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    Clinical Trial Results:
    A Phase II, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of MEGF0444A Dosed to Progression in Combination with Bevacizumab and FOLFOX in Patients with Previously Untreated Metastatic Colorectal Cancer

    Summary
    EudraCT number
    		 2011-001867-28
    Trial protocol
    		 BE   ES   PL  
    Global end of trial date
    24 Feb 2014

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

    Trial information

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    Trial identification
    Sponsor protocol code
    MEF4982g
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01399684
    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
    26 Sep 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Feb 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    This was a Phase II, multicenter, randomized, double-blind, placebo-controlled study. The primary objective was to estimate the efficacy of MEGF0444A combined with modified FOLFOX-6 (mFOLFOX-6; consisting of 5-flourouracil, folinic acid, oxaliplatin), plus bevacizumab therapy in participants with previously untreated metastatic colorectal cancer (mCRC), as measured by progression-free survival (PFS).
    Protection of trial subjects
    The study was conducted in accordance with the United States Food and Drug Administration regulations, the International Conference on Harmonisation E6 guideline for Good Clinical Practice, and applicable local, state, and federal laws, as well as other applicable country laws, according to the regulations and procedures described in the protocol. The investigator, or a person designated by the investigator obtained written informed consent from each participant participating in this study, after adequate explanation of the aims, methods, anticipated benefits, and potential hazards of the study. For participants not qualified or incapable of giving legal consent, written consent was obtained from the legally acceptable representative. Approval from the Independent Ethics Committees (IEC) /Institutional Review Board (IRB) was obtained before starting the study. The protocol amendments were prepared by the Sponsor and approved by the IEC/IRB.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Nov 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy
    Long term follow-up duration
    		 20 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 18
    Country: Number of subjects enrolled
    Poland: 11
    Country: Number of subjects enrolled
    United States: 41
    Country: Number of subjects enrolled
    Belgium: 18
    Country: Number of subjects enrolled
    Spain: 38
    Worldwide total number of subjects
    126
    EEA total number of subjects
    67
    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)
    81
    From 65 to 84 years
    45
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Overall 127 participants were randomized and included in efficacy analysis, 125 were included in safety analysis (1 participant = screen failure; 1 participant = withdrew prior to first treatment) and 126 participants were randomized in the disposition.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 MEGF0444A + mFOLFOX-6 + Bevacizumab
    Arm description
    		 Participants received MEGF0444A at a fixed dose of 400 milligrams (mg) intravenous (IV) infusion, followed by bevacizumab 5 milligram per kilogram (mg/kg) IV infusion, and then mFOLFOX-6 (consisting of oxaliplatin 85 milligrams per square meter [mg/m^2] IV infusion, 400 mg/m^2 folinic acid IV infusion, and 400 mg/m^2 5-FU administered as an initial IV bolus and followed by continuous IV infusion of 2400 mg/m^2) on Day 1 of each 14-day cycle. After 8 cycles, oxaliplatin was stopped and MEGF0444A, bevacizumab, folinic acid, and 5-FU were continued until disease progression, or unacceptable toxicity for a maximum of 24 months (up to 52 cycles).
    Arm type
    		 Experimental

    Investigational medicinal product name
    MEGF0444A
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    MEGF0444A administered at a fixed dose of 400 mg IV infusion on Day 1 of Cycle 1 and on Day 1 of each subsequent 14-day cycle for a maximum of 24 months.

    Arm title
    		 Placebo + mFOLFOX-6 + Bevacizumab
    Arm description
    		 Participants received placebo matched to MEGF0444A at a fixed dose of 400 mg IV infusion, followed by bevacizumab 5 mg/kg IV infusion, and then mFOLFOX-6 (consisting of oxaliplatin 85mg/m^2 IV infusion, 400 mg/m^2 folinic acid IV infusion, and 400 mg/m^2 5-FU administered as an initial IV bolus and followed by continuous IV infusion of 2400 mg/m^2) on Day 1 of each 14-day cycle. After 8 cycles, oxaliplatin was stopped and placebo matched to MEGF0444A, bevacizumab, folinic acid, and 5-FU were continued until disease progression, or unacceptable toxicity for a maximum of 24 months (up to 52 cycles).
    Arm type
    		 Control

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		MEGF0444A + mFOLFOX-6 + Bevacizumab Placebo + mFOLFOX-6 + Bevacizumab
    Started
    63
    63
    Completed
    0
    0
    Not completed
    63
    63
         Consent withdrawn by subject
    4
    3
         Study terminated by Sponsor
    41
    39
         Death
    18
    21

