 2-h infusion Hour 0: Folinic Acid 400 mg/m2 (DL form) or 200 mg/m2 (L form) 2-h infusion Hour 2 (before 5-FU bolus): Bevacizumab 5 mg/kg IV over 90 minutes infusion*. Hour 3.5: 5-FU bolus 400 mg/m2 IV bolus over 2-4 minutes Hour 3.5: 5-FU 2400 mg/m² given as a continuous infusion over 46h. * First infusion over 90 minutes (following other antineoplastic agents); if the infusion is well tolerated, the second dose may be infused over 60 minutes. If this second infusion also is well tolerated, subsequent doses may be infused over 30 minutes. Bevacizumab should be administered in all cycles, except cycle 6 of pre-operative treatment. If a central venous access device (CVAD) is required, at least a 2-day interval between placement of a central line and first bevacizumab administration is recommended. Six cycles pre and six cycles post surgery
    Arm type
    		 Experimental

    Investigational medicinal product name
    Oxaliplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    85 mg/m² IV 2-h infusion

    Investigational medicinal product name
    Folinic Acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    400 mg/m² (DL form) or 200 mg/m2 (L form) IV 2-h infusion

    Investigational medicinal product name
    5-FU
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5-FU 400 mg/m² IV bolus over 2-4 minutes 5-FU 2400 mg/m² given as a continuous infusion over 46h.

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    (before 5-FU bolus): Bevacizumab 5 mg/kg IV over 90 minutes infusion

    Arm title
    		 modified FOLFOX6 + Panitumumab + Surgery
    Arm description
    		 Day 1 of a 14 days cycle Hour - 1 (pre chemotherapy): Panitumumab 6 mg/kg IV over 60 minutes (≤ 1000 mg) or 90 minutes (> 1000 mg) +/- 15 min. infusion*. Hour 0: Oxaliplatin 85 mg/m² IV 2-h infusion Hour 0: Folinic Acid 400 mg/m² (DL form) or 200 mg/m2 (L form) IV 2-h infusion Hour 2: 5-FU 400 mg/m² IV bolus over 2-4 minutes Hour 2: 5-FU 2400 mg/m² given as a continuous infusion over 46h. * If the first infusion is well tolerated (i.e. without any serious infusion-related reactions) all subsequent infusions may be administered over 30 ± 10 minutes.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Oxaliplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    85 mg/m² IV 2-h infusion

    Investigational medicinal product name
    Folinic Acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    400 mg/m² (DL form) or 200 mg/m2 (L form) IV 2-h infusion

    Investigational medicinal product name
    5-FU
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5-FU 400 mg/m² IV bolus over 2-4 minutes 5-FU 2400 mg/m² given as a continuous infusion over 46h.

    Investigational medicinal product name
    Panitumumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    (pre chemotherapy): Panitumumab 6 mg/kg IV over 60 minutes (≤ 1000 mg) or 90 minutes (> 1000 mg) +/- 15 min. infusion

    Number of subjects in period 1
    		modified FOLFOX6 + Surgery modified FOLFOX6 + Bevacizumab + Surgery modified FOLFOX6 + Panitumumab + Surgery
    Started
    16
    15
    13
    Completed
    9
    10
    8
    Not completed
    7
    5
    5
         Consent withdrawn by subject
    1
    -
    -
         Adverse event, non-fatal
    1
    -
    1
         Other
    1
    2
    2
         Unknown
    1
    -
    -
         Missing End of treatment form
    1
    1
    2
         Lack of efficacy
    2
    1
    -
         Protocol deviation
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    modified FOLFOX6 + Surgery
    Reporting group description
    		 Day 1 of a 14 day cycle: Hour 0: Oxaliplatin 85 mg/m² IV 2-h infusion Hour 0: Folinic Acid 400 mg/m² (DL form) or 200 mg/m2 (L form) IV 2-h infusion Hour 2: 5-FU 400 mg/m² IV bolus over 2-4 minutes Hour 2: 5-FU 2400 mg/m² given as a continuous infusion over 46h. Six cycles pre and six cycles post surgery

