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    Clinical Trial Results:
    A Multicentre Randomized Phase II Study to Assess the Safety and Resectability in Patients With Initially Unresectable Liver Metastases Secondary to Colorectal Cancer Receiving First-Line Treatment Either With mFOLFOX-6 Plus Bevacizumab or FOLFOXIRI Plus Bevacizumab (OLIVIA)

    Summary
    EudraCT number
    		 2007-007863-26
    Trial protocol
    		 AT   GB   FR   ES  
    Global end of trial date
    21 Oct 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Apr 2016
    First version publication date
    07 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MO18725
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00778102
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche Ltd, 41 616878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche Ltd, 41 616878333, global.trial_information@roche.com
    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
    28 Apr 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Oct 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This multicenter, randomized, Phase II study was designed to assess the safety and resectability in participants with initially unresectable liver metastases secondary to colorectal cancer receiving first-line treatment with bevacizumab plus 1 of 2 fluoropyrimidine/oxaliplatin-based chemotherapy regimens.
    Protection of trial subjects
    The Investigator has ensured that this study was conducted in full conformance with the principles of the Declaration of Helsinki or with the laws and regulations of the country in which the research was conducted, whichever affords the greater protection to the individual. The study must fully adhere to the principles outlined in Guideline for Good Clinical Practice International Conference on Harmonisation (ICH) Tripartite Guideline (January 1997) or with local law if it affords greater protection to the participant.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Oct 2008
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 17
    Country: Number of subjects enrolled
    Spain: 24
    Country: Number of subjects enrolled
    Austria: 15
    Country: Number of subjects enrolled
    France: 24
    Worldwide total number of subjects
    80
    EEA total number of subjects
    80
    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)
    51
    From 65 to 84 years
    29
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 After informed consent was obtained, a 2-part Screening/Baseline investigation was carried out. During the first part (Day -28 to Day 1), investigations largely involved demography, physical examination, and other noninvasive measurements. The second part (Day -7 to Day 1) involved collection of clinical laboratory data.

    Period 1
    Period 1 title
    Overall Study (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 + mFOLFOX-6
    Arm description
    		 Participants received a chemotherapy regimen of bevacizumab plus oxaliplatin, leucovorin, and 5-fluorouracil (5-FU) (mFOLFOX-6). Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 milligrams per kilogram (mg/kg) via intravenous (IV) infusion; oxaliplatin 85 milligrams per meter-squared (mg/m^2) via IV infusion; leucovorin 400 mg/m^2 via IV infusion; 5-FU 400 mg/m^2 via IV bolus; and 5-FU 2400 mg/m^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants could discontinue oxaliplatin and continue with bevacizumab, leucovorin, and 5-FU. Treatment was continued until resectability, progressive disease (PD), unacceptable toxicity, or participant refusal.
    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 administered on Day 1 of each cycle and repeated every 2 weeks: 5 mg/kg via IV infusion. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.

    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
    Oxaliplatin was administered on Day 1 of each cycle and repeated every 2 weeks: 85 mg/m^2 via IV infusion. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal. Following completion of 12 cycles, participants could discontinue oxaliplatin.

    Investigational medicinal product name
    Leucovorin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Leucovorin was administered on Day 1 of each cycle and repeated every 2 weeks: 200 or 400 mg/m^2 via IV infusion. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.

    Investigational medicinal product name
    5-Fluorouracil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5-FU was administered on Day 1 of each cycle and repeated every 2 weeks. Dosing was based upon treatment assignment. Participants could have received either: 400 mg/m^2 via IV bolus and 2400 mg/m^2 via continuous 46-hour IV infusion, or (without bolus) 3200 mg/m^2 via continuous 46-hour IV infusion. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.

    Arm title
    		 Bevacizumab + FOLFOXIRI
    Arm description
    		 Participants received a chemotherapy regimen of bevacizumab plus oxaliplatin, irinotecan, leucovorin, and 5-FU (FOLFOXIRI). Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 mg/kg via IV infusion; oxaliplatin 85 mg/m^2 via IV infusion; irinotecan 165 mg/m^2 via IV infusion; leucovorin 200 mg/m^2 via IV infusion; and 5-FU 3200 mg/m^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants were to discontinue either irinotecan, oxaliplatin, or both. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.
    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 administered on Day 1 of each cycle and repeated every 2 weeks: 5 mg/kg via IV infusion. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.

    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
    Oxaliplatin was administered on Day 1 of each cycle and repeated every 2 weeks: 85 mg/m^2 via IV infusion. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal. Following completion of 12 cycles, participants could discontinue oxaliplatin.

    Investigational medicinal product name
    Leucovorin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Leucovorin was administered on Day 1 of each cycle and repeated every 2 weeks: 200 or 400 mg/m^2 via IV infusion. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.

    Investigational medicinal product name
    5-Fluorouracil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5-FU was administered on Day 1 of each cycle and repeated every 2 weeks. Dosing was based upon treatment assignment. Participants could have received either: 400 mg/m^2 via IV bolus and 2400 mg/m^2 via continuous 46-hour IV infusion, or (without bolus) 3200 mg/m^2 via continuous 46-hour IV infusion. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.

    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
    Irinotecan was administered on Day 1 of each cycle and repeated every 2 weeks: 165 mg/m^2 via IV infusion. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal. Following completion of 12 cycles, participants could discontinue irinotecan.