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    MEGF0444A + mFOLFOX-6 + Bevacizumab
    Reporting group description
    		 Participants received MEGF0444A at a fixed dose of 400 milligrams (mg) intravenous (IV) infusion, followed by bevacizumab 5 milligram per kilogram (mg/kg) IV infusion, and then mFOLFOX-6 (consisting of oxaliplatin 85 milligrams per square meter [mg/m^2] IV infusion, 400 mg/m^2 folinic acid IV infusion, and 400 mg/m^2 5-FU administered as an initial IV bolus and followed by continuous IV infusion of 2400 mg/m^2) on Day 1 of each 14-day cycle. After 8 cycles, oxaliplatin was stopped and MEGF0444A, bevacizumab, folinic acid, and 5-FU were continued until disease progression, or unacceptable toxicity for a maximum of 24 months (up to 52 cycles).

    Reporting group title
    Placebo + mFOLFOX-6 + Bevacizumab
    Reporting group description
    		 Participants received placebo matched to MEGF0444A at a fixed dose of 400 mg IV infusion, followed by bevacizumab 5 mg/kg IV infusion, and then mFOLFOX-6 (consisting of oxaliplatin 85mg/m^2 IV infusion, 400 mg/m^2 folinic acid IV infusion, and 400 mg/m^2 5-FU administered as an initial IV bolus and followed by continuous IV infusion of 2400 mg/m^2) on Day 1 of each 14-day cycle. After 8 cycles, oxaliplatin was stopped and placebo matched to MEGF0444A, bevacizumab, folinic acid, and 5-FU were continued until disease progression, or unacceptable toxicity for a maximum of 24 months (up to 52 cycles).

    Reporting group values
    		 MEGF0444A + mFOLFOX-6 + Bevacizumab Placebo + mFOLFOX-6 + Bevacizumab Total
    Number of subjects
    		 63 63 126
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 60.9 ( 10.3 ) 60.9 ( 9.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 25 27 52
        Male
    		 38 36 74

    End points

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    End points reporting groups
    Reporting group title
    MEGF0444A + mFOLFOX-6 + Bevacizumab
    Reporting group description
    		 Participants received MEGF0444A at a fixed dose of 400 milligrams (mg) intravenous (IV) infusion, followed by bevacizumab 5 milligram per kilogram (mg/kg) IV infusion, and then mFOLFOX-6 (consisting of oxaliplatin 85 milligrams per square meter [mg/m^2] IV infusion, 400 mg/m^2 folinic acid IV infusion, and 400 mg/m^2 5-FU administered as an initial IV bolus and followed by continuous IV infusion of 2400 mg/m^2) on Day 1 of each 14-day cycle. After 8 cycles, oxaliplatin was stopped and MEGF0444A, bevacizumab, folinic acid, and 5-FU were continued until disease progression, or unacceptable toxicity for a maximum of 24 months (up to 52 cycles).

    Reporting group title
    Placebo + mFOLFOX-6 + Bevacizumab
    Reporting group description
    		 Participants received placebo matched to MEGF0444A at a fixed dose of 400 mg IV infusion, followed by bevacizumab 5 mg/kg IV infusion, and then mFOLFOX-6 (consisting of oxaliplatin 85mg/m^2 IV infusion, 400 mg/m^2 folinic acid IV infusion, and 400 mg/m^2 5-FU administered as an initial IV bolus and followed by continuous IV infusion of 2400 mg/m^2) on Day 1 of each 14-day cycle. After 8 cycles, oxaliplatin was stopped and placebo matched to MEGF0444A, bevacizumab, folinic acid, and 5-FU were continued until disease progression, or unacceptable toxicity for a maximum of 24 months (up to 52 cycles).

    Subject analysis set title
    Placebo + mFOLFOX-6+ Bevacizumab
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    This analyis set included all the participants randomized to placebo part of the study.

