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    Clinical Trial Results:
    MAVERICC (Marker Evaluation for Avastin Research in CRC): A Randomized Phase II Study of Bevacizumab+mFOLFOX6 Vs. Bevacizumab+FOLFIRI With Biomarker Stratification in Patients With Previously Untreated Metastatic Colorectal Cancer

    Summary
    EudraCT number
    2011-004755-39
    Trial protocol
    IE   EE   PT  
    Global end of trial date
    02 Jul 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    16 Jul 2016
    First version publication date
    16 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ML25710
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01374425
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, 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
    27 Jan 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Jul 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This was a randomized, open-label, multicenter, Phase II study with primary objectives to assess whether expression of select chemotherapy markers is associated with progression-free survival (PFS) in participants treated with bevacizumab plus leucovorin, 5-fluorouracil, and oxaliplatin (mFOLFOX6) or bevacizumab plus leucovorin, 5-fluorouracil, and irinotecan (FOLFIRI). The study population consisted of participants with first-line metastatic colorectal cancer (mCRC).
    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 have fully adhered to the principles outlined in the Guideline for Good Clinical Practice International Council for Harmonisation (ICH) Tripartite Guideline (January 1997) or with local law if it affords greater protection to the participant. In other countries where the Guideline for Good Clinical Practice exists, Roche and the investigators have strictly ensured adherence to the stated provisions.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    21 Aug 2011
    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
    Norway: 2
    Country: Number of subjects enrolled
    Portugal: 18
    Country: Number of subjects enrolled
    Estonia: 8
    Country: Number of subjects enrolled
    Ireland: 11
    Country: Number of subjects enrolled
    Canada: 11
    Country: Number of subjects enrolled
    Switzerland: 8
    Country: Number of subjects enrolled
    United States: 318
    Worldwide total number of subjects
    376
    EEA total number of subjects
    39
    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)
    236
    From 65 to 84 years
    139
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    The trial included a 21-day Screening period during which participants provided information for demographics, medical history and cancer/treatment history and completed urinalysis collection.

    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
    No

    Arm title
    Bevacizumab + mFOLFOX6
    Arm description
    Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 milligrams per kilogram (mg/kg), leucovorin as 400 milligrams per meter-squared (mg/m^2), oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via intravenous (IV) infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles.
    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 given as 5 mg/kg IV infusion on Day 1 of each 2-week cycle. For participants who discontinued from oxaliplatin or irinotecan due to unacceptable toxicity, bevacizumab was given in 3-week cycles with capecitabine.

    Investigational medicinal product name
    Leucovorin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Leucovorin was given as 400 mg/m^2 via IV infusion on Day 1 of each 2-week cycle.

    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-Fluorouracil was given as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion started on Day 1 of each 2-week cycle.

    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 given as 85 mg/m^2 via IV infusion on Day 1 of each 2-week cycle.

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Capecitabine was given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14 of each 3-week cycle.

    Arm title
    Bevacizumab + FOLFIRI
    Arm description
    Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles.
    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 given as 5 mg/kg IV infusion on Day 1 of each 2-week cycle. For participants who discontinued from oxaliplatin or irinotecan due to unacceptable toxicity, bevacizumab was given in 3-week cycles with capecitabine.

    Investigational medicinal product name
    Leucovorin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Leucovorin was given as 400 mg/m^2 via IV infusion on Day 1 of each 2-week cycle.

    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-Fluorouracil was given as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion started on Day 1 of each 2-week cycle.

    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 given as 180 mg/m^2 via IV infusion on Day 1 of each 2-week cycle.

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Capecitabine was given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14 of each 3-week cycle.

    Arm title
    Bevacizumab + mFOLFOX/FOLFIRI
    Arm description
    Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles.
    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 given as 5 mg/kg IV infusion on Day 1 of each 2-week cycle. For participants who discontinued from oxaliplatin or irinotecan due to unacceptable toxicity, bevacizumab was given in 3-week cycles with capecitabine.

    Investigational medicinal product name
    Leucovorin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Leucovorin was given as 400 mg/m^2 via IV infusion on Day 1 of each 2-week cycle.

    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-Fluorouracil was given as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion started on Day 1 of each 2-week cycle.

    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 given as 85 mg/m^2 via IV infusion on Day 1 of each 2-week cycle.

    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 given as 180 mg/m^2 via IV infusion on Day 1 of each 2-week cycle.

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Capecitabine was given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14 of each 3-week cycle.

    Number of subjects in period 1
    Bevacizumab + mFOLFOX6 Bevacizumab + FOLFIRI Bevacizumab + mFOLFOX/FOLFIRI
    Started
    188
    188
    376
    Completed
    0
    0
    0
    Not completed
    188
    188
    376
         Death (adverse event)
    2
    4
    6
         Consent withdrawn by subject
    6
    7
    13
         Radiographic disease progression
    86
    81
    167
         Protocol violation
    2
    3
    5
         Not specified
    41
    43
    84
         Death (progression of disease)
    1
    -
    1
         Refused treatment
    10
    24
    34
         Clinical disease progression
    9
    6
    15
         Adverse event
    29
    18
    47
         Lost to follow-up
    2
    1
    3
         Sponsor decision
    -
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Bevacizumab + mFOLFOX6
    Reporting group description
    Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 milligrams per kilogram (mg/kg), leucovorin as 400 milligrams per meter-squared (mg/m^2), oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via intravenous (IV) infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles.

    Reporting group title
    Bevacizumab + FOLFIRI
    Reporting group description
    Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles.

    Reporting group title
    Bevacizumab + mFOLFOX/FOLFIRI
    Reporting group description
    Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles.

    Reporting group values
    Bevacizumab + mFOLFOX6 Bevacizumab + FOLFIRI Bevacizumab + mFOLFOX/FOLFIRI Total
    Number of subjects
    188 188 376
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    59.2 ± 10.88 60.7 ± 10.66 59.9 ± 10.78 -
    Gender categorical
    Units: Subjects
        Female
    66 71 137 137
        Male
    122 117 239 239

    End points

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    End points reporting groups
    Reporting group title
    Bevacizumab + mFOLFOX6
    Reporting group description
    Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 milligrams per kilogram (mg/kg), leucovorin as 400 milligrams per meter-squared (mg/m^2), oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via intravenous (IV) infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles.

    Reporting group title
    Bevacizumab + FOLFIRI
    Reporting group description
    Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles.

    Reporting group title
    Bevacizumab + mFOLFOX/FOLFIRI
    Reporting group description
    Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles.

    Subject analysis set title
    Bevacizumab + mFOLFOX6 (ERCC-1 High)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with excision repair cross-complementing (ERCC)-1 level greater than (>) 1.7 × 10^-3 ERCC-1/B-actin messenger ribonucleic acid (mRNA) at Baseline were included in separate analyses.

    Subject analysis set title
    Bevacizumab + FOLFIRI (ERCC-1 High)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level >1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.

    Subject analysis set title
    Bevacizumab + mFOLFOX6 (ERCC-1 Low)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level less than or equal to (≤) 1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.

    Subject analysis set title
    Bevacizumab + FOLFIRI (ERCC-1 Low)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level ≤1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.

    Subject analysis set title
    Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 High)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level >1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.

    Subject analysis set title
    Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 Low)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level ≤1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.

    Subject analysis set title
    Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A High)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with vascular endothelial growth factor (VEGF)-A level >5 picograms per milliliter (pg/mL) at Baseline were included in separate analyses.

    Subject analysis set title
    Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A Low)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with VEGF-A level ≤5 pg/mL at Baseline were included in separate analyses.

    Subject analysis set title
    Bevacizumab + mFOLFOX6 (ERCC-1 High, VEGF-A Low)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle.Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level >1.7 × 10^-3 ERCC-1/B-actin mRNA and VEGF-A level ≤5 pg/mL at Baseline were included in separate analyses.

    Subject analysis set title
    Bevacizumab + FOLFIRI (ERCC-1 High, VEGF-A Low)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level >1.7 × 10^-3 ERCC-1/B-actin mRNA and VEGF-A level ≤5 pg/mL at Baseline were included in separate analyses.

    Subject analysis set title
    Bevacizumab + mFOLFOX6 (ERCC-1 High, VEGF-A High)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level >1.7 × 10^-3 ERCC-1/B-actin mRNA and VEGF-A level >5 pg/mL at Baseline were included in separate analyses.

    Subject analysis set title
    Bevacizumab + FOLFIRI (ERCC-1 High, VEGF-A High)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level >1.7 × 10^-3 ERCC-1/B-actin mRNA and VEGF-A level >5 pg/mL at Baseline were included in separate analyses.

    Subject analysis set title
    Bevacizumab + mFOLFOX6 (ERCC-1 Low, VEGF-A High)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level ≤1.7 × 10^-3 ERCC-1/B-actin mRNA and VEGF-A level >5 pg/mL at Baseline were included in separate analyses.

    Subject analysis set title
    Bevacizumab + FOLFIRI (ERCC-1 Low, VEGF-A High)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level ≤1.7 × 10^-3 ERCC-1/B-actin mRNA and VEGF-A level >5 pg/mL at Baseline were included in separate analyses.

    Subject analysis set title
    Bevacizumab + mFOLFOX6 (ERCC-1 Low, VEGF-A Low)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level ≤1.7 × 10^-3 ERCC-1/B-actin mRNA and VEGF-A level ≤5 pg/mL at Baseline were included in separate analyses.

    Subject analysis set title
    Bevacizumab + FOLFIRI (ERCC-1 Low, VEGF-A Low)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level ≤1.7 × 10^-3 ERCC-1/B-actin mRNA and VEGF-A level ≤5 pg/mL at Baseline were included in separate analyses.

    Subject analysis set title
    Bevacizumab + mFOLFOX/FOLFIRI (KRAS Wild-Type)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with wild-type V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) at Baseline were included in separate analyses.

    Subject analysis set title
    Bevacizumab + mFOLFOX/FOLFIRI (KRAS Mutant)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with mutant KRAS at Baseline were included in separate analyses.