    Number of subjects in period 1
    		Bevacizumab + mFOLFOX-6 Bevacizumab + FOLFOXIRI
    Started
    39
    41
    Completed
    18
    19
    Not completed
    21
    22
         Consent withdrawn by subject
    1
    1
         Death
    1
    1
         Refused treatment
    2
    3
         Violation of selection criteria
    1
    1
         Adverse event
    8
    5
         Lost to follow-up
    1
    -
         Administrative reason
    7
    10
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Bevacizumab + mFOLFOX-6
    Reporting group description
    		 Participants received a chemotherapy regimen of bevacizumab plus oxaliplatin, leucovorin, and 5-fluorouracil (5-FU) (mFOLFOX-6). Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 milligrams per kilogram (mg/kg) via intravenous (IV) infusion; oxaliplatin 85 milligrams per meter-squared (mg/m^2) via IV infusion; leucovorin 400 mg/m^2 via IV infusion; 5-FU 400 mg/m^2 via IV bolus; and 5-FU 2400 mg/m^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants could discontinue oxaliplatin and continue with bevacizumab, leucovorin, and 5-FU. Treatment was continued until resectability, progressive disease (PD), unacceptable toxicity, or participant refusal.

    Reporting group title
    Bevacizumab + FOLFOXIRI
    Reporting group description
    		 Participants received a chemotherapy regimen of bevacizumab plus oxaliplatin, irinotecan, leucovorin, and 5-FU (FOLFOXIRI). Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 mg/kg via IV infusion; oxaliplatin 85 mg/m^2 via IV infusion; irinotecan 165 mg/m^2 via IV infusion; leucovorin 200 mg/m^2 via IV infusion; and 5-FU 3200 mg/m^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants were to discontinue either irinotecan, oxaliplatin, or both. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.

    Reporting group values
    		 Bevacizumab + mFOLFOX-6 Bevacizumab + FOLFOXIRI Total
    Number of subjects
    		 39 41 80
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 57.1 ± 10.32 61.8 ± 11.02 -
    Gender categorical
    Units: Subjects
        Female
    		 21 12 33
        Male
    		 18 29 47

    End points

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    End points reporting groups
    Reporting group title
    Bevacizumab + mFOLFOX-6
    Reporting group description
    		 Participants received a chemotherapy regimen of bevacizumab plus oxaliplatin, leucovorin, and 5-fluorouracil (5-FU) (mFOLFOX-6). Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 milligrams per kilogram (mg/kg) via intravenous (IV) infusion; oxaliplatin 85 milligrams per meter-squared (mg/m^2) via IV infusion; leucovorin 400 mg/m^2 via IV infusion; 5-FU 400 mg/m^2 via IV bolus; and 5-FU 2400 mg/m^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants could discontinue oxaliplatin and continue with bevacizumab, leucovorin, and 5-FU. Treatment was continued until resectability, progressive disease (PD), unacceptable toxicity, or participant refusal.

    Reporting group title
    Bevacizumab + FOLFOXIRI
    Reporting group description
    		 Participants received a chemotherapy regimen of bevacizumab plus oxaliplatin, irinotecan, leucovorin, and 5-FU (FOLFOXIRI). Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 mg/kg via IV infusion; oxaliplatin 85 mg/m^2 via IV infusion; irinotecan 165 mg/m^2 via IV infusion; leucovorin 200 mg/m^2 via IV infusion; and 5-FU 3200 mg/m^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants were to discontinue either irinotecan, oxaliplatin, or both. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.

    Primary: Percentage of Participants With Complete Resection or Residual (Microscopic or Macroscopic) Tumor

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    End point title
    		 Percentage of Participants With Complete Resection or Residual (Microscopic or Macroscopic) Tumor
    End point description
    Following resective surgery, participants were evaluated for complete resection (R0) or the presence of microscopic (R1) or macroscopic (R2) residual tumor. The percentage of participants within each residual tumor classification was calculated as [number of participants with R0, R1, and/or R2 divided by the total number of participants] multiplied by 100. Associated 95% confidence intervals were calculated for one-sample binomial using the Clopper-Pearson method. Intent-to-Treat (ITT) Population: All randomized participants. Participants were analyzed according to which treatment group they were randomized, regardless of the treatment actually received.
    End point type
    Primary
    End point timeframe
    Up to 5 years (at Screening; every 6 weeks, and within 4 weeks prior to surgery; and at time of/after surgery)
    End point values
    		 Bevacizumab + mFOLFOX-6 Bevacizumab + FOLFOXIRI
    Number of subjects analysed
    39
    41
    Units: percentage of participants
    number (confidence interval 95%)
        R0, R1, or R2
    48.7 (32.4 to 65.2)
    61 (44.5 to 75.8)
        R0 or R1
    33.3 (19.1 to 50.2)
    51.2 (35.1 to 67.1)
        R0
    23.1 (11.1 to 39.3)
    48.8 (32.9 to 64.9)
    Statistical analysis title
    		 Difference in resection rate (R0, R1, R2)
    Statistical analysis description
    Difference between groups in the collective percentage of participants with R0, R1, or R2.
    Comparison groups
    Bevacizumab + mFOLFOX-6 v Bevacizumab + FOLFOXIRI
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2707
    Method
    		 Chi-squared
    Parameter type
    		 Difference in resection rate
    Point estimate
    12.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11
         upper limit
    		 35.5