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

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    End point title
    		 PFS According to Response Evaluation Criteria in Solid Tumors (RECIST) Version (v)1.1 [1]
    End point description
    PFS was defined as the time from randomization to the first occurrence of documented disease progression (PD) based on RECIST v1.1 or death due to any cause within 30 days of the last treatment, whichever occurs earlier as determined by the investigator. For target lesions, PD was defined as at least a 20 percent (%) increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum of the longest diameter recorded since treatment started or the appearance of 1 or more new lesions. For non-target lesions, PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing non-target lesions. In the event of no disease progression or documented death prior to study termination, PFS was censored at the date of the last evaluable tumor assessment. Analysis population: All randomized participants.
    End point type
    Primary
    End point timeframe
    Baseline until 20 months
    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: All the randomized participants were included in the end point analysis.
    End point values
    		 MEGF0444A + mFOLFOX-6 + Bevacizumab Placebo + mFOLFOX-6+ Bevacizumab
    Number of subjects analysed
    63
    64
    Units: months
        median (confidence interval 95%)
    12 (9.1 to 15.77)
    11.9 (9.63 to 15.77)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The hazard ratio (HR) and 95% confidence interval (CI) was estimated using Cox proportional hazards methodology. The stratification factors used in the analysis were Eastern Cooperative Oncology Group performance status (ECOG PS) (0 vs 1), number of affected organs (1 vs greater than [>]1), and adjuvant therapy (yes vs no).
    Comparison groups
    MEGF0444A + mFOLFOX-6 + Bevacizumab v Placebo + mFOLFOX-6+ Bevacizumab
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6141
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.149
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.684
         upper limit
    		 1.932
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Unstratified analysis.
    Comparison groups
    MEGF0444A + mFOLFOX-6 + Bevacizumab v Placebo + mFOLFOX-6+ Bevacizumab
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5475
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.169
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.708
         upper limit
    		 1.93

    Primary: Percentage of Participants with Disease Progression or Death According to RECIST v1.1

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    End point title
    		 Percentage of Participants with Disease Progression or Death According to RECIST v1.1 [2] [3]
    End point description
    For target lesions, progressive disease was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum of the longest diameter recorded since treatment started or the appearance of 1 or more new lesions. For non-target lesions, progressive disease was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing non-target lesions. Analysis population: All randomized participants.
    End point type
    Primary
    End point timeframe
    Baseline until 20 months
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analysis was planned only for PFS duration and reported in respective end points.
    [3] - 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: All the randomized participants were included in the end point analysis.
    End point values
    		 MEGF0444A + mFOLFOX-6 + Bevacizumab Placebo + mFOLFOX-6+ Bevacizumab
    Number of subjects analysed
    63
    64
    Units: percentage of participants
        number (not applicable)
    50.8
    46.9
    No statistical analyses for this end point

    Primary: PFS (Surgery Included) According to RECIST v1.1

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    End point title
    		 PFS (Surgery Included) According to RECIST v1.1 [4]
    End point description
    PFS was defined as the time from randomization to the first occurrence of documented disease progression based on RECIST v1.1 or death due to any cause within 30 days of the last treatment, whichever occurs earlier as determined by the investigator. For target lesions, PD was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum of the longest diameter recorded since treatment started or the appearance of 1 or more new lesions. For non-target lesions, PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing non-target lesions. In the event of no disease progression or documented death prior to study termination, PFS was censored at the date of the last evaluable tumor assessment. Analysis population: All randomized participants considered for surgery.
    End point type
    Primary
    End point timeframe
    Baseline until 20 months
    Notes
    [4] - 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: All the randomized participants were included in the end point analysis.
    End point values
    		 MEGF0444A + mFOLFOX-6 + Bevacizumab Placebo + mFOLFOX-6+ Bevacizumab
    Number of subjects analysed
    63
    64
    Units: months
        median (confidence interval 95%)
    12.9 (9.26 to 13.77)
    12.6 (9.69 to 15.28)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The HR and 95% CI was estimated using Cox proportional hazards methodology. The stratification factors used in the analysis were ECOG PS (0 vs 1), number of affected organs (1 vs >1), and adjuvant therapy (yes vs no).
    Comparison groups
    MEGF0444A + mFOLFOX-6 + Bevacizumab v Placebo + mFOLFOX-6+ Bevacizumab
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7032
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.109
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.67
         upper limit
    		 1.837
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Unstratified analysis.
    Comparison groups
    MEGF0444A + mFOLFOX-6 + Bevacizumab v Placebo + mFOLFOX-6+ Bevacizumab
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6831
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.107
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.684
         upper limit
    		 1.791