    Primary: PFS According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1

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    End point title
    PFS According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 [1]
    End point description
    Tumor assessments were performed according to RECIST Version 1.1. Disease progression was defined as greater than or equal to (≥) 20 percent (%) increase in sum of largest diameters (LD) of target lesions in reference to the smallest sum of LD on study, in addition to an absolute increase ≥5 millimeters (mm). Disease progression was further defined as the last documented progression determined by the Investigator no later than 1 day before initiation of second-line therapy. Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. PFS was defined as the time from randomization to death or disease progression, whichever occurred first. The median duration of PFS was estimated by Kaplan-Meier analysis and expressed in months. The 95% confidence interval (CI) was computed using the method of Brookmeyer and Crowley. Intent-to-Treat (ITT) Population: All randomized participants regardless of receiving any study drug.
    End point type
    Primary
    End point timeframe
    From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Analyses were planned and reported for the separate Bevacizumab + mFOLFOX6 and Bevacizumab + FOLFIRI arms, not for all participants combined.
    End point values
    Bevacizumab + mFOLFOX6 Bevacizumab + FOLFIRI
    Number of subjects analysed
    188
    188
    Units: months
        median (confidence interval 95%)
    10.09 (8.8 to 11.56)
    12.55 (10.48 to 14.29)
    Statistical analysis title
    Hazard Ratio
    Statistical analysis description
    Analysis stratified by high/low ERCC-1 level and region of enrollment. Hazard ratio (HR, relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.
    Comparison groups
    Bevacizumab + mFOLFOX6 v Bevacizumab + FOLFIRI
    Number of subjects included in analysis
    376
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0555 [2]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.79
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.61
         upper limit
    1.01
    Notes
    [2] - P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided stratified log rank test and not adjusted for multiple comparisons.

    Primary: PFS According to RECIST Version 1.1 in Participants With High ERCC-1 Levels

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    End point title
    PFS According to RECIST Version 1.1 in Participants With High ERCC-1 Levels
    End point description
    Tumor assessments were performed according to RECIST Version 1.1. Disease progression was defined as ≥20% increase in sum of LD of target lesions in reference to the smallest sum of LD on study, in addition to an absolute increase ≥5 mm. Disease progression was further defined as the last documented progression determined by the Investigator no later than 1 day before initiation of second-line therapy. Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. PFS was defined as the time from randomization to death or disease progression, whichever occurred first. The median duration of PFS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
    End point type
    Primary
    End point timeframe
    From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)
    End point values
    Bevacizumab + mFOLFOX6 (ERCC-1 High) Bevacizumab + FOLFIRI (ERCC-1 High)
    Number of subjects analysed
    64
    67
    Units: months
        median (confidence interval 95%)
    9.92 (8.51 to 12.48)
    11.17 (9.1 to 17.84)
    Statistical analysis title
    Hazard Ratio
    Statistical analysis description
    Analysis stratified by region of enrollment. HR (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.
    Comparison groups
    Bevacizumab + mFOLFOX6 (ERCC-1 High) v Bevacizumab + FOLFIRI (ERCC-1 High)
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.3944 [3]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.84
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.56
         upper limit
    1.26
    Notes
    [3] - P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided stratified log rank test and not adjusted for multiple comparisons.

    Primary: PFS According to RECIST Version 1.1 in Participants With Low ERCC-1 Levels

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    End point title
    PFS According to RECIST Version 1.1 in Participants With Low ERCC-1 Levels
    End point description
    Tumor assessments were performed according to RECIST Version 1.1. Disease progression was defined as ≥20% increase in sum of LD of target lesions in reference to the smallest sum of LD on study, in addition to an absolute increase ≥5 mm. Disease progression was further defined as the last documented progression determined by the Investigator no later than 1 day before initiation of second-line therapy. Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. PFS was defined as the time from randomization to death or disease progression, whichever occurred first. The median duration of PFS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
    End point type
    Primary
    End point timeframe
    From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)
    End point values
    Bevacizumab + mFOLFOX6 (ERCC-1 Low) Bevacizumab + FOLFIRI (ERCC-1 Low)
    Number of subjects analysed
    124
    120
    Units: months
        median (confidence interval 95%)
    10.97 (8.54 to 12.29)
    12.68 (10.48 to 14.49)
    Statistical analysis title
    Hazard Ratio
    Statistical analysis description
    Analysis stratified by region of enrollment. HR (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.
    Comparison groups
    Bevacizumab + mFOLFOX6 (ERCC-1 Low) v Bevacizumab + FOLFIRI (ERCC-1 Low)
    Number of subjects included in analysis
    244
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0786 [4]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.76
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.55
         upper limit
    1.03
    Notes
    [4] - P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided stratified log rank test and not adjusted for multiple comparisons.

    Primary: PFS According to RECIST Version 1.1 in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels

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    End point title
    PFS According to RECIST Version 1.1 in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels
    End point description
    Tumor assessments were performed according to RECIST Version 1.1. Disease progression was defined as ≥20% increase in sum of LD of target lesions in reference to the smallest sum of LD on study, in addition to an absolute increase ≥5 mm. Disease progression was further defined as the last documented progression determined by the Investigator no later than 1 day before initiation of second-line therapy. Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. PFS was defined as the time from randomization to death or disease progression, whichever occurred first. The median duration of PFS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
    End point type
    Primary
    End point timeframe
    From Baseline until death or disease progression (maximum up to 45 months overall)
    End point values
    Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 High) Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 Low)
    Number of subjects analysed
    131
    244
    Units: months
        median (confidence interval 95%)
    10.87 (9.1 to 12.68)
    11.56 (9.95 to 12.98)
    Statistical analysis title
    Hazard Ratio
    Statistical analysis description
    Analysis stratified by region of enrollment. HR (relative to ERCC-1 Low subgroup) was estimated by Cox regression.
    Comparison groups
    Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 High) v Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 Low)
    Number of subjects included in analysis
    375
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.9576 [5]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.99
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.77
         upper limit
    1.28
    Notes
    [5] - P-value (relative to ERCC-1 Low subgroup) based on two-sided stratified log rank test and not adjusted for multiple comparisons.

    Primary: PFS According to RECIST Version 1.1 in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels

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    End point title
    PFS According to RECIST Version 1.1 in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels
    End point description
    Tumor assessments were performed according to RECIST Version 1.1. Disease progression was defined as ≥20% increase in sum of LD of target lesions in reference to the smallest sum of LD on study, in addition to an absolute increase ≥5 mm. Disease progression was further defined as the last documented progression determined by the Investigator no later than 1 day before initiation of second-line therapy. Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. PFS was defined as the time from randomization to death or disease progression, whichever occurred first. The median duration of PFS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
    End point type
    Primary
    End point timeframe
    From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)
    End point values
    Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A High) Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A Low)
    Number of subjects analysed
    185
    185
    Units: months
        median (confidence interval 95%)
    10.02 (8.8 to 11.17)
    12.68 (10.9 to 14.26)
    Statistical analysis title
    Hazard Ratio
    Statistical analysis description
    Analysis stratified by high/low ERCC-1 level and region of enrollment. HR (relative to VEGF-A Low subgroup) was estimated by Cox regression.
    Comparison groups
    Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A High) v Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A Low)
    Number of subjects included in analysis
    370
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1658 [6]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.19
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.93
         upper limit
    1.53
    Notes
    [6] - P-value (relative to VEGF-A Low subgroup) based on two-sided stratified log rank test and not adjusted for multiple comparisons.

    Secondary: PFS According to RECIST Version 1.1 in Participants With High ERCC-1 and High VEGF-A Levels

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    End point title
    PFS According to RECIST Version 1.1 in Participants With High ERCC-1 and High VEGF-A Levels
    End point description
    Tumor assessments were performed according to RECIST Version 1.1. Disease progression was defined as ≥20% increase in sum of LD of target lesions in reference to the smallest sum of LD on study, in addition to an absolute increase ≥5 mm. Disease progression was further defined as the last documented progression determined by the Investigator no later than 1 day before initiation of second-line therapy. Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. PFS was defined as the time from randomization to death or disease progression, whichever occurred first. The median duration of PFS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
    End point type
    Secondary
    End point timeframe
    From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)
    End point values
    Bevacizumab + mFOLFOX6 (ERCC-1 High, VEGF-A High) Bevacizumab + FOLFIRI (ERCC-1 High, VEGF-A High)
    Number of subjects analysed
    28
    31
    Units: months
        median (confidence interval 95%)
    8.8 (5.91 to 10.02)
    11.17 (8.11 to 18.07)
    Statistical analysis title
    Hazard Ratio Stratified
    Statistical analysis description
    Analysis stratified by region of enrollment. HR (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.
    Comparison groups
    Bevacizumab + mFOLFOX6 (ERCC-1 High, VEGF-A High) v Bevacizumab + FOLFIRI (ERCC-1 High, VEGF-A High)
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.3019 [7]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.73
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.41
         upper limit
    1.32
    Notes
    [7] - P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided stratified log rank test and not adjusted for multiple comparisons.
    Statistical analysis title
    Hazard Ratio Unstratified
    Statistical analysis description
    Unstratified analysis. HR (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.
    Comparison groups
    Bevacizumab + mFOLFOX6 (ERCC-1 High, VEGF-A High) v Bevacizumab + FOLFIRI (ERCC-1 High, VEGF-A High)
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.5308 [8]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.83
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.47
         upper limit
    1.47
    Notes
    [8] - P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided unstratified log rank test and not adjusted for multiple comparisons.

    Secondary: PFS According to RECIST Version 1.1 in Participants With High ERCC-1 and Low VEGF-A Levels

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    End point title
    PFS According to RECIST Version 1.1 in Participants With High ERCC-1 and Low VEGF-A Levels
    End point description
    Tumor assessments were performed according to RECIST Version 1.1. Disease progression was defined as ≥20% increase in sum of LD of target lesions in reference to the smallest sum of LD on study, in addition to an absolute increase ≥5 mm. Disease progression was further defined as the last documented progression determined by the Investigator no later than 1 day before initiation of second-line therapy. Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. PFS was defined as the time from randomization to death or disease progression, whichever occurred first. The median duration of PFS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
    End point type
    Secondary
    End point timeframe
    From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)
    End point values
    Bevacizumab + mFOLFOX6 (ERCC-1 High, VEGF-A Low) Bevacizumab + FOLFIRI (ERCC-1 High, VEGF-A Low)
    Number of subjects analysed
    35
    35
    Units: months
        median (confidence interval 95%)
    12.52 (9.43 to 15.64)
    12.68 (8.18 to 20.83)
    Statistical analysis title
    Hazard Ratio Stratified
    Statistical analysis description
    Analysis stratified by region of enrollment. HR (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.
    Comparison groups
    Bevacizumab + mFOLFOX6 (ERCC-1 High, VEGF-A Low) v Bevacizumab + FOLFIRI (ERCC-1 High, VEGF-A Low)
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.6035 [9]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.86
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.48
         upper limit
    1.53
    Notes
    [9] - P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided stratified log rank test and not adjusted for multiple comparisons.
    Statistical analysis title
    Hazard Ratio Unstratified
    Statistical analysis description
    Unstratified analysis. HR (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.
    Comparison groups
    Bevacizumab + mFOLFOX6 (ERCC-1 High, VEGF-A Low) v Bevacizumab + FOLFIRI (ERCC-1 High, VEGF-A Low)
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.5026 [10]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.82
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.46
         upper limit
    1.46
    Notes
    [10] - P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided unstratified log rank test and not adjusted for multiple comparisons.