    Secondary: Time to Resection

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    End point title
    		 Time to Resection
    End point description
    Time to resection was defined as the time from randomization to the date of first resective surgery. For participants who did not undergo resective surgery, time to resection was censored at Day 1. Time to resection was estimated by Kaplan-Meier analysis. ITT Population.
    End point type
    Secondary
    End point timeframe
    Up to 5 years (at Screening; prior to each cycle, and within 7 days prior to surgery; and at time of surgery)
    End point values
    		 Bevacizumab + mFOLFOX-6 Bevacizumab + FOLFOXIRI
    Number of subjects analysed
    39
    41
    Units: months
        median (confidence interval 95%)
    4.4 (4.1 to 5.8)
    4.3 (3.9 to 5.5)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Histopathological Response

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    End point title
    		 Percentage of Participants With Histopathological Response
    End point description
    At the time of resective surgery, participants were evaluated for histopathological response as defined through pathologist review of the resected metastatic lesions, including assessment of margin status and tumor cell viability. Histopathological response classification was based upon the percentage of viable tumor cells, where 'Complete response' was considered for those with 0 percent (%) viable tumor cells, 'Major response' for those with 1% to 49% viable tumor cells, 'Minor response' for 50% to 99% viable tumor cells, and 'No response' for 100% viable tumor cells. The response could not be determined in some cases and was documented as 'Unknown.' The percentage of participants within each response category was calculated as [number of participants with a given response divided by the number of participants who completed the assessment] multiplied by 100. ITT Population.
    End point type
    Secondary
    End point timeframe
    Up to 5 years (at Screening; every 6 weeks, and within 4 weeks prior to surgery; and at time of/after surgery)
    End point values
    		 Bevacizumab + mFOLFOX-6 Bevacizumab + FOLFOXIRI
    Number of subjects analysed
    14 [1]
    21 [2]
    Units: percentage of participants
    number (not applicable)
        Complete response
    0
    4.8
        Major response
    57.1
    47.6
        Minor response
    28.6
    33.3
        No response
    0
    0
        Unknown
    14.3
    14.3
    Notes
    [1] - Only participants with histopathological assessment after first resective surgery were considered.
    [2] - Only participants with histopathological assessment after first resective surgery were considered.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Complete or Major Histopathological Response

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    End point title
    		 Percentage of Participants With Complete or Major Histopathological Response
    End point description
    At the time of resective surgery, participants were evaluated for histopathological response as defined through pathologist review of the resected metastatic lesions, including assessment of margin status and tumor cell viability. Histopathological response classification was based upon the percentage of viable tumor cells, as described previously. The collective percentage of participants assessed as having a complete or major response was calculated as [number of participants with complete or major response divided by the number of participants who completed the assessment] multiplied by 100. Associated 95% confidence intervals were calculated for one-sample binomial using the Clopper-Pearson method. ITT Population.
    End point type
    Secondary
    End point timeframe
    Up to 5 years (at Screening; every 6 weeks, and within 4 weeks prior to surgery; and at time of/after surgery)
    End point values
    		 Bevacizumab + mFOLFOX-6 Bevacizumab + FOLFOXIRI
    Number of subjects analysed
    14 [3]
    21 [4]
    Units: percentage of participants
        number (confidence interval 95%)
    57.1 (28.9 to 82.3)
    52.4 (29.8 to 74.3)
    Notes
    [3] - Only participants with histopathological assessment after first resective surgery were included.
    [4] - Only participants with histopathological assessment after first resective surgery were included.
    Statistical analysis title
    		 Difference in response rate
    Statistical analysis description
    Difference between groups in the collective percentage of participants with complete or major histopathological response.
    Comparison groups
    Bevacizumab + mFOLFOX-6 v Bevacizumab + FOLFOXIRI
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7817
    Method
    		 Chi-squared
    Parameter type
    		 Difference in response rate
    Point estimate
    -4.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -43
         upper limit
    		 33.5

    Secondary: Percentage of Participants Experiencing Relapse Following Curative Resection

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    End point title
    		 Percentage of Participants Experiencing Relapse Following Curative Resection
    End point description
    Among participants with curative resection (complete resection [R0] or microscopic residual tumor [R1]), relapse was defined as the first new occurrence of cancer or death. The percentage of participants who experienced relapse was calculated as [number of participants with a relapse event divided by the number of participants initially classified as R0 or R1 following resective surgery] multiplied by 100. ITT Population.
    End point type
    Secondary
    End point timeframe
    Up to 5 years (at time of surgery; 48 hours and 4 and 12 weeks after surgery; within 4 weeks after completion of treatment; every 3 to 6 months for 1 year; then annually)
    End point values
    		 Bevacizumab + mFOLFOX-6 Bevacizumab + FOLFOXIRI
    Number of subjects analysed
    13 [5]
    21 [6]
    Units: percentage of participants
        number (not applicable)
    76.9
    57.1
    Notes
    [5] - Only those with residual tumor classification of R0 or R1 were considered in the analysis.
    [6] - Only those with residual tumor classification of R0 or R1 were considered in the analysis.
    No statistical analyses for this end point

    Secondary: Relapse-Free Survival (RFS)