    Primary: PFS by Baseline Characteristics Used for Stratification

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    End point title
    		 PFS by Baseline Characteristics Used for Stratification [5]
    End point description
    PFS was defined as time from randomization to first occurrence of documented disease progression based on RECIST v1.1 or death due to any cause within 30 days of last treatment, whichever occurs earlier as determined by investigator, and reported according to following baseline risk factors: ECOG PS (0 vs 1), adjuvant therapy (yes vs no), and metastatic sites at enrollment (1 vs > 1). ECOG PS 0 equals (=) to fully active, able to carry on all pre-disease performance without restriction; 1= restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature. In event of no disease progression or documented death prior to study termination, PFS was censored at date of the last evaluable tumor assessment. Analysis population: All randomized participants. '-99999' and '99999' signifies that analyses was not performed due to lack of efficacy and closure of development of molecule.
    End point type
    Primary
    End point timeframe
    Baseline until 20 months
    Notes
    [5] - 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: All the randomized participants were included in the end point analysis.
    End point values
    		 MEGF0444A + mFOLFOX-6 + Bevacizumab Placebo + mFOLFOX-6+ Bevacizumab
    Number of subjects analysed
    63
    64
    Units: months
    median (confidence interval 95%)
        ECOG PS = 0 (n= 30, 36)
    13.7 (-99999 to 99999)
    11.9 (-99999 to 99999)
        ECOG PS = 1 (n= 33, 28)
    9.3 (-99999 to 99999)
    11.5 (-99999 to 99999)
        Adjuvant therapy = No (n= 53, 56)
    11.6 (-99999 to 99999)
    11.9 (-99999 to 99999)
        Adjuvant therapy = Yes (n= 10, 7)
    99999 (-99999 to 99999)
    14.5 (-99999 to 99999)
        One metastatic site (n= 29, 24)
    12.9 (-99999 to 99999)
    15.8 (-99999 to 99999)
        Two metastatic sites (n= 34, 39)
    11.6 (-99999 to 99999)
    9.7 (-99999 to 99999)
    Statistical analysis title
    		 Subgroup analysis: ECOG PS = 0
    Statistical analysis description
    The HR and 95% CI was estimated using Cox proportional hazards methodology.
    Comparison groups
    MEGF0444A + mFOLFOX-6 + Bevacizumab v Placebo + mFOLFOX-6+ Bevacizumab
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4498
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.766
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.369
         upper limit
    		 1.591
    Statistical analysis title
    		 Subgroup analysis: ECOG PS = 1
    Statistical analysis description
    The HR and 95% CI was estimated using Cox proportional hazards methodology.
    Comparison groups
    MEGF0444A + mFOLFOX-6 + Bevacizumab v Placebo + mFOLFOX-6+ Bevacizumab
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.176
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.655
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.792
         upper limit
    		 3.459
    Statistical analysis title
    		 Subgroup analysis: Adjuvant therapy = No
    Statistical analysis description
    The HR and 95% CI was estimated using Cox proportional hazards methodology.
    Comparison groups
    MEGF0444A + mFOLFOX-6 + Bevacizumab v Placebo + mFOLFOX-6+ Bevacizumab
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2761
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.349
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.789
         upper limit
    		 2.309
    Statistical analysis title
    		 Subgroup analysis: Adjuvant therapy = Yes
    Statistical analysis description
    The HR and 95% CI was estimated using Cox proportional hazards methodology.
    Comparison groups
    MEGF0444A + mFOLFOX-6 + Bevacizumab v Placebo + mFOLFOX-6+ Bevacizumab
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3078
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.482
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.115
         upper limit
    		 2.012
    Statistical analysis title
    		 Subgroup analysis: One metastatic site
    Statistical analysis description
    The HR and 95% CI was estimated using Cox proportional hazards methodology.
    Comparison groups
    MEGF0444A + mFOLFOX-6 + Bevacizumab v Placebo + mFOLFOX-6+ Bevacizumab
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1672
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.763
         upper limit
    		 4.88
    Statistical analysis title
    		 Subgroup analysis: Two metastatic sites
    Statistical analysis description
    The HR and 95% CI was estimated using Cox proportional hazards methodology.
    Comparison groups
    MEGF0444A + mFOLFOX-6 + Bevacizumab v Placebo + mFOLFOX-6+ Bevacizumab
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8406
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.512
         upper limit
    		 1.725

    Primary: PFS (Surgery Included) by Baseline Characteristics Used for Stratification