    Secondary: PFS According to RECIST Version 1.1 in Participants With Low ERCC-1 and High VEGF-A Levels

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    End point title
    PFS According to RECIST Version 1.1 in Participants With Low ERCC-1 and High VEGF-A Levels
    End point description
    Tumor assessments were performed according to RECIST Version 1.1. Disease progression was defined as ≥20% increase in sum of LD of target lesions in reference to the smallest sum of LD on study, in addition to an absolute increase ≥5 mm. Disease progression was further defined as the last documented progression determined by the Investigator no later than 1 day before initiation of second-line therapy. Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. PFS was defined as the time from randomization to death or disease progression, whichever occurred first. The median duration of PFS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
    End point type
    Secondary
    End point timeframe
    From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)
    End point values
    Bevacizumab + mFOLFOX6 (ERCC-1 Low, VEGF-A High) Bevacizumab + FOLFIRI (ERCC-1 Low, VEGF-A High)
    Number of subjects analysed
    66
    59
    Units: months
        median (confidence interval 95%)
    9.76 (8.18 to 12.45)
    11.07 (8.18 to 14.29)
    Statistical analysis title
    Hazard Ratio Stratified
    Statistical analysis description
    Analysis stratified by region of enrollment. HR (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.
    Comparison groups
    Bevacizumab + mFOLFOX6 (ERCC-1 Low, VEGF-A High) v Bevacizumab + FOLFIRI (ERCC-1 Low, VEGF-A High)
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.4032 [11]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.83
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.54
         upper limit
    1.28
    Notes
    [11] - P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided stratified log rank test and not adjusted for multiple comparisons.
    Statistical analysis title
    Hazard Ratio Unstratified
    Statistical analysis description
    Unstratified analysis. HR (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.
    Comparison groups
    Bevacizumab + mFOLFOX6 (ERCC-1 Low, VEGF-A High) v Bevacizumab + FOLFIRI (ERCC-1 Low, VEGF-A High)
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.235 [12]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.77
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.51
         upper limit
    1.18
    Notes
    [12] - P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided unstratified log rank test and not adjusted for multiple comparisons.

    Secondary: PFS According to RECIST Version 1.1 in Participants With Low ERCC-1 and Low VEGF-A Levels

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    End point title
    PFS According to RECIST Version 1.1 in Participants With Low ERCC-1 and Low VEGF-A Levels
    End point description
    Tumor assessments were performed according to RECIST Version 1.1. Disease progression was defined as ≥20% increase in sum of LD of target lesions in reference to the smallest sum of LD on study, in addition to an absolute increase ≥5 mm. Disease progression was further defined as the last documented progression determined by the Investigator no later than 1 day before initiation of second-line therapy. Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. PFS was defined as the time from randomization to death or disease progression, whichever occurred first. The median duration of PFS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
    End point type
    Secondary
    End point timeframe
    From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)
    End point values
    Bevacizumab + mFOLFOX6 (ERCC-1 Low, VEGF-A Low) Bevacizumab + FOLFIRI (ERCC-1 Low, VEGF-A Low)
    Number of subjects analysed
    55
    60
    Units: months
        median (confidence interval 95%)
    11.1 (8.54 to 13.08)
    14.32 (11.56 to 14.98)
    Statistical analysis title
    Hazard Ratio Stratified
    Statistical analysis description
    Analysis stratified by region of enrollment. HR (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.
    Comparison groups
    Bevacizumab + mFOLFOX6 (ERCC-1 Low, VEGF-A Low) v Bevacizumab + FOLFIRI (ERCC-1 Low, VEGF-A Low)
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0647 [13]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.65
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.41
         upper limit
    1.03
    Notes
    [13] - P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided stratified log rank test and not adjusted for multiple comparisons.
    Statistical analysis title
    Hazard Ratio Unstratified
    Statistical analysis description
    Unstratified analysis. HR (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.
    Comparison groups
    Bevacizumab + mFOLFOX6 (ERCC-1 Low, VEGF-A Low) v Bevacizumab + FOLFIRI (ERCC-1 Low, VEGF-A Low)
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0856 [14]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.67
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.43
         upper limit
    1.06
    Notes
    [14] - P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided unstratified log rank test and not adjusted for multiple comparisons.

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS) [15]
    End point description
    Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. OS was defined as the time from randomization to death. The median duration of OS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley. ITT Population.
    End point type
    Secondary
    End point timeframe
    From Baseline until death (maximum up to 45 months overall)
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Analyses were planned and reported for the separate Bevacizumab + mFOLFOX6 and Bevacizumab + FOLFIRI arms, not for all participants combined.
    End point values
    Bevacizumab + mFOLFOX6 Bevacizumab + FOLFIRI
    Number of subjects analysed
    188
    188
    Units: months
        median (confidence interval 95%)
    23.85 (20.4 to 26.05)
    27.47 (24.64 to 36.73)
    Statistical analysis title
    Hazard Ratio
    Statistical analysis description
    Analysis stratified by high/low ERCC-1 level and region of enrollment. HR (relative to Bevacizumab + mFOLFOX6)was estimated by Cox regression.
    Comparison groups
    Bevacizumab + mFOLFOX6 v Bevacizumab + FOLFIRI
    Number of subjects included in analysis
    376
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0861 [16]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.76
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.56
         upper limit
    1.04
    Notes
    [16] - P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided stratified log rank test and not adjusted for multiple comparisons.

    Secondary: OS in Participants With High ERCC-1 Levels

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    End point title
    OS in Participants With High ERCC-1 Levels
    End point description
    Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. OS was defined as the time from randomization to death. The median duration of OS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
    End point type
    Secondary
    End point timeframe
    From Baseline until death (maximum up to 45 months overall)
    End point values
    Bevacizumab + mFOLFOX6 (ERCC-1 High) Bevacizumab + FOLFIRI (ERCC-1 High)
    Number of subjects analysed
    64
    67
    Units: months
        median (confidence interval 95%)
    22.54 (17.02 to 26.05)
    26.51 (19.09 to 36.73)
    Statistical analysis title
    Hazard Ratio
    Statistical analysis description
    Analysis stratified by region of enrollment. HR (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.
    Comparison groups
    Bevacizumab + FOLFIRI (ERCC-1 High) v Bevacizumab + mFOLFOX6 (ERCC-1 High)
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.3295 [17]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.51
         upper limit
    1.26
    Notes
    [17] - P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided stratified log rank test and not adjusted for multiple comparisons.

    Secondary: OS in Participants With Low ERCC-1 Levels

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    End point title
    OS in Participants With Low ERCC-1 Levels
    End point description
    Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. OS was defined as the time from randomization to death. The median duration of OS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
    End point type
    Secondary
    End point timeframe
    From Baseline until death (maximum up to 45 months overall)
    End point values
    Bevacizumab + mFOLFOX6 (ERCC-1 Low) Bevacizumab + FOLFIRI (ERCC-1 Low)
    Number of subjects analysed
    124
    120
    Units: months
        median (confidence interval 95%)
    25.53 (20.4 to 28.75)
    27.93 (24.97 to 38.44)
    Statistical analysis title
    Hazard Ratio
    Statistical analysis description
    Analysis stratified by region of enrollment. HR (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.
    Comparison groups
    Bevacizumab + mFOLFOX6 (ERCC-1 Low) v Bevacizumab + FOLFIRI (ERCC-1 Low)
    Number of subjects included in analysis
    244
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1519 [18]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.74
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.49
         upper limit
    1.12
    Notes
    [18] - P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided stratified log rank test and not adjusted for multiple comparisons.

    Secondary: OS in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels

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    End point title
    OS in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels
    End point description
    Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. OS was defined as the time from randomization to death. The median duration of OS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
    End point type
    Secondary
    End point timeframe
    From Baseline until death (maximum up to 45 months overall)
    End point values
    Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 High) Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 Low)
    Number of subjects analysed
    131
    244
    Units: months
        median (confidence interval 95%)
    23.23 (19.09 to 26.94)
    27.27 (24.34 to 31.28)
    Statistical analysis title
    Hazard Ratio
    Statistical analysis description
    Analysis stratified by region of enrollment. HR (relative to ERCC-1 Low subgroup) was estimated by Cox regression.
    Comparison groups
    Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 High) v Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 Low)
    Number of subjects included in analysis
    375
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.2774 [19]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.19
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.87
         upper limit
    1.62
    Notes
    [19] - P-value (relative to ERCC-1 Low subgroup) based on two-sided stratified log rank test and not adjusted for multiple comparisons.