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    End point title
    		 Relapse-Free Survival (RFS)
    End point description
    RFS was defined as the time from curative resection (complete resection [R0] or microscopic residual tumor [R1]) to the date of first diagnosis of relapse. For participants with curative resection and without relapse, RFS was censored at the last known relapse-free assessment. RFS was estimated by Kaplan-Meier analysis. ITT Population. (99999 = not estimable due to insufficient follow-up.)
    End point type
    Secondary
    End point timeframe
    Up to 5 years (at time of surgery; 48 hours and 4 and 12 weeks after surgery; within 4 weeks after completion of treatment; every 3 to 6 months for 1 year; then annually)
    End point values
    		 Bevacizumab + mFOLFOX-6 Bevacizumab + FOLFOXIRI
    Number of subjects analysed
    13 [7]
    21 [8]
    Units: months
        median (confidence interval 95%)
    8.1 (3.8 to 11.7)
    17.1 (12.3 to 99999)
    Notes
    [7] - Only those with residual tumor classification of R0 or R1 were considered in the analysis.
    [8] - Only those with residual tumor classification of R0 or R1 were considered in the analysis.
    No statistical analyses for this end point

    Secondary: Percentage of Participants Experiencing Death or Disease Progression

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    End point title
    		 Percentage of Participants Experiencing Death or Disease Progression
    End point description
    PD was defined, using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, as at least a 20% increase in the sum of the longest diameter of target lesions, or the appearance of one or more new lesions. The percentage of participants experiencing PD or death was calculated as [number of participants with event divided by the number of participants analyzed] multiplied by 100. ITT Population.
    End point type
    Secondary
    End point timeframe
    Up to 5 years (at Screening; every 6 weeks, and within 4 weeks prior to surgery; 4 and 12 weeks after surgery; and at the end of Cycles 4 and 8 if assessed as R0 or R1, or every 6 weeks until progression or resectability if assessed as R2)
    End point values
    		 Bevacizumab + mFOLFOX-6 Bevacizumab + FOLFOXIRI
    Number of subjects analysed
    39
    41
    Units: percentage of participants
        number (not applicable)
    89.7
    68.3
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS)

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    End point title
    		 Progression-Free Survival (PFS)
    End point description
    PFS was defined, using RECIST version 1.0, as the time from randomization to the date of first documented PD or death from any cause. PD was defined as at least a 20% increase in the sum of the longest diameter of target lesions, or the appearance of one or more new lesions. For participants without documented PD or death, PFS was censored at the time of last tumor assessment. PFS was estimated by Kaplan-Meier analysis. ITT Population.
    End point type
    Secondary
    End point timeframe
    Up to 5 years (at Screening; every 6 weeks, and within 4 weeks prior to surgery; 4 and 12 weeks after surgery; and at the end of Cycles 4 and 8 if assessed as R0 or R1, or every 6 weeks until progression or resectability if assessed as R2)
    End point values
    		 Bevacizumab + mFOLFOX-6 Bevacizumab + FOLFOXIRI
    Number of subjects analysed
    39
    41
    Units: months
        median (confidence interval 95%)
    11.5 (9.6 to 13.6)
    18.6 (12.9 to 22.3)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Died

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    End point title
    		 Percentage of Participants Who Died
    End point description
    ITT Population.
    End point type
    Secondary
    End point timeframe
    Up to 5 years (prior to each cycle, and within 7 days prior to surgery; at time of surgery; 48 hours and 4 and 12 weeks after surgery; within 4 weeks after completion of treatment; every 3 to 6 months for 1 year; then annually)
    End point values
    		 Bevacizumab + mFOLFOX-6 Bevacizumab + FOLFOXIRI
    Number of subjects analysed
    39
    41
    Units: percentage of participants
        number (not applicable)
    48.7
    19.5
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS was defined as the time from randomization to death from any cause. For participants without an event of death, OS was censored at the last-known alive date. OS was estimated by Kaplan-Meier analysis. ITT Population. (99999 = not estimable due to insufficient follow-up.)
    End point type
    Secondary
    End point timeframe
    Up to 5 years (prior to each cycle, and within 7 days prior to surgery; at time of surgery; 48 hours and 4 and 12 weeks after surgery; within 4 weeks after completion of treatment; every 3 to 6 months for 1 year; then annually)
    End point values
    		 Bevacizumab + mFOLFOX-6 Bevacizumab + FOLFOXIRI
    Number of subjects analysed
    39
    41
    Units: months
        median (confidence interval 95%)
    32.2 (21.5 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With a Confirmed Best Overall Response of Complete Response (CR) or Partial Response (PR) According to RECIST Version 1.0

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    End point title
    		 Percentage of Participants With a Confirmed Best Overall Response of Complete Response (CR) or Partial Response (PR) According to RECIST Version 1.0
    End point description
    Using RECIST version 1.0, participants were considered to have achieved CR upon the disappearance of all target and non-target lesions. Participants who achieved PR demonstrated at least a 30% decrease in the sum of the largest diameter of target lesions, taking as reference the Screening sum largest diameter. Responses were confirmed by repeat assessments no less than 4 weeks after criteria for response were first met. The collective percentage of participants with confirmed best overall response of CR or PR was calculated as [number of participants meeting RECIST criteria for CR or PR divided by the number of participants analyzed] multiplied by 100. Associated 95% confidence intervals were calculated for one-sample binomial using the Clopper-Pearson method. ITT Population.
    End point type
    Secondary
    End point timeframe
    Up to 5 years (at Screening; every 6 weeks, and within 4 weeks prior to surgery; 4 and 12 weeks after surgery; and at the end of Cycles 4 and 8 if assessed as R0 or R1, or every 6 weeks until progression or resectability if assessed as R2)
    End point values
    		 Bevacizumab + mFOLFOX-6 Bevacizumab + FOLFOXIRI
    Number of subjects analysed
    39
    41
    Units: percentage of participants
        number (confidence interval 95%)
    61.5 (44.6 to 76.6)
    80.5 (65.1 to 91.2)
    Statistical analysis title
    		 Difference in response rate (CR or PR)
    Statistical analysis description
    Difference between groups in the collective percentage of participants with confirmed best overall response of CR or PR.
    Comparison groups
    Bevacizumab + mFOLFOX-6 v Bevacizumab + FOLFOXIRI
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0612
    Method
    		 Chi-squared
    Parameter type
    		 Difference in response rate
    Point estimate
    18.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.1
         upper limit
    		 40