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    End point title
    		 PFS (Surgery Included) by Baseline Characteristics Used for Stratification [6]
    End point description
    PFS was defined as the time from randomization to the first occurrence of documented disease progression based on RECIST v1.1 or death due to any cause within 30 days of the last treatment, whichever occurs earlier as determined by the investigator, and reported according to the following baseline risk factors: ECOG PS (0 vs 1), adjuvant therapy (yes vs no), and metastatic sites at enrollment (1 vs > 1). ECOG PS 0 = to fully active, able to carry on all pre-disease performance without restriction; 1= restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature. In the event of no disease progression or documented death prior to study termination, PFS was censored at the date of the last evaluable tumor assessment. Analysis population: All randomized participants considered for surgery. '-99999' and '99999' signifies that analyses was not performed due to lack of efficacy and closure of development of molecule.
    End point type
    Primary
    End point timeframe
    Baseline until 20 months
    Notes
    [6] - 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: All the randomized participants were included in the end point analysis.
    End point values
    		 MEGF0444A + mFOLFOX-6 + Bevacizumab Placebo + mFOLFOX-6+ Bevacizumab
    Number of subjects analysed
    63
    64
    Units: months
    median (confidence interval 95%)
        ECOG PS = 0 (n= 30, 36)
    13.4 (-99999 to 99999)
    12.6 (-99999 to 99999)
        ECOG PS = 1 (n= 33, 28)
    9.3 (-99999 to 99999)
    99999 (-99999 to 99999)
        Adjuvant therapy = No (n= 53, 56)
    12.9 (-99999 to 99999)
    12.6 (-99999 to 99999)
        Adjuvant therapy = Yes (n= 10, 7)
    13.4 (-99999 to 99999)
    14.5 (-99999 to 99999)
        One metastatic site (n= 29, 24)
    13 (-99999 to 99999)
    15.8 (-99999 to 99999)
        Two metastatic sites (n= 34, 39)
    11.6 (-99999 to 99999)
    11 (-99999 to 99999)
    Statistical analysis title
    		 Subgroup analysis: ECOG PS = 0
    Statistical analysis description
    The HR and 95% CI was estimated using Cox proportional hazards methodology.
    Comparison groups
    MEGF0444A + mFOLFOX-6 + Bevacizumab v Placebo + mFOLFOX-6+ Bevacizumab
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3547
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.736
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.374
         upper limit
    		 1.449
    Statistical analysis title
    		 Subgroup analysis: ECOG PS = 1
    Statistical analysis description
    The HR and 95% CI was estimated using Cox proportional hazards methodology.
    Comparison groups
    MEGF0444A + mFOLFOX-6 + Bevacizumab v Placebo + mFOLFOX-6+ Bevacizumab
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.141
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.728
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.827
         upper limit
    		 3.612
    Statistical analysis title
    		 Subgroup analysis: Adjuvant therapy = No
    Statistical analysis description
    The HR and 95% CI was estimated using Cox proportional hazards methodology.
    Comparison groups
    MEGF0444A + mFOLFOX-6 + Bevacizumab v Placebo + mFOLFOX-6+ Bevacizumab
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5021
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.194
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.713
         upper limit
    		 2.001
    Statistical analysis title
    		 Subgroup analysis: Adjuvant therapy = Yes
    Statistical analysis description
    The HR and 95% CI was estimated using Cox proportional hazards methodology.
    Comparison groups
    MEGF0444A + mFOLFOX-6 + Bevacizumab v Placebo + mFOLFOX-6+ Bevacizumab
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7533
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.803
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.204
         upper limit
    		 3.159
    Statistical analysis title
    		 Subgroup analysis: One metastatic site
    Statistical analysis description
    The HR and 95% CI was estimated using Cox proportional hazards methodology.
    Comparison groups
    MEGF0444A + mFOLFOX-6 + Bevacizumab v Placebo + mFOLFOX-6+ Bevacizumab
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1893
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.764
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.753
         upper limit
    		 4.129
    Statistical analysis title
    		 Subgroup analysis: Two metastatic sites
    Statistical analysis description
    The HR and 95% CI was estimated using Cox proportional hazards methodology.
    Comparison groups
    MEGF0444A + mFOLFOX-6 + Bevacizumab v Placebo + mFOLFOX-6+ Bevacizumab
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7037
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.891
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.491
         upper limit
    		 1.617

    Secondary: Percentage of Participants with Objective Response According to RECIST v1.1