    Secondary: Percentage of Participants With Objective Response According to RECIST Version 1.1

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    End point title
    Percentage of Participants With Objective Response According to RECIST Version 1.1 [20]
    End point description
    Objective response was defined as complete response (CR) or partial response (PR) according to RECIST Version 1.1. CR was defined as disappearance of all target lesions and short-axis reduction to less than (<) 10 mm of any pathological lymph nodes. PR was defined as ≥30% decrease in sum of LD of target lesions in reference to sum of LD at Baseline. Confirmation of response at a consecutive assessment was not required. The percentage of participants with CR or PR was reported. The 95% CI was computed using normal approximation to the binomial distribution. ITT Population.
    End point type
    Secondary
    End point timeframe
    From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Analyses were planned and reported for the separate Bevacizumab + mFOLFOX6 and Bevacizumab + FOLFIRI arms, not for all participants combined.
    End point values
    Bevacizumab + mFOLFOX6 Bevacizumab + FOLFIRI
    Number of subjects analysed
    188
    188
    Units: percentage of participants
        number (confidence interval 95%)
    61.2 (54.2 to 68.1)
    65.4 (58.6 to 72.2)
    Statistical analysis title
    Difference in Objective Response Rates
    Statistical analysis description
    The difference was calculated as the percentage of participants with objective response in the Bevacizumab + FOLFIRI arm minus the Bevacizumab + mFOLFOX6 arm. The 95% CI was computed using normal approximation to the binomial distribution.
    Comparison groups
    Bevacizumab + mFOLFOX6 v Bevacizumab + FOLFIRI
    Number of subjects included in analysis
    376
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Difference in objective response rates
    Point estimate
    4.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.5
         upper limit
    14

    Secondary: Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With High ERCC-1 Levels

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    End point title
    Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With High ERCC-1 Levels
    End point description
    Objective response was defined as CR or PR according to RECIST Version 1.1. CR was defined as disappearance of all target lesions and short-axis reduction to <10 mm of any pathological lymph nodes. PR was defined as ≥30% decrease in sum of LD of target lesions in reference to sum of LD at Baseline. Confirmation of response at a consecutive assessment was not required. The percentage of participants with CR or PR was reported. The 95% CI was computed using normal approximation to the binomial distribution. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
    End point type
    Secondary
    End point timeframe
    From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)
    End point values
    Bevacizumab + mFOLFOX6 (ERCC-1 High) Bevacizumab + FOLFIRI (ERCC-1 High)
    Number of subjects analysed
    64
    67
    Units: percentage of participants
        number (confidence interval 95%)
    56.3 (44.1 to 68.4)
    65.7 (54.3 to 77)
    Statistical analysis title
    Difference in Objective Response Rates
    Statistical analysis description
    The difference was calculated as the percentage of participants with objective response in the Bevacizumab + FOLFIRI arm minus the Bevacizumab + mFOLFOX6 arm. The 95% CI was computed using normal approximation to the binomial distribution.
    Comparison groups
    Bevacizumab + mFOLFOX6 (ERCC-1 High) v Bevacizumab + FOLFIRI (ERCC-1 High)
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Difference in objective response rates
    Point estimate
    9.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    7.2
         upper limit
    26.1

    Secondary: Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With Low ERCC-1 Levels

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    End point title
    Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With Low ERCC-1 Levels
    End point description
    Objective response was defined as CR or PR according to RECIST Version 1.1. CR was defined as disappearance of all target lesions and short-axis reduction to <10 mm of any pathological lymph nodes. PR was defined as ≥30% decrease in sum of LD of target lesions in reference to sum of LD at Baseline. Confirmation of response at a consecutive assessment was not required. The percentage of participants with CR or PR was reported. The 95% CI was computed using normal approximation to the binomial distribution. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
    End point type
    Secondary
    End point timeframe
    From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)
    End point values
    Bevacizumab + mFOLFOX6 (ERCC-1 Low) Bevacizumab + FOLFIRI (ERCC-1 Low)
    Number of subjects analysed
    124
    120
    Units: percentage of participants
        number (confidence interval 95%)
    63.7 (55.2 to 72.2)
    65.8 (57.3 to 74.3)
    Statistical analysis title
    Difference in Objective Response Rates
    Statistical analysis description
    The difference was calculated as the percentage of participants with objective response in the Bevacizumab + FOLFIRI arm minus the Bevacizumab + mFOLFOX6 arm. The 95% CI was computed using normal approximation to the binomial distribution.
    Comparison groups
    Bevacizumab + mFOLFOX6 (ERCC-1 Low) v Bevacizumab + FOLFIRI (ERCC-1 Low)
    Number of subjects included in analysis
    244
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Difference in objective response rates
    Point estimate
    2.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.9
         upper limit
    14.1

    Secondary: Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels

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    End point title
    Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels
    End point description
    Objective response was defined as CR or PR according to RECIST Version 1.1. CR was defined as disappearance of all target lesions and short-axis reduction to <10 mm of any pathological lymph nodes. PR was defined as ≥30% decrease in sum of LD of target lesions in reference to sum of LD at Baseline. Confirmation of response at a consecutive assessment was not required. The percentage of participants with CR or PR was reported. The 95% CI was computed using normal approximation to the binomial distribution. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
    End point type
    Secondary
    End point timeframe
    From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)
    End point values
    Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 High) Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 Low)
    Number of subjects analysed
    131
    244
    Units: percentage of participants
        number (confidence interval 95%)
    61.1 (52.7 to 69.4)
    64.8 (58.8 to 70.7)
    Statistical analysis title
    Difference in Objective Response Rates
    Statistical analysis description
    The difference was calculated as the percentage of participants with objective response in the ERCC-1 High subgroup minus the ERCC-1 Low subgroup. The 95% CI was computed using normal approximation to the binomial distribution.
    Comparison groups
    Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 High) v Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 Low)
    Number of subjects included in analysis
    375
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Difference in objective response rates
    Point estimate
    -3.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -14
         upper limit
    6.6

    Secondary: Percentage of Participants With Disease Control According to RECIST Version 1.1

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    End point title
    Percentage of Participants With Disease Control According to RECIST Version 1.1 [21]
    End point description
    Disease control was defined as CR, PR, or stable disease (SD) according to RECIST Version 1.1. CR was defined as disappearance of all target lesions and short-axis reduction to <10 mm of any pathological lymph nodes. PR was defined as ≥30% decrease in sum of LD of target lesions in reference to sum of LD at Baseline. Confirmation of response at a consecutive assessment was not required. SD was defined as neither sufficient shrinkage to quality for PR nor sufficient increase to qualify for disease progression (≥20% increase in sum of LD of target lesions plus absolute increase ≥5 mm) in reference to the smallest sum of LD on study. The percentage of participants with CR, PR, or SD was reported. The 95% CI was computed using normal approximation to the binomial distribution. ITT Population.
    End point type
    Secondary
    End point timeframe
    From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Analyses were planned and reported for the separate Bevacizumab + mFOLFOX6 and Bevacizumab + FOLFIRI arms, not for all participants combined.
    End point values
    Bevacizumab + mFOLFOX6 Bevacizumab + FOLFIRI
    Number of subjects analysed
    188
    188
    Units: percentage of participants
        number (confidence interval 95%)
    93.1 (89.5 to 96.7)
    91 (86.9 to 95.1)
    Statistical analysis title
    Difference in Disease Control Rates
    Statistical analysis description
    The difference was calculated as the percentage of participants with disease control in the Bevacizumab + FOLFIRI arm minus the Bevacizumab + mFOLFOX6 arm. The 95% CI was computed using normal approximation to the binomial distribution.
    Comparison groups
    Bevacizumab + mFOLFOX6 v Bevacizumab + FOLFIRI
    Number of subjects included in analysis
    376
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Difference in response rates
    Point estimate
    2.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.6
         upper limit
    3.3

    Secondary: Percentage of Participants With Disease Control According to RECIST Version 1.1 in Participants With High ERCC-1 Levels

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    End point title
    Percentage of Participants With Disease Control According to RECIST Version 1.1 in Participants With High ERCC-1 Levels
    End point description
    Disease control was defined as CR, PR, or SD according to RECIST Version 1.1. CR was defined as disappearance of all target lesions and short-axis reduction to <10 mm of any pathological lymph nodes. PR was defined as ≥30% decrease in sum of LD of target lesions in reference to sum of LD at Baseline. Confirmation of response at a consecutive assessment was not required. SD was defined as neither sufficient shrinkage to quality for PR nor sufficient increase to qualify for disease progression (≥20% increase in sum of LD of target lesions plus absolute increase ≥5 mm) in reference to the smallest sum of LD on study. The percentage of participants with CR, PR, or SD was reported. The 95% CI was computed using normal approximation to the binomial distribution. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
    End point type
    Secondary
    End point timeframe
    From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)
    End point values
    Bevacizumab + mFOLFOX6 (ERCC-1 High) Bevacizumab + FOLFIRI (ERCC-1 High)
    Number of subjects analysed
    64
    67
    Units: percentage of participants
        number (confidence interval 95%)
    93.8 (87.8 to 99.7)
    85.1 (76.5 to 93.6)
    Statistical analysis title
    Difference in Disease Control Rates
    Statistical analysis description
    The difference was calculated as the percentage of participants with disease control in the Bevacizumab + FOLFIRI arm minus the Bevacizumab + mFOLFOX6 arm. The 95% CI was computed using normal approximation to the binomial distribution.
    Comparison groups
    Bevacizumab + mFOLFOX6 (ERCC-1 High) v Bevacizumab + FOLFIRI (ERCC-1 High)
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Difference in disease control rates
    Point estimate
    -8.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -19.1
         upper limit
    1.7

    Secondary: Percentage of Participants With Disease Control According to RECIST Version 1.1 in Participants With Low ERCC-1 Levels

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    End point title
    Percentage of Participants With Disease Control According to RECIST Version 1.1 in Participants With Low ERCC-1 Levels
    End point description
    Disease control was defined as CR, PR, or SD according to RECIST Version 1.1. CR was defined as disappearance of all target lesions and short-axis reduction to <10 mm of any pathological lymph nodes. PR was defined as ≥30% decrease in sum of LD of target lesions in reference to sum of LD at Baseline. Confirmation of response at a consecutive assessment was not required. SD was defined as neither sufficient shrinkage to quality for PR nor sufficient increase to qualify for disease progression (≥20% increase in sum of LD of target lesions plus absolute increase ≥5 mm) in reference to the smallest sum of LD on study. The percentage of participants with CR, PR, or SD was reported. The 95% CI was computed using normal approximation to the binomial distribution. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
    End point type
    Secondary
    End point timeframe
    From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)
    End point values
    Bevacizumab + mFOLFOX6 (ERCC-1 Low) Bevacizumab + FOLFIRI (ERCC-1 Low)
    Number of subjects analysed
    124
    120
    Units: percentage of participants
        number (confidence interval 95%)
    92.7 (88.2 to 97.3)
    95 (91.1 to 98.9)
    Statistical analysis title
    Difference in Disease Control Rates
    Statistical analysis description
    The difference was calculated as the percentage of participants with disease control in the Bevacizumab + FOLFIRI arm minus the Bevacizumab + mFOLFOX6 arm. The 95% CI was computed using normal approximation to the binomial distribution.
    Comparison groups
    Bevacizumab + mFOLFOX6 (ERCC-1 Low) v Bevacizumab + FOLFIRI (ERCC-1 Low)
    Number of subjects included in analysis
    244
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Difference in disease control rates
    Point estimate
    2.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.7
         upper limit
    8.3

    Secondary: Percentage of Participants With Disease Control According to RECIST Version 1.1 in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels

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    End point title
    Percentage of Participants With Disease Control According to RECIST Version 1.1 in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels
    End point description
    Disease control was defined as CR, PR, or SD according to RECIST Version 1.1. CR was defined as disappearance of all target lesions and short-axis reduction to <10 mm of any pathological lymph nodes. PR was defined as ≥30% decrease in sum of LD of target lesions in reference to sum of LD at Baseline. Confirmation of response at a consecutive assessment was not required. SD was defined as neither sufficient shrinkage to quality for PR nor sufficient increase to qualify for disease progression (≥20% increase in sum of LD of target lesions plus absolute increase ≥5 mm) in reference to the smallest sum of LD on study. The percentage of participants with CR, PR, or SD was reported. The 95% CI was computed using normal approximation to the binomial distribution. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
    End point type
    Secondary
    End point timeframe
    From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)
    End point values
    Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 High) Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 Low)
    Number of subjects analysed
    131
    244
    Units: percentage of participants
        number (confidence interval 95%)
    89.3 (84 to 94.6)
    93.9 (90.8 to 96.9)
    Statistical analysis title
    Difference in Disease Control Rates
    Statistical analysis description
    The difference was calculated as the percentage of participants with disease control in the ERCC-1 High subgroup minus the ERCC-1 Low subgroup. The 95% CI was computed using normal approximation to the binomial distribution.
    Comparison groups
    Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 High) v Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 Low)
    Number of subjects included in analysis
    375
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Difference in disease control rates
    Point estimate
    -4.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.6
         upper limit
    1.5

    Secondary: Percentage of Participants With Liver Metastasis Resection

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    End point title
    Percentage of Participants With Liver Metastasis Resection [22]
    End point description
    The timing of resective surgery was not defined in the protocol and was left at the discretion of the Investigator. Resection was classified as R0, R1, or R2 following surgery. R0 was defined as complete resection with clear margins ≥1 mm. R1 was defined as the presence of exposed tumor or histologically detected tumor cells at the line of transection, or <1 mm microscopic margins. In the case of use of radiofrequency ablation or cryotherapy, the resection was considered as R1. R2 was defined as macroscopic positive margins or incomplete resection at time of surgery. The percentage of participants with resection of liver or liver plus lymph node metastases was reported. The 95% CI was computed using normal approximation to the binomial distribution. ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis.
    End point type
    Secondary
    End point timeframe
    At time of resective surgery during study (maximum up to 45 months overall)
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Analyses were planned and reported for the separate Bevacizumab + mFOLFOX6 and Bevacizumab + FOLFIRI arms, not for all participants combined.
    End point values
    Bevacizumab + mFOLFOX6 Bevacizumab + FOLFIRI
    Number of subjects analysed
    67
    55
    Units: percentage of participants
        number (confidence interval 95%)
    14.9 (6.4 to 23.5)
    10.9 (2.7 to 19.1)
    Statistical analysis title
    Difference in Resection Rates
    Statistical analysis description
    The difference was calculated as the percentage of participants with resection in the Bevacizumab + FOLFIRI arm minus the Bevacizumab + mFOLFOX6 arm. The 95% CI was computed using normal approximation to the binomial distribution.
    Comparison groups
    Bevacizumab + FOLFIRI v Bevacizumab + mFOLFOX6
    Number of subjects included in analysis
    122
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Difference in resection rates
    Point estimate
    -4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -15.9
         upper limit
    7.8

    Secondary: Percentage of Participants With Complete Liver Metastasis Resection

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    End point title
    Percentage of Participants With Complete Liver Metastasis Resection [23]
    End point description
    The timing of resective surgery was not defined in the protocol and was left at the discretion of the Investigator. Resection was classified as R0, R1, or R2 following surgery. R0 was defined as complete resection with clear margins ≥1 mm. The percentage of participants with R0 resection of liver or liver plus lymph node metastases was reported. The 95% CI was computed using normal approximation to the binomial distribution. ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis.
    End point type
    Secondary
    End point timeframe
    At time of resective surgery during study (maximum up to 45 months overall)
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Analyses were planned and reported for the separate Bevacizumab + mFOLFOX6 and Bevacizumab + FOLFIRI arms, not for all participants combined.
    End point values
    Bevacizumab + mFOLFOX6 Bevacizumab + FOLFIRI
    Number of subjects analysed
    67
    55
    Units: percentage of participants
        number (confidence interval 95%)
    11.9 (4.2 to 19.7)
    5.5 (0 to 11.5)
    Statistical analysis title
    Difference in Complete Resection Rates
    Statistical analysis description
    The difference was calculated as the percentage of participants with complete resection in the Bevacizumab + FOLFIRI arm minus the Bevacizumab + mFOLFOX6 arm. The 95% CI was computed using normal approximation to the binomial distribution.
    Comparison groups
    Bevacizumab + mFOLFOX6 v Bevacizumab + FOLFIRI
    Number of subjects included in analysis
    122
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Difference in complete resection rates
    Point estimate
    -6.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -16.3
         upper limit
    3.3

    Secondary: Percentage of Participants With Liver Metastasis Resection in Participants With High ERCC-1 Levels

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    End point title
    Percentage of Participants With Liver Metastasis Resection in Participants With High ERCC-1 Levels
    End point description
    The timing of resective surgery was not defined in the protocol and was left at the discretion of the Investigator. Resection was classified as R0, R1, or R2 following surgery. R0 was defined as complete resection with clear margins ≥1 mm. R1 was defined as the presence of exposed tumor or histologically detected tumor cells at the line of transection, or <1 mm microscopic margins. In the case of use of radiofrequency ablation or cryotherapy, the resection was considered as R1. R2 was defined as macroscopic positive margins or incomplete resection at time of surgery. The percentage of participants with resection of liver or liver plus lymph node metastases was reported. The 95% CI was computed using normal approximation to the binomial distribution. ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
    End point type
    Secondary
    End point timeframe
    At time of resective surgery during study (maximum up to 45 months overall)
    End point values
    Bevacizumab + mFOLFOX6 (ERCC-1 High) Bevacizumab + FOLFIRI (ERCC-1 High)
    Number of subjects analysed
    17
    15
    Units: percentage of participants
        number (confidence interval 95%)
    17.6 (0 to 35.8)
    6.7 (0 to 19.3)
    Statistical analysis title
    Difference in Resection Rates
    Statistical analysis description
    The difference was calculated as the percentage of participants with resection in the Bevacizumab + FOLFIRI arm minus the Bevacizumab + mFOLFOX6 arm. The 95% CI was computed using normal approximation to the binomial distribution.
    Comparison groups
    Bevacizumab + mFOLFOX6 (ERCC-1 High) v Bevacizumab + FOLFIRI (ERCC-1 High)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Difference in resection rates
    Point estimate
    -11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -33.1
         upper limit
    11.1

    Secondary: Percentage of Participants With Complete Liver Metastasis Resection in Participants With High ERCC-1 Levels

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    End point title
    Percentage of Participants With Complete Liver Metastasis Resection in Participants With High ERCC-1 Levels
    End point description
    The timing of resective surgery was not defined in the protocol and was left at the discretion of the Investigator. Resection was classified as R0, R1, or R2 following surgery. R0 was defined as complete resection with clear margins ≥1 mm. The percentage of participants with R0 resection of liver or liver plus lymph node metastases was reported. The 95% CI was computed using normal approximation to the binomial distribution. ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
    End point type
    Secondary
    End point timeframe
    At time of resective surgery during study (maximum up to 45 months overall)
    End point values
    Bevacizumab + mFOLFOX6 (ERCC-1 High) Bevacizumab + FOLFIRI (ERCC-1 High)
    Number of subjects analysed
    17
    15
    Units: percentage of participants
        number (confidence interval 95%)
    17.6 (0 to 35.8)
    6.7 (0 to 19.3)
    Statistical analysis title
    Difference in Complete Resection Rates
    Statistical analysis description
    The difference was calculated as the percentage of participants with complete resection in the Bevacizumab + FOLFIRI arm minus the Bevacizumab + mFOLFOX6 arm. The 95% CI was computed using normal approximation to the binomial distribution.
    Comparison groups
    Bevacizumab + mFOLFOX6 (ERCC-1 High) v Bevacizumab + FOLFIRI (ERCC-1 High)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Difference in complete resection rates
    Point estimate
    -11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -33.1
         upper limit
    11.1

    Secondary: Percentage of Participants With Liver Metastasis Resection in Participants With Low ERCC-1 Levels

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    End point title
    Percentage of Participants With Liver Metastasis Resection in Participants With Low ERCC-1 Levels
    End point description
    The timing of resective surgery was not defined in the protocol and was left at the discretion of the Investigator. Resection was classified as R0, R1, or R2 following surgery. R0 was defined as complete resection with clear margins ≥1 mm. R1 was defined as the presence of exposed tumor or histologically detected tumor cells at the line of transection, or <1 mm microscopic margins. In the case of use of radiofrequency ablation or cryotherapy, the resection was considered as R1. R2 was defined as macroscopic positive margins or incomplete resection at time of surgery. The percentage of participants with resection of liver or liver plus lymph node metastases was reported. The 95% CI was computed using normal approximation to the binomial distribution. ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
    End point type
    Secondary
    End point timeframe
    At time of resective surgery during study (maximum up to 45 months overall)
    End point values
    Bevacizumab + mFOLFOX6 (ERCC-1 Low) Bevacizumab + FOLFIRI (ERCC-1 Low)
    Number of subjects analysed
    124
    120
    Units: percentage of participants
        number (confidence interval 95%)
    10.5 (5.1 to 15.9)
    7.5 (2.8 to 12.2)
    Statistical analysis title
    Difference in Resection Rates
    Statistical analysis description
    The difference was calculated as the percentage of participants with resection in the Bevacizumab + FOLFIRI arm minus the Bevacizumab + mFOLFOX6 arm. The 95% CI was computed using normal approximation to the binomial distribution.
    Comparison groups
    Bevacizumab + mFOLFOX6 (ERCC-1 Low) v Bevacizumab + FOLFIRI (ERCC-1 Low)
    Number of subjects included in analysis
    244
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Difference in resection rates
    Point estimate
    -3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.1
         upper limit
    4.2

    Secondary: Percentage of Participants With Complete Liver Metastasis Resection in Participants With Low ERCC-1 Levels