    Secondary: Time to Response

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    End point title
    		 Time to Response
    End point description
    Time to response according to RECIST version 1.0 was defined as the time from randomization to the date of first documented CR or PR. Participants were considered to have achieved CR upon the disappearance of all target and non-target lesions. Participants who achieved PR demonstrated at least a 30% decrease in the sum of the largest diameter of target lesions, taking as reference the Screening sum largest diameter. Responses were confirmed by repeat assessments no less than 4 weeks after criteria for response were first met. For participants who did not complete a confirmatory tumor assessment, time to response was censored at the date of last tumor assessment, or if unavailable, at the date of first dose. Time to response was estimated by Kaplan-Meier analysis. ITT Population.
    End point type
    Secondary
    End point timeframe
    Up to 5 years (at Screening; every 6 weeks, and within 4 weeks prior to surgery; 4 and 12 weeks after surgery; and at the end of Cycles 4 and 8 if assessed as R0 or R1, or every 6 weeks until progression or resectability if assessed as R2)
    End point values
    		 Bevacizumab + mFOLFOX-6 Bevacizumab + FOLFOXIRI
    Number of subjects analysed
    39
    41
    Units: months
        median (confidence interval 95%)
    3.1 (2.7 to 8.6)
    3.1 (1.9 to 3.9)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Complications Related to First Resective Surgery

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    End point title
    		 Percentage of Participants With Complications Related to First Resective Surgery
    End point description
    Complications related to the first resective surgery were evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0, and classified according to severity. The NCI-CTCAE severity classification criteria are as follows: Grade 5 equals (=) resulting in death; Grade 4 = life-threatening; Grade 3 = severe; Grade 2 = moderate; and Grade 1 = mild. The percentage of participants experiencing a given adverse event (AE) by severity grade was calculated as [number of participants with an AE divided by the number of participants who underwent first resective surgery] multiplied by 100. Safety Population (First Surgery Subpopulation): All participants who underwent a first resective surgery and who received at least one dose of trial medication, whether prematurely withdrawn or not. Participants were analyzed according to the actual treatment they received.
    End point type
    Secondary
    End point timeframe
    Up to 5 years (at time of surgery; 48 hours and 4 and 12 weeks after surgery; within 4 weeks after completion of treatment; every 3 to 6 months for 1 year; then annually)
    End point values
    		 Bevacizumab + mFOLFOX-6 Bevacizumab + FOLFOXIRI
    Number of subjects analysed
    19
    25
    Units: percentage of participants
    number (not applicable)
        Any complication, Total
    73.7
    52
        Any complication, Grade 1
    15.8
    4
        Any complication, Grade 2
    36.8
    12
        Any complication, Grade 3
    10.5
    24
        Any complication, Grade 4
    0
    12
        Any complication, Grade 5
    10.5
    0
        Bleeding, Total
    15.8
    8
        Bleeding, Grade 1
    5.3
    0
        Bleeding, Grade 2
    5.3
    4
        Bleeding, Grade 3
    5.3
    4
        Cardiovascular, Total
    10.5
    4
        Cardiovascular, Grade 2
    0
    4
        Cardiovascular, Grade 3
    5.3
    0
        Cardiovascular, Grade 4
    5.3
    0
        Infections, Total
    26.3
    32
        Infections, Grade 1
    10.5
    12
        Infections, Grade 2
    5.3
    0
        Infections, Grade 3
    5.3
    16
        Infections, Grade 4
    5.3
    4
        Liver insufficiency, Total
    10.5
    0
        Liver insufficiency, Grade 5
    10.5
    0
        Neural disorder, Total
    5.3
    0
        Neural disorder, Grade 2
    5.3
    0
        Noninfected perihepatic fluid collections, Total
    0
    4
        Noninfected perihepatic fluid collections, Grade 2
    0
    4
        Other complication, Total
    52.6
    28
        Other complication, Grade 1
    26.3
    8
        Other complication, Grade 2
    21.1
    8
        Other complication, Grade 3
    0
    12
        Other complication, Grade 4
    5.3
    0
        Pulmonary, Total
    5.3
    4
        Pulmonary, Grade 3
    5.3
    4
        Renal impairment, Total
    10.5
    4
        Renal impairment, Grade 2
    5.3
    4
        Renal impairment, Grade 4
    5.3
    0
        Wound healing, Total
    5.3
    12
        Wound healing, Grade 1
    5.3
    0
        Wound healing, Grade 3
    0
    4
        Wound healing, Grade 4
    0
    8
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Complications Related to Second Resective Surgery