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    End point title
    		 Percentage of Participants with Objective Response According to RECIST v1.1 [7]
    End point description
    Objective response was defined as a complete response (CR) plus partial response (PR), as determined by the investigator using RECIST v1.1. CR was defined as disappearance of all target lesions and PR was defined as at least a 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum of diameters. Analysis population: All randomized participants with measurable disease at baseline.
    End point type
    Secondary
    End point timeframe
    Baseline until 20 months
    Notes
    [7] - 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: All the randomized participants were included in the end point analysis.
    End point values
    		 MEGF0444A + mFOLFOX-6 + Bevacizumab Placebo + mFOLFOX-6+ Bevacizumab
    Number of subjects analysed
    63
    63
    Units: percentage of participants
        number (confidence interval 95%)
    58.7 (45.6 to 71)
    63.5 (51.2 to 75.3)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Unstratified analysis.
    Comparison groups
    MEGF0444A + mFOLFOX-6 + Bevacizumab v Placebo + mFOLFOX-6+ Bevacizumab
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7149
    Method
    		 Logrank
    Parameter type
    		 Difference in objective response rate
    Point estimate
    -4.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21.8
         upper limit
    		 12.2

    Secondary: Duration of Objective Response

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    End point title
    		 Duration of Objective Response [8]
    End point description
    Duration of objective response was defined as the time from initial occurrence of complete response (CR) or partial response (PR), until documented disease progression using RECIST v1.1 as determined by investigator or death, whichever occurred first. CR was defined as disappearence of all target lesions, and PR was defined as at least a 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum of diameters in the absence of CR. Participants were censored at the date of last tumor assessment. Duration of response was not analyzed as Sponsor terminated study because of lack of efficacy.
    End point type
    Secondary
    End point timeframe
    Baseline until 20 months
    Notes
    [8] - 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: All the randomized participants were included in the end point analysis. However, duration of response was not analyzed as Sponsor terminated study because of lack of efficacy.
    End point values
    		 MEGF0444A + mFOLFOX-6 + Bevacizumab Placebo + mFOLFOX-6+ Bevacizumab
    Number of subjects analysed
    0 [9]
    0 [10]
    Units: months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [9] - Duration of response was not analyzed as Sponsor terminated study because of lack of efficacy.
    [10] - Duration of response was not analyzed as Sponsor terminated study because of lack of efficacy.
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS) [11]
    End point description
    OS is defined as the time from randomization until death from any cause. All deaths were included, without regard to whether they occur on study or following treatment discontinuation. For participants who did not die, OS was censored at the date of last contact. Analysis population: All randomized participants. '99999' signifies that data was not evaluable due to high number of censored participants.
    End point type
    Secondary
    End point timeframe
    Baseline until 20 months
    Notes
    [11] - 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: All the randomized participants were included in the end point analysis.
    End point values
    		 MEGF0444A + mFOLFOX-6 + Bevacizumab Placebo + mFOLFOX-6+ Bevacizumab
    Number of subjects analysed
    63
    64
    Units: months
        median (confidence interval 95%)
    19 (17.28 to 19)
    99999 (16.49 to 99999)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Unstratified analysis
    Comparison groups
    MEGF0444A + mFOLFOX-6 + Bevacizumab v Placebo + mFOLFOX-6+ Bevacizumab
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.943
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.973
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.456
         upper limit
    		 2.074
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    The HR and 95% CI was estimated using Cox proportional hazards methodology. The stratification factors used in the analysis were ECOG PS (0 vs 1), number of affected organs (1 vs >1), and adjuvant therapy (yes vs. no).
    Comparison groups
    MEGF0444A + mFOLFOX-6 + Bevacizumab v Placebo + mFOLFOX-6+ Bevacizumab
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6647
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.838
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.377
         upper limit
    		 1.864

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline until 3 years
    Adverse event reporting additional description
    Of 127 randomized participants, one participant was screen failure, and one participant was withdrawn prior to first treatment, and therefore 125 randomized participants who received at least one dose of study treatment were included in safety analysis.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    MEGF0444A + mFOLFOX-6 + Bevacizumab
    Reporting group description
    		 Participants received MEGF0444A at a fixed dose of 400 mg IV infusion, followed by bevacizumab 5 mg/kg, IV infusion, and then mFOLFOX-6 (consisting of oxaliplatin 85 mg/m^2 IV infusion, 400 mg/m^2 folinic acid IV infusion, and 400 mg/m^2 5-FU administered as an initial IV bolus and followed by continuous IV infusion of 2400 mg/m^2) on Day 1 of each 14-day cycle. After 8 cycles, oxaliplatin was stopped and MEGF0444A, bevacizumab, folinic acid, and 5-FU were continued until disease progression, or unacceptable toxicity for a maximum of 24 months (up to 52 cycles).