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    End point title
    Percentage of Participants With Complete Liver Metastasis Resection in Participants With Low ERCC-1 Levels
    End point description
    The timing of resective surgery was not defined in the protocol and was left at the discretion of the Investigator. Resection was classified as R0, R1, or R2 following surgery. R0 was defined as complete resection with clear margins ≥1 mm. The percentage of participants with R0 resection of liver or liver plus lymph node metastases was reported. The 95% CI was computed using normal approximation to the binomial distribution. ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
    End point type
    Secondary
    End point timeframe
    At time of resective surgery during study (maximum up to 45 months overall)
    End point values
    Bevacizumab + mFOLFOX6 (ERCC-1 Low) Bevacizumab + FOLFIRI (ERCC-1 Low)
    Number of subjects analysed
    124
    120
    Units: percentage of participants
        number (confidence interval 95%)
    8.9 (3.9 to 13.9)
    3.3 (0.1 to 6.5)
    Statistical analysis title
    Difference in Complete Resection Rates
    Statistical analysis description
    The difference was calculated as the percentage of participants with complete resection in the Bevacizumab + FOLFIRI arm minus the Bevacizumab + mFOLFOX6 arm. The 95% CI was computed using normal approximation to the binomial distribution.
    Comparison groups
    Bevacizumab + mFOLFOX6 (ERCC-1 Low) v Bevacizumab + FOLFIRI (ERCC-1 Low)
    Number of subjects included in analysis
    244
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Difference in complete resection rates
    Point estimate
    -5.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -11.5
         upper limit
    0.4

    Secondary: Percentage of Participants With Liver Metastasis Resection in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels

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    End point title
    Percentage of Participants With Liver Metastasis Resection in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels
    End point description
    The timing of resective surgery was not defined in the protocol and was left at the discretion of the Investigator. Resection was classified as R0, R1, or R2 following surgery. R0 was defined as complete resection with clear margins ≥1 mm. R1 was defined as the presence of exposed tumor or histologically detected tumor cells at the line of transection, or <1 mm microscopic margins. In the case of use of radiofrequency ablation or cryotherapy, the resection was considered as R1. R2 was defined as macroscopic positive margins or incomplete resection at time of surgery. The percentage of participants with resection of liver or liver plus lymph node metastases was reported. The 95% CI was computed using normal approximation to the binomial distribution. ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
    End point type
    Secondary
    End point timeframe
    At time of resective surgery during study (maximum up to 45 months overall)
    End point values
    Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 High) Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 Low)
    Number of subjects analysed
    131
    244
    Units: percentage of participants
        number (confidence interval 95%)
    4.6 (1 to 8.2)
    9 (5.4 to 12.6)
    Statistical analysis title
    Difference in Resection Rates
    Statistical analysis description
    The difference was calculated as the percentage of participants with resection in the ERCC-1 High subgroup minus the ERCC-1 Low subgroup. The 95% CI was computed using normal approximation to the binomial distribution.
    Comparison groups
    Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 High) v Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 Low)
    Number of subjects included in analysis
    375
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Difference in resection rates
    Point estimate
    -4.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.5
         upper limit
    0.6

    Secondary: Percentage of Participants With Complete Liver Metastasis Resection in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels

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    End point title
    Percentage of Participants With Complete Liver Metastasis Resection in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels
    End point description
    The timing of resective surgery was not defined in the protocol and was left at the discretion of the Investigator. Resection was classified as R0, R1, or R2 following surgery. R0 was defined as complete resection with clear margins ≥1 mm. The percentage of participants with R0 resection of liver or liver plus lymph node metastases was reported. The 95% CI was computed using normal approximation to the binomial distribution. ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
    End point type
    Secondary
    End point timeframe
    At time of resective surgery during study (maximum up to 45 months overall)
    End point values
    Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 High) Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 Low)
    Number of subjects analysed
    131
    244
    Units: percentage of participants
        number (confidence interval 95%)
    4.6 (1 to 8.2)
    6.1 (3.1 to 9.2)
    Statistical analysis title
    Difference in Complete Resection Rates
    Statistical analysis description
    The difference was calculated as the percentage of participants with complete resection in the ERCC-1 High subgroup minus the ERCC-1 Low subgroup. The 95% CI was computed using normal approximation to the binomial distribution.
    Comparison groups
    Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 High) v Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 Low)
    Number of subjects included in analysis
    375
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Difference in complete resection rates
    Point estimate
    -1.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.2
         upper limit
    3.1

    Secondary: PFS According to RECIST Version 1.1 in Participants With Wild-Type KRAS Versus Participants With Mutant KRAS

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    End point title
    PFS According to RECIST Version 1.1 in Participants With Wild-Type KRAS Versus Participants With Mutant KRAS
    End point description
    Tumor assessments were performed according to RECIST Version 1.1. Disease progression was defined as ≥20% increase in sum of LD of target lesions in reference to the smallest sum of LD on study, in addition to an absolute increase ≥5 mm. Disease progression was further defined as the last documented progression determined by the Investigator no later than 1 day before initiation of second-line therapy. Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. PFS was defined as the time from randomization to death or disease progression, whichever occurred first. The median duration of PFS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
    End point type
    Secondary
    End point timeframe
    From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)
    End point values
    Bevacizumab + mFOLFOX/FOLFIRI (KRAS Wild-Type) Bevacizumab + mFOLFOX/FOLFIRI (KRAS Mutant)
    Number of subjects analysed
    208
    128
    Units: months
        median (confidence interval 95%)
    12.45 (10.48 to 14.06)
    10.94 (8.77 to 12.35)
    Statistical analysis title
    Hazard Ratio
    Comparison groups
    Bevacizumab + mFOLFOX/FOLFIRI (KRAS Mutant) v Bevacizumab + mFOLFOX/FOLFIRI (KRAS Wild-Type)
    Number of subjects included in analysis
    336
    Analysis specification
    Pre-specified
    Analysis type
    other [24]
    P-value
    = 0.0593 [25]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.29
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.99
         upper limit
    1.69
    Notes
    [24] - Analysis stratified by high/low ERCC-1 level and region of enrollment. HR (relative to KRAS Wild-Type subgroup) was estimated by Cox regression.
    [25] - P-value (relative to KRAS Wild-Type subgroup) based on two-sided stratified log rank test and not adjusted for multiple comparisons.

    Secondary: OS in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels

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    End point title
    OS in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels
    End point description
    Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. OS was defined as the time from randomization to death. The median duration of OS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
    End point type
    Secondary
    End point timeframe
    From Baseline until death (maximum up to 45 months overall)
    End point values
    Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A High) Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A Low)
    Number of subjects analysed
    185
    185
    Units: months
        median (confidence interval 95%)
    22.83 (18.76 to 27.27)
    27.93 (24.97 to 36.01)
    Statistical analysis title
    Hazard Ratio
    Statistical analysis description
    Analysis stratified by high/low ERCC-1 level and region of enrollment. HR (relative to VEGF-A Low subgroup) was estimated by Cox regression.
    Comparison groups
    Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A High) v Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A Low)
    Number of subjects included in analysis
    370
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.002 [26]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.64
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.2
         upper limit
    2.24
    Notes
    [26] - P-value (relative to VEGF-A Low subgroup) based on two-sided stratified log rank test and not adjusted for multiple comparisons.

    Secondary: OS in Participants With Wild-Type KRAS Versus Participants With Mutant KRAS

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    End point title
    OS in Participants With Wild-Type KRAS Versus Participants With Mutant KRAS
    End point description
    Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. OS was defined as the time from randomization to death. The median duration of OS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
    End point type
    Secondary
    End point timeframe
    From Baseline until death (maximum up to 45 months overall)
    End point values
    Bevacizumab + mFOLFOX/FOLFIRI (KRAS Wild-Type) Bevacizumab + mFOLFOX/FOLFIRI (KRAS Mutant)
    Number of subjects analysed
    208
    128
    Units: months
        median (confidence interval 95%)
    28.75 (24.77 to 36.73)
    24.64 (19.98 to 26.94)
    Statistical analysis title
    Hazard Ratio
    Statistical analysis description
    Analysis stratified by high/low ERCC-1 level and region of enrollment. HR (relative to KRAS Wild-Type subgroup) was estimated by Cox regression.
    Comparison groups
    Bevacizumab + mFOLFOX/FOLFIRI (KRAS Wild-Type) v Bevacizumab + mFOLFOX/FOLFIRI (KRAS Mutant)
    Number of subjects included in analysis
    336
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0955 [27]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.34
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.95
         upper limit
    1.88
    Notes
    [27] - P-value (relative to KRAS Wild-Type subgroup) based on two-sided stratified log rank test and not adjusted for multiple comparisons.

    Secondary: Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels

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    End point title
    Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels
    End point description
    Objective response was defined as CR or PR according to RECIST Version 1.1. CR was defined as disappearance of all target lesions and short-axis reduction to <10 mm of any pathological lymph nodes. PR was defined as ≥30% decrease in sum of LD of target lesions in reference to sum of LD at Baseline. Confirmation of response at a consecutive assessment was not required. The percentage of participants with CR or PR was reported. The 95% CI was computed using normal approximation to the binomial distribution. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
    End point type
    Secondary
    End point timeframe
    From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)
    End point values
    Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A High) Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A Low)
    Number of subjects analysed
    185
    185
    Units: percentage of participants
        number (confidence interval 95%)
    60.5 (53.5 to 67.6)
    66.5 (59.7 to 73.3)
    Statistical analysis title
    Difference in Objective Response Rates
    Statistical analysis description
    The difference was calculated as the percentage of participants with objective response in the VEGF-A High subgroup minus the VEGF-A Low subgroup. The 95% CI was computed using normal approximation to the binomial distribution.
    Comparison groups
    Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A High) v Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A Low)
    Number of subjects included in analysis
    370
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Difference in objective response rates
    Point estimate
    -5.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -15.7
         upper limit
    3.8

    Secondary: Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With Wild-Type KRAS Versus Participants With Mutant KRAS

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    End point title
    Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With Wild-Type KRAS Versus Participants With Mutant KRAS
    End point description
    Objective response was defined as CR or PR according to RECIST Version 1.1. CR was defined as disappearance of all target lesions and short-axis reduction to <10 mm of any pathological lymph nodes. PR was defined as ≥30% decrease in sum of LD of target lesions in reference to sum of LD at Baseline. Confirmation of response at a consecutive assessment was not required. The percentage of participants with CR or PR was reported. The 95% CI was computed using normal approximation to the binomial distribution. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
    End point type
    Secondary
    End point timeframe
    From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)
    End point values
    Bevacizumab + mFOLFOX/FOLFIRI (KRAS Wild-Type) Bevacizumab + mFOLFOX/FOLFIRI (KRAS Mutant)
    Number of subjects analysed
    208
    128
    Units: percentage of participants
        number (confidence interval 95%)
    66.3 (59.9 to 72.8)
    60.9 (52.5 to 69.4)
    Statistical analysis title
    Difference in Objective Response Rates
    Statistical analysis description
    The difference was calculated as the percentage of participants with objective response in the KRAS Mutant subgroup minus the KRAS Wild-Type subgroup. The 95% CI was computed using normal approximation to the binomial distribution.
    Comparison groups
    Bevacizumab + mFOLFOX/FOLFIRI (KRAS Wild-Type) v Bevacizumab + mFOLFOX/FOLFIRI (KRAS Mutant)
    Number of subjects included in analysis
    336
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Difference in objective response rates
    Point estimate
    -5.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -16
         upper limit
    5.2