    Reporting group title
    modified FOLFOX6 + Bevacizumab + Surgery
    Reporting group description
    		 Day 1 of a 14 day cycle Hour 0: Oxaliplatin 85 mg/m2 2-h infusion Hour 0: Folinic Acid 400 mg/m2 (DL form) or 200 mg/m2 (L form) 2-h infusion Hour 2 (before 5-FU bolus): Bevacizumab 5 mg/kg IV over 90 minutes infusion*. Hour 3.5: 5-FU bolus 400 mg/m2 IV bolus over 2-4 minutes Hour 3.5: 5-FU 2400 mg/m² given as a continuous infusion over 46h. * First infusion over 90 minutes (following other antineoplastic agents); if the infusion is well tolerated, the second dose may be infused over 60 minutes. If this second infusion also is well tolerated, subsequent doses may be infused over 30 minutes. Bevacizumab should be administered in all cycles, except cycle 6 of pre-operative treatment. If a central venous access device (CVAD) is required, at least a 2-day interval between placement of a central line and first bevacizumab administration is recommended. Six cycles pre and six cycles post surgery

    Reporting group title
    modified FOLFOX6 + Panitumumab + Surgery
    Reporting group description
    		 Day 1 of a 14 days cycle Hour - 1 (pre chemotherapy): Panitumumab 6 mg/kg IV over 60 minutes (≤ 1000 mg) or 90 minutes (> 1000 mg) +/- 15 min. infusion*. Hour 0: Oxaliplatin 85 mg/m² IV 2-h infusion Hour 0: Folinic Acid 400 mg/m² (DL form) or 200 mg/m2 (L form) IV 2-h infusion Hour 2: 5-FU 400 mg/m² IV bolus over 2-4 minutes Hour 2: 5-FU 2400 mg/m² given as a continuous infusion over 46h. * If the first infusion is well tolerated (i.e. without any serious infusion-related reactions) all subsequent infusions may be administered over 30 ± 10 minutes.

    Reporting group values
    		 modified FOLFOX6 + Surgery modified FOLFOX6 + Bevacizumab + Surgery modified FOLFOX6 + Panitumumab + Surgery Total
    Number of subjects
    		 16 15 13 44
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 61.3 (30.4 to 82.4) 63.9 (34.4 to 74.6) 62.2 (42.0 to 75.8) -
    Gender categorical
    Units: Subjects
        Female
    		 4 5 4 13
        Male
    		 12 10 9 31
    WHO Performance Status
    Units: Subjects
        PS 0
    		 9 13 11 33
        PS 1
    		 7 2 2 11

    End points

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    End points reporting groups
    Reporting group title
    modified FOLFOX6 + Surgery
    Reporting group description
    		 Day 1 of a 14 day cycle: Hour 0: Oxaliplatin 85 mg/m² IV 2-h infusion Hour 0: Folinic Acid 400 mg/m² (DL form) or 200 mg/m2 (L form) IV 2-h infusion Hour 2: 5-FU 400 mg/m² IV bolus over 2-4 minutes Hour 2: 5-FU 2400 mg/m² given as a continuous infusion over 46h. Six cycles pre and six cycles post surgery

    Reporting group title
    modified FOLFOX6 + Bevacizumab + Surgery
    Reporting group description
    		 Day 1 of a 14 day cycle Hour 0: Oxaliplatin 85 mg/m2 2-h infusion Hour 0: Folinic Acid 400 mg/m2 (DL form) or 200 mg/m2 (L form) 2-h infusion Hour 2 (before 5-FU bolus): Bevacizumab 5 mg/kg IV over 90 minutes infusion*. Hour 3.5: 5-FU bolus 400 mg/m2 IV bolus over 2-4 minutes Hour 3.5: 5-FU 2400 mg/m² given as a continuous infusion over 46h. * First infusion over 90 minutes (following other antineoplastic agents); if the infusion is well tolerated, the second dose may be infused over 60 minutes. If this second infusion also is well tolerated, subsequent doses may be infused over 30 minutes. Bevacizumab should be administered in all cycles, except cycle 6 of pre-operative treatment. If a central venous access device (CVAD) is required, at least a 2-day interval between placement of a central line and first bevacizumab administration is recommended. Six cycles pre and six cycles post surgery