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    End point title
    		 Percentage of Participants With Complications Related to Second Resective Surgery
    End point description
    Complications related to the second resective surgery were evaluated using the NCI-CTCAE version 3.0, and classified according to severity. The NCI-CTCAE severity classification criteria are as follows: Grade 5 = resulting in death; Grade 4 = life-threatening; Grade 3 = severe; Grade 2 = moderate; and Grade 1 = mild. The percentage of participants experiencing a given AE by severity grade was calculated as [number of participants with an AE divided by the number of participants who underwent second resective surgery] multiplied by 100. Safety Population (Second Surgery Subpopulation): All participants who underwent a second resective surgery and who received at least one dose of trial medication, whether prematurely withdrawn or not. Participants were analyzed according to the actual treatment they received.
    End point type
    Secondary
    End point timeframe
    Up to 5 years (at time of surgery; 48 hours and 4 and 12 weeks after surgery; within 4 weeks after completion of treatment; every 3 to 6 months for 1 year; then annually)
    End point values
    		 Bevacizumab + mFOLFOX-6 Bevacizumab + FOLFOXIRI
    Number of subjects analysed
    3
    3
    Units: percentage of participants
    number (not applicable)
        Any complication, Total
    100
    66.7
        Any complication, Grade 1
    0
    33.3
        Any complication, Grade 2
    66.7
    0
        Any complication, Grade 3
    0
    33.3
        Any complication, Grade 3a
    33.3
    0
        Bleeding, Total
    33.3
    33.3
        Bleeding, Grade 1
    0
    33.3
        Bleeding, Grade 2
    33.3
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 5 years (at Screening; prior to each cycle, and within 7 days prior to surgery; at time of surgery; 48 hours and 4 and 12 weeks after surgery; within 4 weeks after completion of treatment; every 3 to 6 months for 1 year; then annually)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Bevacizumab + mFOLFOX-6
    Reporting group description
    		 Participants received a chemotherapy regimen of bevacizumab plus mFOLFOX-6. Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 mg/kg via IV infusion; oxaliplatin 85 mg/m^2 via IV infusion; leucovorin 400 mg/m^2 via IV infusion; 5-FU 400 mg/m^2 via IV bolus; and 5-FU 2400 mg/m^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants could discontinue oxaliplatin and continue with bevacizumab, leucovorin, and 5-FU. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.

    Reporting group title
    Bevacizumab + FOLFOXIRI
    Reporting group description
    		 Participants received a chemotherapy regimen of bevacizumab plus FOLFOXIRI. Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 mg/kg via IV infusion; oxaliplatin 85 mg/m^2 via IV infusion; irinotecan 165 mg/m^2 via IV infusion; leucovorin 200 mg/m^2 via IV infusion; and 5-FU 3200 mg/m^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants were to discontinue either irinotecan, oxaliplatin, or both. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.