    Secondary: Percentage of Participants With Disease Control According to RECIST Version 1.1 in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels

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    End point title
    Percentage of Participants With Disease Control According to RECIST Version 1.1 in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels
    End point description
    Disease control was defined as CR, PR, or SD according to RECIST Version 1.1. CR was defined as disappearance of all target lesions and short-axis reduction to <10 mm of any pathological lymph nodes. PR was defined as ≥30% decrease in sum of LD of target lesions in reference to sum of LD at Baseline. Confirmation of response at a consecutive assessment was not required. SD was defined as neither sufficient shrinkage to quality for PR nor sufficient increase to qualify for disease progression (≥20% increase in sum of LD of target lesions plus absolute increase ≥5 mm) in reference to the smallest sum of LD on study. The percentage of participants with CR, PR, or SD was reported. The 95% CI was computed using normal approximation to the binomial distribution. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
    End point type
    Secondary
    End point timeframe
    From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)
    End point values
    Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A High) Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A Low)
    Number of subjects analysed
    185
    185
    Units: percentage of participants
        number (confidence interval 95%)
    91.9 (88 to 95.8)
    93 (89.3 to 96.7)
    Statistical analysis title
    Difference in Disease Control Rates
    Statistical analysis description
    The difference was calculated as the percentage of participants with disease control in the VEGF-A High subgroup minus the VEGF-A Low subgroup. The 95% CI was computed using normal approximation to the binomial distribution.
    Comparison groups
    Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A High) v Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A Low)
    Number of subjects included in analysis
    370
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Difference in disease control rates
    Point estimate
    -1.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.5
         upper limit
    4.3

    Secondary: Percentage of Participants With Liver Metastasis Resection in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels

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    End point title
    Percentage of Participants With Liver Metastasis Resection in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels
    End point description
    The timing of resective surgery was not defined in the protocol and was left at the discretion of the Investigator. Resection was classified as R0, R1, or R2 following surgery. R0 was defined as complete resection with clear margins ≥1 mm. R1 was defined as the presence of exposed tumor or histologically detected tumor cells at the line of transection, or <1 mm microscopic margins. In the case of use of radiofrequency ablation or cryotherapy, the resection was considered as R1. R2 was defined as macroscopic positive margins or incomplete resection at time of surgery. The percentage of participants with resection of liver or liver plus lymph node metastases was reported. The 95% CI was computed using normal approximation to the binomial distribution. ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
    End point type
    Secondary
    End point timeframe
    At time of resective surgery during study (maximum up to 45 months overall)
    End point values
    Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A High) Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A Low)
    Number of subjects analysed
    185
    185
    Units: percentage of participants
        number (confidence interval 95%)
    5.9 (2.5 to 9.4)
    9.2 (5 to 13.4)
    Statistical analysis title
    Difference in Resection Rates
    Statistical analysis description
    The difference was calculated as the percentage of participants with resection in the VEGF-A High subgroup minus the VEGF-A Low subgroup. The 95% CI was computed using normal approximation to the binomial distribution.
    Comparison groups
    Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A High) v Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A Low)
    Number of subjects included in analysis
    370
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Difference in resection rates
    Point estimate
    -3.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.6
         upper limit
    2.1

    Secondary: Percentage of Participants With Complete Liver Metastasis Resection in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels

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    End point title
    Percentage of Participants With Complete Liver Metastasis Resection in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels
    End point description
    The timing of resective surgery was not defined in the protocol and was left at the discretion of the Investigator. Resection was classified as R0, R1, or R2 following surgery. R0 was defined as complete resection with clear margins ≥1 mm. The percentage of participants with R0 resection of liver or liver plus lymph node metastases was reported. The 95% CI was computed using normal approximation to the binomial distribution. ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.
    End point type
    Secondary
    End point timeframe
    At time of resective surgery during study (maximum up to 45 months overall)
    End point values
    Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A High) Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A Low)
    Number of subjects analysed
    185
    185
    Units: percentage of participants
        number (confidence interval 95%)
    3.2 (0.7 to 5.8)
    8.1 (4.2 to 12)
    Statistical analysis title
    Difference in Complete Resection Rates
    Statistical analysis description
    The difference was calculated as the percentage of participants with complete resection in the VEGF-A High subgroup minus the VEGF-A Low subgroup. The 95% CI was computed using normal approximation to the binomial distribution.
    Comparison groups
    Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A High) v Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A Low)
    Number of subjects included in analysis
    370
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Difference in complete resection rates
    Point estimate
    -4.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.6
         upper limit
    -0.2

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious Adverse Events (AEs): Baseline until 3 months after last dose or study discontinuation/termination (up to 45 months overall); Non-Serious AEs: Baseline until 28 days after last dose or study discontinuation/termination (up to 45 months overall).
    Adverse event reporting additional description
    Safety Population: All randomized participants who received at least one partial or complete dose of study drug.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Bevacizumab + mFOLFOX6
    Reporting group description
    Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles.

    Reporting group title
    Bevacizumab + FOLFIRI
    Reporting group description
    Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles.