    Reporting group title
    modified FOLFOX6 + Panitumumab + Surgery
    Reporting group description
    		 Day 1 of a 14 days cycle Hour - 1 (pre chemotherapy): Panitumumab 6 mg/kg IV over 60 minutes (≤ 1000 mg) or 90 minutes (> 1000 mg) +/- 15 min. infusion*. Hour 0: Oxaliplatin 85 mg/m² IV 2-h infusion Hour 0: Folinic Acid 400 mg/m² (DL form) or 200 mg/m2 (L form) IV 2-h infusion Hour 2: 5-FU 400 mg/m² IV bolus over 2-4 minutes Hour 2: 5-FU 2400 mg/m² given as a continuous infusion over 46h. * If the first infusion is well tolerated (i.e. without any serious infusion-related reactions) all subsequent infusions may be administered over 30 ± 10 minutes.

    Primary: Pathological response (according to Rubbia-Brandt)

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    End point title
    		 Pathological response (according to Rubbia-Brandt) [1]
    End point description
    The study was closed for poor accrual in 2015. Statistical guidelines for data analysis as specified in the protocol could not be applied due to the low number of patients. No follow-up data has been collected. Therefore the primary endpoint specified in the protocol "progression-free survival (PFS)" could not be computed. The secondary endpoint pathological response (according to Rubbia-Brandt) is the only efficacy endpoint that has been collected. Also, the database cannot be considered complete and clean. Descriptive analysis of pathological response has been done in the subset of patients that have completed a surgery and central pathology form (N=30).
    End point type
    Primary
    End point timeframe
    Pathologists graded the resected specimens according to the grading systems by Rubbia-Brandt et al. Pathological response has been determined by central reference laboratory.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The study was closed for poor accrual. As a consequence, the database cannot be considered complete and clean. No formal statistical analysis could be carried out. The analysis for the pathological response is just descriptive.
    End point values
    		 modified FOLFOX6 + Surgery modified FOLFOX6 + Bevacizumab + Surgery modified FOLFOX6 + Panitumumab + Surgery
    Number of subjects analysed
    12 [2]
    11 [3]
    7 [4]
    Units: Patient
        1- Major or complete response (MjHR)
    1
    7
    3
        2- Partial response (PHR)
    4
    3
    2
        3- No regressive or response changes (NHR)
    6
    0
    0
        Missing
    1
    1
    2
    Notes
    [2] - Randomized patients who have completed a surgery and a central pathology form.
    [3] - Randomized patients who have completed a surgery and a central pathology form.
    [4] - Randomized patients who have completed a surgery and a central pathology form.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected on a CRF to be submitted at pre-specified timepoint : at baseline, at the end of each preop cycle, 1week after surgery, within 4-8weeks post surgery, at the end of each postop cycle
    Adverse event reporting additional description
    AEs are evaluated using CTC grading, SAEs using MedDRA. Non-SAEs have not been collected specifically, therefore AEs will be reported in non-SAE section. Only the pre-specified items of the CRF are reported; laboratory values and "Other" AEs from the CRF are not reported (unless they are SAEs in which case they are reported in the SAE section).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    modified FOLFOX6 + Surgery
    Reporting group description
    		 The analysis of the safety endpoints “Toxicity” were carried out in the safety population defined as all patients who have started their allocated treatment (at least one dose of the study drug(s) in chemotherapy trials).

    Reporting group title
    modified FOLFOX6 + Bevacizumab + Surgery
    Reporting group description
    		 The analysis of the safety endpoints “Toxicity” were carried out in the safety population defined as all patients who have started their allocated treatment (at least one dose of the study drug(s) in chemotherapy trials).