    Serious adverse events
    		 Bevacizumab + mFOLFOX-6 Bevacizumab + FOLFOXIRI
    Total subjects affected by serious adverse events
         subjects affected / exposed
    24 / 37 (64.86%)
    24 / 40 (60.00%)
         number of deaths (all causes)
    19
    8
         number of deaths resulting from adverse events
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    2 / 37 (5.41%)
    2 / 40 (5.00%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 40 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired healing
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Pelvic fluid collection
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 40 (2.50%)
         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
    Pulmonary embolism
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Endoscopic retrograde cholangiopancreatography
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 40 (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
    1 / 37 (2.70%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Wound dehiscence
         subjects affected / exposed
    0 / 37 (0.00%)
    3 / 40 (7.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to anastomose
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Paraesthesia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    3 / 37 (8.11%)
    6 / 40 (15.00%)
         occurrences causally related to treatment / all
    3 / 3
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    3 / 37 (8.11%)
    4 / 40 (10.00%)
         occurrences causally related to treatment / all
    3 / 3
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 37 (2.70%)
    6 / 40 (15.00%)
         occurrences causally related to treatment / all
    1 / 1
    6 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal hypomotility
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 40 (2.50%)
         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 / 37 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised intraabdominal fluid collection
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritoneal haemorrhage
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retroperitoneal haematoma
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 40 (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
    1 / 37 (2.70%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Cholangitis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Portal vein thrombosis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal disorder
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 40 (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
    Peritonitis
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 40 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Campylobacter infection
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Bevacizumab + mFOLFOX-6 Bevacizumab + FOLFOXIRI
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    36 / 37 (97.30%)
    40 / 40 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    8 / 37 (21.62%)
    5 / 40 (12.50%)
         occurrences all number
    12
    5
    Hyptotension
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 40 (0.00%)
         occurrences all number
    2
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    14 / 37 (37.84%)
    16 / 40 (40.00%)
         occurrences all number
    35
    40
    Mucosal inflammation
         subjects affected / exposed
    20 / 37 (54.05%)
    17 / 40 (42.50%)
         occurrences all number
    37
    31
    Fatigue
         subjects affected / exposed
    10 / 37 (27.03%)
    12 / 40 (30.00%)
         occurrences all number
    27
    35
    Pyrexia
         subjects affected / exposed
    7 / 37 (18.92%)
    12 / 40 (30.00%)
         occurrences all number
    15
    15
    Catheter site pain
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 40 (2.50%)
         occurrences all number
    2
    1
    Pain
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 40 (5.00%)
         occurrences all number
    1
    2
    Chest pain
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 40 (0.00%)
         occurrences all number
    2
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    3 / 37 (8.11%)
    3 / 40 (7.50%)
         occurrences all number
    4
    4
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    13 / 37 (35.14%)
    16 / 40 (40.00%)
         occurrences all number
    17
    26
    Cough
         subjects affected / exposed
    3 / 37 (8.11%)
    5 / 40 (12.50%)
         occurrences all number
    5
    6
    Rhinorrhoea
         subjects affected / exposed
    3 / 37 (8.11%)
    3 / 40 (7.50%)
         occurrences all number
    6
    4
    Dyspnoea
         subjects affected / exposed
    3 / 37 (8.11%)
    2 / 40 (5.00%)
         occurrences all number
    4
    2
    Dysphonia
         subjects affected / exposed
    2 / 37 (5.41%)
    2 / 40 (5.00%)
         occurrences all number
    2
    3
    Dyspnoea exertional
         subjects affected / exposed
    2 / 37 (5.41%)
    2 / 40 (5.00%)
         occurrences all number
    3
    2
    Oropharyngeal pain
         subjects affected / exposed
    1 / 37 (2.70%)
    4 / 40 (10.00%)
         occurrences all number
    1
    4
    Nasal congestion
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 40 (5.00%)
         occurrences all number
    1
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    7 / 37 (18.92%)
    2 / 40 (5.00%)
         occurrences all number
    8
    2
    Anxiety
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 40 (2.50%)
         occurrences all number
    3
    1
    Investigations
    Platelet count decreased
         subjects affected / exposed
    5 / 37 (13.51%)
    3 / 40 (7.50%)
         occurrences all number
    12
    5
    Haemoglobin decreased
         subjects affected / exposed
    2 / 37 (5.41%)
    2 / 40 (5.00%)
         occurrences all number
    10
    3
    White blood cell count decreased
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 40 (2.50%)
         occurrences all number
    2
    6
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    3 / 37 (8.11%)
    1 / 40 (2.50%)
         occurrences all number
    6
    1
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 40 (0.00%)
         occurrences all number
    5
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 40 (2.50%)
         occurrences all number
    2
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 40 (2.50%)
         occurrences all number
    3
    1
    Weight decreased
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 40 (2.50%)
         occurrences all number
    2
    2
    Blood alkaline phosphatase increased
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 40 (0.00%)
         occurrences all number
    3
    0
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    1 / 37 (2.70%)
    3 / 40 (7.50%)
         occurrences all number
    2
    3
    Nervous system disorders
    Neuropathy peripheral
         subjects affected / exposed
    22 / 37 (59.46%)
    19 / 40 (47.50%)
         occurrences all number
    63
    56
    Paraesthesia
         subjects affected / exposed
    12 / 37 (32.43%)
    7 / 40 (17.50%)
         occurrences all number
    26
    12
    Peripheral sensory neuropathy
         subjects affected / exposed
    4 / 37 (10.81%)
    4 / 40 (10.00%)
         occurrences all number
    22
    10
    Headache
         subjects affected / exposed
    9 / 37 (24.32%)
    7 / 40 (17.50%)
         occurrences all number
    15
    8
    Dysgeusia
         subjects affected / exposed
    5 / 37 (13.51%)
    10 / 40 (25.00%)
         occurrences all number
    8
    13
    Lethargy
         subjects affected / exposed
    3 / 37 (8.11%)
    2 / 40 (5.00%)
         occurrences all number
    8
    12
    Dysaesthesia
         subjects affected / exposed
    3 / 37 (8.11%)
    2 / 40 (5.00%)
         occurrences all number
    5
    3
    Dizziness
         subjects affected / exposed
    3 / 37 (8.11%)
    1 / 40 (2.50%)
         occurrences all number
    3
    1
    Polyneuropathy
         subjects affected / exposed
    3 / 37 (8.11%)
    1 / 40 (2.50%)
         occurrences all number
    3
    1
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    20 / 37 (54.05%)
    26 / 40 (65.00%)
         occurrences all number
    33
    75
    Thrombocytopenia