    Reporting group title
    Placebo + mFOLFOX-6+ Bevacizumab
    Reporting group description
    		 Participants received placebo matched to MEGF0444A at a fixed dose of 400 mg IV infusion, followed by bevacizumab 5 mg/kg, IV infusion, and then mFOLFOX-6 (consisting of oxaliplatin 85 mg/m^2 IV infusion, 400 mg/m^2 folinic acid IV infusion, and 400 mg/m^2 5-FU administered as an initial IV bolus and followed by continuous IV infusion of 2400 mg/m^2) on Day 1 of each 14-day cycle. After 8 cycles, oxaliplatin was stopped and placebo matched to MEGF0444A, bevacizumab, folinic acid, and 5-FU were continued until disease progression, or unacceptable toxicity for a maximum of 24 months (up to 52 cycles).

    Serious adverse events
    		 MEGF0444A + mFOLFOX-6 + Bevacizumab Placebo + mFOLFOX-6+ Bevacizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    24 / 63 (38.10%)
    24 / 62 (38.71%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
         subjects affected / exposed
    2 / 63 (3.17%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic neoplasm
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 63 (0.00%)
    3 / 62 (4.84%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device dislocation
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         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
    Pleuritic pain
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Body temperature increased
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thalamus haemorrhage
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 63 (0.00%)
    2 / 62 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Intestinal obstruction
         subjects affected / exposed
    1 / 63 (1.59%)
    2 / 62 (3.23%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 63 (0.00%)
    2 / 62 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 63 (1.59%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 63 (1.59%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Enterocutaneous fistula
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal stenosis
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal perforation
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic colitis
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary colic
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         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 / 63 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle haemorrhage
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (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
    Abdominal wall abscess
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis suppurative
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic infection
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumococcal sepsis
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative abscess
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         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
    1 / 63 (1.59%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 MEGF0444A + mFOLFOX-6 + Bevacizumab Placebo + mFOLFOX-6+ Bevacizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    62 / 63 (98.41%)
    62 / 62 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    18 / 63 (28.57%)
    21 / 62 (33.87%)
         occurrences all number
    27
    29
    Deep vein thrombosis
         subjects affected / exposed
    1 / 63 (1.59%)
    5 / 62 (8.06%)
         occurrences all number
    1
    5
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    31 / 63 (49.21%)
    28 / 62 (45.16%)
         occurrences all number
    60
    41
    Mucosal inflammation
         subjects affected / exposed
    24 / 63 (38.10%)
    29 / 62 (46.77%)
         occurrences all number
    44
    59
    Asthenia
         subjects affected / exposed
    24 / 63 (38.10%)
    18 / 62 (29.03%)
         occurrences all number
    45
    46
    Pyrexia
         subjects affected / exposed
    9 / 63 (14.29%)
    11 / 62 (17.74%)
         occurrences all number
    15
    15
    Temperature intolerance
         subjects affected / exposed
    7 / 63 (11.11%)
    5 / 62 (8.06%)
         occurrences all number
    8
    5
    Oedema peripheral
         subjects affected / exposed
    5 / 63 (7.94%)
    6 / 62 (9.68%)
         occurrences all number
    5
    9
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    28 / 63 (44.44%)
    25 / 62 (40.32%)
         occurrences all number
    50
    36
    Dysphonia
         subjects affected / exposed
    8 / 63 (12.70%)
    12 / 62 (19.35%)
         occurrences all number
    12
    18
    Dyspnoea
         subjects affected / exposed
    10 / 63 (15.87%)
    9 / 62 (14.52%)
         occurrences all number
    16
    17
    Rhinorrhoea
         subjects affected / exposed
    6 / 63 (9.52%)
    5 / 62 (8.06%)
         occurrences all number
    9
    7
    Oropharyngeal pain
         subjects affected / exposed
    4 / 63 (6.35%)