    Reporting group title
    modified FOLFOX6 + Panitumumab + Surgery
    Reporting group description
    		 The analysis of the safety endpoints “Toxicity” were carried out in the safety population defined as all patients who have started their allocated treatment (at least one dose of the study drug(s) in chemotherapy trials).

    Serious adverse events
    		 modified FOLFOX6 + Surgery modified FOLFOX6 + Bevacizumab + Surgery modified FOLFOX6 + Panitumumab + Surgery
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 16 (43.75%)
    5 / 15 (33.33%)
    7 / 12 (58.33%)
         number of deaths (all causes)
    2
    1
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    POST PROCEDURAL COMPLICATION
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    WOUND EVISCERATION
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    ACUTE CORONARY SYNDROME
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    FEBRILE NEUTROPENIA
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LEUKOPENIA
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    MUCOSAL INFLAMMATION
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PYREXIA
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SUDDEN DEATH
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Immune system disorders
    DRUG HYPERSENSITIVITY
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    MACULAR DETACHMENT
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL PAIN
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DIARRHOEA
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    2 / 12 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ILEUS
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ILEUS PARALYTIC
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    INGUINAL HERNIA
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MECHANICAL ILEUS
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SUBILEUS
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    VOMITING
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    2 / 12 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    BILOMA
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CHOLANGITIS
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HEPATIC HAEMORRHAGE
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    ACUTE RESPIRATORY DISTRESS SYNDROME
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ATELECTASIS
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DYSPNOEA
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PLEURAL EFFUSION
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PNEUMONITIS
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PNEUMOTHORAX
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    RASH
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RASH ERYTHEMATOUS
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    ABDOMINAL INFECTION
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    INFECTION
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LIVER ABSCESS
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PERIHEPATIC ABSCESS
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    POST PROCEDURAL PNEUMONIA
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    URINARY TRACT INFECTION
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    WOUND INFECTION
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DEHYDRATION
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPOKALAEMIA
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 modified FOLFOX6 + Surgery modified FOLFOX6 + Bevacizumab + Surgery modified FOLFOX6 + Panitumumab + Surgery
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 16 (100.00%)
    15 / 15 (100.00%)
    12 / 12 (100.00%)
    Injury, poisoning and procedural complications
    WOUND DEHISCENCE
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 16 (0.00%)
    3 / 15 (20.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    3
    0
    Vascular disorders
    HYPERTENSION
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 16 (0.00%)
    3 / 15 (20.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    18
    0
    THROMBOEMBOLIC EVENT
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    1
    Cardiac disorders
    MYOCARDIAL INFARCTION
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Nervous system disorders
    DIZZINESS
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    3
    PERIPHERAL MOTOR NEUROPATHY
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    2 / 16 (12.50%)
    2 / 15 (13.33%)
    2 / 12 (16.67%)
         occurrences all number
    5
    2
    6
    PERIPHERAL SENSORY NEUROPATHY
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    14 / 16 (87.50%)
    11 / 15 (73.33%)
    10 / 12 (83.33%)
         occurrences all number
    86
    75
    44
    Blood and lymphatic system disorders
    FEBRILE NEUTROPENIA
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    General disorders and administration site conditions
    FATIGUE
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    8 / 16 (50.00%)
    7 / 15 (46.67%)
    6 / 12 (50.00%)
         occurrences all number
    47
    25
    22
    FEVER
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    3 / 16 (18.75%)
    2 / 15 (13.33%)
    3 / 12 (25.00%)
         occurrences all number
    3
    3
    9
    INJECTION SITE REACTION
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    2
    Immune system disorders
    ALLERGIC REACTION