         subjects affected / exposed
    4 / 37 (10.81%)
    8 / 40 (20.00%)
         occurrences all number
    8
    16
    Anaemia
         subjects affected / exposed
    4 / 37 (10.81%)
    6 / 40 (15.00%)
         occurrences all number
    4
    8
    Leukopenia
         subjects affected / exposed
    1 / 37 (2.70%)
    4 / 40 (10.00%)
         occurrences all number
    1
    6
    Lymphopenia
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 40 (0.00%)
         occurrences all number
    4
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 37 (5.41%)
    2 / 40 (5.00%)
         occurrences all number
    2
    5
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    20 / 37 (54.05%)
    33 / 40 (82.50%)
         occurrences all number
    39
    103
    Nausea
         subjects affected / exposed
    23 / 37 (62.16%)
    21 / 40 (52.50%)
         occurrences all number
    64
    66
    Vomiting
         subjects affected / exposed
    14 / 37 (37.84%)
    25 / 40 (62.50%)
         occurrences all number
    19
    56
    Constipation
         subjects affected / exposed
    18 / 37 (48.65%)
    15 / 40 (37.50%)
         occurrences all number
    31
    25
    Abdominal pain
         subjects affected / exposed
    15 / 37 (40.54%)
    15 / 40 (37.50%)
         occurrences all number
    20
    28
    Dry mouth
         subjects affected / exposed
    7 / 37 (18.92%)
    8 / 40 (20.00%)
         occurrences all number
    13
    11
    Abdominal pain upper
         subjects affected / exposed
    8 / 37 (21.62%)
    5 / 40 (12.50%)
         occurrences all number
    11
    8
    Stomatitis
         subjects affected / exposed
    5 / 37 (13.51%)
    3 / 40 (7.50%)
         occurrences all number
    5
    6
    Toothache
         subjects affected / exposed
    4 / 37 (10.81%)
    2 / 40 (5.00%)
         occurrences all number
    6
    3
    Dyspepsia
         subjects affected / exposed
    2 / 37 (5.41%)
    2 / 40 (5.00%)
         occurrences all number
    2
    2
    Proctalgia
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 40 (5.00%)
         occurrences all number
    2
    2
    Haemorrhoids
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 40 (5.00%)
         occurrences all number
    1
    2
    Flatulence
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 40 (0.00%)
         occurrences all number
    2
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    2 / 37 (5.41%)
    12 / 40 (30.00%)
         occurrences all number
    2
    13
    Pruritus
         subjects affected / exposed
    2 / 37 (5.41%)
    3 / 40 (7.50%)
         occurrences all number
    5
    3
    Rash
         subjects affected / exposed
    5 / 37 (13.51%)
    2 / 40 (5.00%)
         occurrences all number
    6
    2
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    2 / 37 (5.41%)
    3 / 40 (7.50%)
         occurrences all number
    2
    5
    Skin hyperpigmentation
         subjects affected / exposed
    2 / 37 (5.41%)
    2 / 40 (5.00%)
         occurrences all number
    2
    2
    Skin lesion
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 40 (0.00%)
         occurrences all number
    2
    0
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    2 / 37 (5.41%)
    4 / 40 (10.00%)
         occurrences all number
    2
    4
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    8 / 37 (21.62%)
    7 / 40 (17.50%)
         occurrences all number
    8
    7
    Musculoskeletal pain
         subjects affected / exposed
    3 / 37 (8.11%)
    4 / 40 (10.00%)
         occurrences all number
    4
    9
    Pain in extremity
         subjects affected / exposed
    2 / 37 (5.41%)
    6 / 40 (15.00%)
         occurrences all number
    6
    6
    Neck pain
         subjects affected / exposed
    4 / 37 (10.81%)
    1 / 40 (2.50%)
         occurrences all number
    5
    1
    Arthralgia
         subjects affected / exposed
    0 / 37 (0.00%)
    4 / 40 (10.00%)
         occurrences all number
    0
    4
    Muscle spasms
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 40 (5.00%)
         occurrences all number
    1
    3
    Myalgia
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 40 (2.50%)
         occurrences all number
    2
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 40 (0.00%)
         occurrences all number
    2
    0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    4 / 37 (10.81%)
    4 / 40 (10.00%)
         occurrences all number
    5
    4
    Nasopharyngitis
         subjects affected / exposed
    4 / 37 (10.81%)
    1 / 40 (2.50%)
         occurrences all number
    5
    1
    Oral herpes
         subjects affected / exposed
    3 / 37 (8.11%)
    3 / 40 (7.50%)
         occurrences all number
    3
    3
    Rhinitis
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 40 (5.00%)
         occurrences all number
    1
    3
    Device related infection
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 40 (2.50%)
         occurrences all number
    2
    1
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 37 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    0
    3
    Candida infection
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 40 (0.00%)
         occurrences all number
    2
    0
    Tracheitis
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    8 / 37 (21.62%)
    13 / 40 (32.50%)
         occurrences all number
    16
    19
    Hypokalaemia
         subjects affected / exposed
    2 / 37 (5.41%)
    6 / 40 (15.00%)
         occurrences all number
    2
    7
    Hypocalcaemia
         subjects affected / exposed
    0 / 37 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    0
    3
    Hypophosphataemia
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Feb 2009
    The protocol was amended to remove an eligible age upper limit and to allow all participants at least 18 years of age. Select prior intervention-related exclusion criteria were omitted based upon new safety findings. Additional guidance was provided for the maximum duration (12 cycles) of the full regimen of FOLFOXIRI, and dosing criteria were updated to reflect the most current bevacizumab safety and dose modification guidance. Tumor tissue collection methods were modified, and the schedule of objective tumor assessments was changed from a 6-month to a 3-month frequency to ensure timely capturing of relapse data. A new action plan for the management of several specific AEs was added, and guidance for the assessment of causality for clinical AEs was updated. Further, AEs caused by underlying disease were not to be reported as AEs in accordance with common oncology practice.
    30 Aug 2011
    The protocol was amended to exclude participants with a diagnosis of metastatic disease for more than 3 months prior to study entry and to allow participants who received prior therapy for a primary tumor in the case of synchronous metastatic rectal cancer, as well as to clarify additional eligibility criteria. Participants with R1 residual tumor classification were considered as having achieved complete resection. The analysis of AEs was also expanded and clarified, and the Schedule of Assessments was updated to include several missing assessments previously specified elsewhere in the protocol. Study treatment was updated, so that participants with complete resection (R0 or R1) could continue to receive the original randomized treatment post-surgery. Discontinuation of oxaliplatin was allowed in the Bevacizumab + mFOLFOX-6 arm, and the protocol-required discontinuation of at least one cytotoxic agent in the Bevacizumab + FOLFOXIRI arm was clarified. Resumption of treatment and second resective surgery was permitted, at the discretion of the investigator, among participants who relapsed after a previous complete resection. Further, participants with PD were to discontinue treatment and enter a follow-up period.
    30 Apr 2013
    The protocol was amended to shorten the treatment period to 2 years, resulting in an expected length of study approximately 5 years. The procedure for reporting and managing serious AEs was updated and clarified.

    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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    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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