    Serious adverse events
    Bevacizumab + mFOLFOX6 Bevacizumab + FOLFIRI
    Total subjects affected by serious adverse events
         subjects affected / exposed
    79 / 185 (42.70%)
    87 / 183 (47.54%)
         number of deaths (all causes)
    96
    73
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Meningioma
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    5 / 185 (2.70%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    3 / 185 (1.62%)
    6 / 183 (3.28%)
         occurrences causally related to treatment / all
    3 / 3
    9 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arterial thrombosis
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 185 (0.54%)
    4 / 183 (2.19%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism venous
         subjects affected / exposed
    1 / 185 (0.54%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    1 / 185 (0.54%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Colostomy
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    3 / 185 (1.62%)
    4 / 183 (2.19%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 185 (1.62%)
    4 / 183 (2.19%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device dislocation
         subjects affected / exposed
    2 / 185 (1.08%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 185 (0.54%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Peripheral swelling
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device malfunction
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 185 (0.00%)
    3 / 183 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised oedema
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         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
    9 / 185 (4.86%)
    9 / 183 (4.92%)
         occurrences causally related to treatment / all
    8 / 10
    7 / 9
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    2 / 185 (1.08%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory distress
         subjects affected / exposed
    2 / 185 (1.08%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 185 (0.54%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 185 (0.54%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hiccups
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary thrombosis
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary artery thrombosis
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 185 (0.54%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 185 (0.00%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Platelet count decreased
         subjects affected / exposed
    2 / 185 (1.08%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 185 (0.00%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stoma site haemorrhage
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal wound dehiscence
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal anastomosis complication
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial flutter
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 185 (0.54%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 185 (0.00%)
    3 / 183 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial thrombosis
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Aphonia
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ataxia
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 185 (0.54%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 185 (0.54%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombotic stroke
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    3 / 185 (1.62%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    2 / 185 (1.08%)
    4 / 183 (2.19%)
         occurrences causally related to treatment / all
    1 / 2
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 185 (0.54%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune thrombocytopenic purpura
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 185 (0.54%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 185 (0.54%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    6 / 185 (3.24%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    4 / 6
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    5 / 185 (2.70%)
    6 / 183 (3.28%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    4 / 185 (2.16%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    3 / 185 (1.62%)
    7 / 183 (3.83%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    3 / 185 (1.62%)
    3 / 183 (1.64%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 185 (1.62%)
    4 / 183 (2.19%)
         occurrences causally related to treatment / all
    0 / 6
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 185 (1.08%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    2 / 185 (1.08%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    2 / 185 (1.08%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 185 (1.08%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    2 / 185 (1.08%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 185 (1.08%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileal perforation
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Large intestinal haemorrhage
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic colitis
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal motility disorder
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal varices haemorrhage
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumoperitoneum
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Small intestinal perforation
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal distension
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 185 (0.00%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 185 (0.00%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenitis
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterovesical fistula
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 185 (0.00%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 185 (0.00%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pancreatitis
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reflux gastritis
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 185 (0.54%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic hepatitis
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Biloma
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic steatosis
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 185 (0.54%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Proteinuria
         subjects affected / exposed
    1 / 185 (0.54%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    1 / 185 (0.54%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyarthritis
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (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
    Sepsis
         subjects affected / exposed
    4 / 185 (2.16%)
    3 / 183 (1.64%)
         occurrences causally related to treatment / all
    1 / 6
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    Pneumonia
         subjects affected / exposed
    3 / 185 (1.62%)
    7 / 183 (3.83%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 185 (1.08%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    2 / 185 (1.08%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 185 (1.08%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal abscess
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal infection
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Candida sepsis
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Infection
         subjects affected / exposed
    1 / 185 (0.54%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 185 (0.54%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 185 (0.00%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kidney infection
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perineal abscess
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia parainfluenzae viral
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    8 / 185 (4.32%)
    5 / 183 (2.73%)
         occurrences causally related to treatment / all
    2 / 10
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    1 / 185 (0.54%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 185 (0.54%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 185 (0.54%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic alkalosis
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Bevacizumab + mFOLFOX6 Bevacizumab + FOLFIRI
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    185 / 185 (100.00%)
    181 / 183 (98.91%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    61 / 185 (32.97%)
    54 / 183 (29.51%)
         occurrences all number
    110
    96
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    105 / 185 (56.76%)
    104 / 183 (56.83%)
         occurrences all number
    145
    177
    Mucosal inflammation
         subjects affected / exposed
    37 / 185 (20.00%)
    51 / 183 (27.87%)
         occurrences all number
    50
    82
    Pyrexia
         subjects affected / exposed
    18 / 185 (9.73%)
    29 / 183 (15.85%)
         occurrences all number
    23
    38
    Asthenia
         subjects affected / exposed
    21 / 185 (11.35%)
    18 / 183 (9.84%)
         occurrences all number
    24
    28
    Oedema peripheral
         subjects affected / exposed
    18 / 185 (9.73%)
    18 / 183 (9.84%)
         occurrences all number
    22
    20
    Temperature intolerance
         subjects affected / exposed
    34 / 185 (18.38%)
    1 / 183 (0.55%)
         occurrences all number
    39
    1
    Chest pain
         subjects affected / exposed
    15 / 185 (8.11%)
    10 / 183 (5.46%)
         occurrences all number
    19
    12
    Chills
         subjects affected / exposed
    10 / 185 (5.41%)
    10 / 183 (5.46%)
         occurrences all number
    12
    13
    Influenza like illness
         subjects affected / exposed
    10 / 185 (5.41%)
    6 / 183 (3.28%)
         occurrences all number
    13
    6
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    10 / 185 (5.41%)
    0 / 183 (0.00%)
         occurrences all number
    11
    0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    41 / 185 (22.16%)
    59 / 183 (32.24%)
         occurrences all number
    51
    82
    Cough
         subjects affected / exposed
    31 / 185 (16.76%)
    29 / 183 (15.85%)
         occurrences all number
    37
    43
    Dyspnoea
         subjects affected / exposed
    28 / 185 (15.14%)
    26 / 183 (14.21%)
         occurrences all number
    39
    38
    Rhinorrhoea
         subjects affected / exposed
    12 / 185 (6.49%)
    21 / 183 (11.48%)
         occurrences all number
    16
    23
    Dysphonia
         subjects affected / exposed
    14 / 185 (7.57%)
    18 / 183 (9.84%)
         occurrences all number
    17
    39
    Hiccups
         subjects affected / exposed
    8 / 185 (4.32%)
    14 / 183 (7.65%)
         occurrences all number
    11
    16
    Oropharyngeal pain
         subjects affected / exposed
    11 / 185 (5.95%)
    8 / 183 (4.37%)
         occurrences all number
    11
    12
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    29 / 185 (15.68%)
    35 / 183 (19.13%)
         occurrences all number
    31
    44
    Depression
         subjects affected / exposed
    24 / 185 (12.97%)
    18 / 183 (9.84%)
         occurrences all number
    26
    24
    Anxiety
         subjects affected / exposed
    19 / 185 (10.27%)
    20 / 183 (10.93%)
         occurrences all number
    20
    23
    Investigations
    Weight decreased
         subjects affected / exposed
    33 / 185 (17.84%)
    29 / 183 (15.85%)
         occurrences all number
    40
    32
    Neutrophil count decreased
         subjects affected / exposed
    33 / 185 (17.84%)
    23 / 183 (12.57%)
         occurrences all number
    55
    33
    Platelet count decreased
         subjects affected / exposed
    24 / 185 (12.97%)
    3 / 183 (1.64%)
         occurrences all number
    64
    6
    White blood cell count decreased
         subjects affected / exposed
    15 / 185 (8.11%)
    9 / 183 (4.92%)
         occurrences all number
    25
    25
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    15 / 185 (8.11%)
    8 / 183 (4.37%)
         occurrences all number
    27
    13
    Nervous system disorders
    Neuropathy peripheral
         subjects affected / exposed
    85 / 185 (45.95%)
    23 / 183 (12.57%)
         occurrences all number
    134
    30
    Headache
         subjects affected / exposed
    31 / 185 (16.76%)
    38 / 183 (20.77%)
         occurrences all number
    40
    51
    Dysgeusia
         subjects affected / exposed
    33 / 185 (17.84%)
    31 / 183 (16.94%)
         occurrences all number
    38
    38
    Paraesthesia
         subjects affected / exposed
    35 / 185 (18.92%)
    15 / 183 (8.20%)
         occurrences all number
    66
    18
    Peripheral sensory neuropathy
         subjects affected / exposed
    35 / 185 (18.92%)
    12 / 183 (6.56%)
         occurrences all number
    50
    12
    Dizziness
         subjects affected / exposed
    15 / 185 (8.11%)
    28 / 183 (15.30%)
         occurrences all number
    15
    36
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    65 / 185 (35.14%)
    86 / 183 (46.99%)
         occurrences all number
    103
    158
    Anaemia
         subjects affected / exposed
    25 / 185 (13.51%)
    34 / 183 (18.58%)
         occurrences all number
    31
    45
    Thrombocytopenia
         subjects affected / exposed
    44 / 185 (23.78%)
    13 / 183 (7.10%)
         occurrences all number
    134
    22
    Eye disorders
    Vision blurred
         subjects affected / exposed
    13 / 185 (7.03%)
    12 / 183 (6.56%)
         occurrences all number
    16
    13
    Lacrimation increased
         subjects affected / exposed
    4 / 185 (2.16%)
    10 / 183 (5.46%)
         occurrences all number
    4
    13
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    99 / 185 (53.51%)
    123 / 183 (67.21%)
         occurrences all number
    189
    242
    Nausea
         subjects affected / exposed
    106 / 185 (57.30%)
    109 / 183 (59.56%)
         occurrences all number
    201
    203
    Constipation
         subjects affected / exposed
    63 / 185 (34.05%)
    65 / 183 (35.52%)
         occurrences all number
    86
    115
    Vomiting
         subjects affected / exposed
    58 / 185 (31.35%)
    57 / 183 (31.15%)
         occurrences all number
    80
    89
    Abdominal pain
         subjects affected / exposed
    39 / 185 (21.08%)
    54 / 183 (29.51%)
         occurrences all number
    47
    82
    Stomatitis
         subjects affected / exposed
    35 / 185 (18.92%)
    38 / 183 (20.77%)
         occurrences all number
    50
    56
    Gastrooesophageal reflux disease
         subjects affected / exposed
    17 / 185 (9.19%)
    18 / 183 (9.84%)
         occurrences all number
    19
    20
    Dyspepsia
         subjects affected / exposed
    19 / 185 (10.27%)
    14 / 183 (7.65%)
         occurrences all number
    22
    15
    Rectal haemorrhage
         subjects affected / exposed
    11 / 185 (5.95%)
    18 / 183 (9.84%)
         occurrences all number
    16
    31
    Abdominal pain upper
         subjects affected / exposed
    8 / 185 (4.32%)
    15 / 183 (8.20%)
         occurrences all number
    8
    22
    Oral pain
         subjects affected / exposed
    8 / 185 (4.32%)
    14 / 183 (7.65%)
         occurrences all number
    9
    14
    Haemorrhoids
         subjects affected / exposed
    6 / 185 (3.24%)
    16 / 183 (8.74%)
         occurrences all number
    6
    17
    Proctalgia
         subjects affected / exposed
    7 / 185 (3.78%)
    13 / 183 (7.10%)
         occurrences all number
    7
    13
    Dry mouth
         subjects affected / exposed
    7 / 185 (3.78%)
    11 / 183 (6.01%)
         occurrences all number
    8
    12
    Abdominal distension
         subjects affected / exposed
    5 / 185 (2.70%)
    12 / 183 (6.56%)
         occurrences all number
    5
    14
    Dysphagia
         subjects affected / exposed
    10 / 185 (5.41%)
    2 / 183 (1.09%)
         occurrences all number
    10
    2
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    26 / 185 (14.05%)
    61 / 183 (33.33%)
         occurrences all number
    30
    69
    Dry skin
         subjects affected / exposed
    27 / 185 (14.59%)
    26 / 183 (14.21%)
         occurrences all number
    36
    38
    Rash
         subjects affected / exposed
    19 / 185 (10.27%)
    26 / 183 (14.21%)
         occurrences all number
    25
    31
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    24 / 185 (12.97%)
    18 / 183 (9.84%)
         occurrences all number
    37
    22
    Skin hyperpigmentation
         subjects affected / exposed
    18 / 185 (9.73%)
    13 / 183 (7.10%)
         occurrences all number
    19
    17
    Pruritus
         subjects affected / exposed
    11 / 185 (5.95%)
    9 / 183 (4.92%)
         occurrences all number
    17
    14
    Hyperhidrosis
         subjects affected / exposed
    2 / 185 (1.08%)
    10 / 183 (5.46%)
         occurrences all number
    2
    14
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    38 / 185 (20.54%)
    39 / 183 (21.31%)
         occurrences all number
    58
    52
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    22 / 185 (11.89%)
    25 / 183 (13.66%)
         occurrences all number
    24
    36
    Back pain
         subjects affected / exposed
    21 / 185 (11.35%)
    23 / 183 (12.57%)
         occurrences all number
    25
    31
    Pain in extremity
         subjects affected / exposed
    22 / 185 (11.89%)
    19 / 183 (10.38%)
         occurrences all number
    23
    25
    Musculoskeletal pain
         subjects affected / exposed
    17 / 185 (9.19%)
    11 / 183 (6.01%)
         occurrences all number
    17
    12
    Muscle spasms
         subjects affected / exposed
    7 / 185 (3.78%)
    11 / 183 (6.01%)
         occurrences all number
    8
    14
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    18 / 185 (9.73%)
    20 / 183 (10.93%)
         occurrences all number
    19
    21
    Upper respiratory tract infection
         subjects affected / exposed
    15 / 185 (8.11%)
    18 / 183 (9.84%)
         occurrences all number
    18
    18
    Sinusitis
         subjects affected / exposed
    9 / 185 (4.86%)
    13 / 183 (7.10%)
         occurrences all number
    10
    13
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    56 / 185 (30.27%)
    55 / 183 (30.05%)
         occurrences all number
    93
    76
    Hypokalaemia
         subjects affected / exposed
    36 / 185 (19.46%)
    33 / 183 (18.03%)
         occurrences all number
    44
    39
    Dehydration
         subjects affected / exposed
    28 / 185 (15.14%)
    27 / 183 (14.75%)
         occurrences all number
    51
    36
    Hyperglycaemia
         subjects affected / exposed
    9 / 185 (4.86%)
    23 / 183 (12.57%)
         occurrences all number
    15
    26
    Hyponatraemia
         subjects affected / exposed
    8 / 185 (4.32%)
    15 / 183 (8.20%)
         occurrences all number
    10
    18

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Jul 2012
    The protocol was modified to include geographic region (United States or non-United States) as a stratification factor for enrollment. The start of Screening was also changed to the date that biopsy tissue became available, and biomarker samplings were updated.
    26 Oct 2012
    The protocol was amended primarily to modify the requirement for follow-up after study discontinuation. Participants who discontinued bevacizumab or other study drug were to continue with the rest of the treatment regimen until progression or unacceptable toxicity, and the end of treatment was re-defined as the time at which all study drugs were discontinued or the participant progressed. Thereafter, participants could enter the survival follow-up phase.

    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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