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    5 / 12 (41.67%)
         occurrences all number
    0
    0
    10
    Gastrointestinal disorders
    CONSTIPATION
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    6 / 16 (37.50%)
    3 / 15 (20.00%)
    7 / 12 (58.33%)
         occurrences all number
    11
    7
    13
    DIARRHEA
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    11 / 16 (68.75%)
    6 / 15 (40.00%)
    5 / 12 (41.67%)
         occurrences all number
    28
    19
    22
    MUCOSITIS ORAL
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    3 / 16 (18.75%)
    6 / 15 (40.00%)
    6 / 12 (50.00%)
         occurrences all number
    8
    13
    12
    NAUSEA
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    8 / 16 (50.00%)
    10 / 15 (66.67%)
    8 / 12 (66.67%)
         occurrences all number
    36
    28
    29
    VOMITING
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    6 / 16 (37.50%)
    4 / 15 (26.67%)
    6 / 12 (50.00%)
         occurrences all number
    9
    12
    13
    Respiratory, thoracic and mediastinal disorders
    COUGH
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    1 / 16 (6.25%)
    3 / 15 (20.00%)
    1 / 12 (8.33%)
         occurrences all number
    2
    6
    1
    DYSPNEA
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    1 / 16 (6.25%)
    3 / 15 (20.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    5
    0
    EPISTAXIS
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 16 (0.00%)
    4 / 15 (26.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    12
    0
    PLEURAL EFFUSION
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    1
    RESPIRATORY FAILURE
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Skin and subcutaneous tissue disorders
    ALOPECIA
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    1 / 12 (8.33%)
         occurrences all number
    1
    6
    3
    DRY SKIN
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    6
    PALMAR-PLANTAR ERYTHRODYSESTHESIA SYNDROME
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    5 / 12 (41.67%)
         occurrences all number
    0
    4
    14
    PRURITUS
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    4 / 12 (33.33%)
         occurrences all number
    10
    1
    12
    RASH MACULO-PAPULAR
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    8 / 12 (66.67%)
         occurrences all number
    0
    0
    28
    Infections and infestations
    WOUND INFECTION
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    2 / 16 (12.50%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
         occurrences all number
    3
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Aug 2012
    Rationale for the amendment 1) Stratification factors : A few selected stratification factors related to liver metastases’ number, size and location were judged more appropriate in the )setting of a perioperative chemotherapy than the Nordlinger scoring system. In addition, the numerous categories from the Nordlinger scoring system would not have allowed an easy adjustment of the analyses for this factor in the context of sensitivity analyses. 2) Prognostic factor analyses : Some clarifications were brought on the statistical analyses to be performed in order to investigate the correlation between pathological response and disease free survival. 3) Add details about the FDG-PET/CT imaging TR sub-study 4) Update the Reporting of Serious Adverse Events chapter (chapter 14) according to the new standard chapter
    07 Feb 2013
    Rationale for the amendment: 1) a demand from the French authorities to include a condition on creatinine clearance in the patient selection criteria. 2) the need to include guidelines for the local pathologist in charge of reviewing the pathological response. 3) the need to modify the description of the type of biological material to be collected in order to centrally assess the pathological response and to conduct further translational research on tissue blocks.
    03 Apr 2014
    Rationale for the amendment: 1) Redefinition of which mutations constitute KRAS and NRAS wild type (WT)/mutated patients, with the inclusion or NRAS mutations. 2) With the inclusion of extended KRAS and NRAS mutations the frequency of wild type patients will drop in the patient population from 60% to nearly 50% therefore this will require the screening of an estimated additional 120 patients. 3) The possibility of central testing for extended KRAS and NRAS, in centers who do not perform it locally. 4) The need to include in the protocol a new adverse effect for bevacizumab: necrotizing fasciitis and update information on other adverse events. 5) The need to address some comments from the Swiss authorities (AEs follow-up duration). 6) Addition of a new optional Translational Research (TR) project. 7) Statistical clarifications (Clarification of PFS* definition and addition of a definition for DFS)

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    14 Dec 2015
    In December 2015 the study was closed for poor accrual. 44 patients had entered the study at this time.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to the low accrual, the statistical analysis plan could not be applied (only descriptive). No follow-up data was collected. Also, the database cannot be considered complete and clean.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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