    6 / 62 (9.68%)
         occurrences all number
    5
    6
    Cough
         subjects affected / exposed
    6 / 63 (9.52%)
    2 / 62 (3.23%)
         occurrences all number
    6
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    10 / 63 (15.87%)
    9 / 62 (14.52%)
         occurrences all number
    10
    10
    Depression
         subjects affected / exposed
    3 / 63 (4.76%)
    6 / 62 (9.68%)
         occurrences all number
    7
    6
    Investigations
    Weight decreased
         subjects affected / exposed
    10 / 63 (15.87%)
    4 / 62 (6.45%)
         occurrences all number
    16
    4
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    4 / 63 (6.35%)
    1 / 62 (1.61%)
         occurrences all number
    5
    4
    Nervous system disorders
    Dysaesthesia
         subjects affected / exposed
    15 / 63 (23.81%)
    21 / 62 (33.87%)
         occurrences all number
    38
    44
    Neuropathy peripheral
         subjects affected / exposed
    17 / 63 (26.98%)
    18 / 62 (29.03%)
         occurrences all number
    23
    30
    Dysgeusia
         subjects affected / exposed
    17 / 63 (26.98%)
    16 / 62 (25.81%)
         occurrences all number
    31
    26
    Headache
         subjects affected / exposed
    15 / 63 (23.81%)
    14 / 62 (22.58%)
         occurrences all number
    22
    23
    Paraesthesia
         subjects affected / exposed
    10 / 63 (15.87%)
    9 / 62 (14.52%)
         occurrences all number
    13
    19
    Neurotoxicity
         subjects affected / exposed
    10 / 63 (15.87%)
    7 / 62 (11.29%)
         occurrences all number
    18
    14
    Dizziness
         subjects affected / exposed
    7 / 63 (11.11%)
    9 / 62 (14.52%)
         occurrences all number
    8
    11
    Peripheral sensory neuropathy
         subjects affected / exposed
    8 / 63 (12.70%)
    8 / 62 (12.90%)
         occurrences all number
    11
    11
    Polyneuropathy
         subjects affected / exposed
    8 / 63 (12.70%)
    7 / 62 (11.29%)
         occurrences all number
    25
    16
    Hypoaesthesia
         subjects affected / exposed
    5 / 63 (7.94%)
    4 / 62 (6.45%)
         occurrences all number
    7
    4
    Lethargy
         subjects affected / exposed
    2 / 63 (3.17%)
    5 / 62 (8.06%)
         occurrences all number
    3
    9
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    18 / 63 (28.57%)
    20 / 62 (32.26%)
         occurrences all number
    28
    30
    Anaemia
         subjects affected / exposed
    8 / 63 (12.70%)
    10 / 62 (16.13%)
         occurrences all number
    14
    15
    Thrombocytopenia
         subjects affected / exposed
    4 / 63 (6.35%)
    3 / 62 (4.84%)
         occurrences all number
    8
    5
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    5 / 63 (7.94%)
    3 / 62 (4.84%)
         occurrences all number
    5
    3
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    43 / 63 (68.25%)
    39 / 62 (62.90%)
         occurrences all number
    92
    96
    Nausea
         subjects affected / exposed
    40 / 63 (63.49%)
    41 / 62 (66.13%)
         occurrences all number
    72
    81
    Constipation
         subjects affected / exposed
    23 / 63 (36.51%)
    27 / 62 (43.55%)
         occurrences all number
    48
    45
    Vomiting
         subjects affected / exposed
    21 / 63 (33.33%)
    18 / 62 (29.03%)
         occurrences all number
    43
    39
    Abdominal pain
         subjects affected / exposed
    18 / 63 (28.57%)
    17 / 62 (27.42%)
         occurrences all number
    23
    24
    Stomatitis
         subjects affected / exposed
    14 / 63 (22.22%)
    14 / 62 (22.58%)
         occurrences all number
    24
    30
    Abdominal pain upper
         subjects affected / exposed
    11 / 63 (17.46%)
    12 / 62 (19.35%)
         occurrences all number
    20
    19
    Dyspepsia
         subjects affected / exposed
    6 / 63 (9.52%)
    9 / 62 (14.52%)
         occurrences all number
    6
    12
    Gastrooesophagial reflux disease
         subjects affected / exposed
    4 / 63 (6.35%)
    5 / 62 (8.06%)
         occurrences all number
    5
    5
    Oral pain
         subjects affected / exposed
    4 / 63 (6.35%)
    5 / 62 (8.06%)
         occurrences all number
    4
    5
    Gingival bleeding
         subjects affected / exposed
    3 / 63 (4.76%)
    5 / 62 (8.06%)
         occurrences all number
    7
    8
    Toothache
         subjects affected / exposed
    4 / 63 (6.35%)
    4 / 62 (6.45%)
         occurrences all number
    5
    7
    Abdominal distension
         subjects affected / exposed
    5 / 63 (7.94%)
    1 / 62 (1.61%)
         occurrences all number
    5
    1
    Haemorrhoids
         subjects affected / exposed
    5 / 63 (7.94%)
    1 / 62 (1.61%)
         occurrences all number
    6
    1
    Proctalgia
         subjects affected / exposed
    4 / 63 (6.35%)
    2 / 62 (3.23%)
         occurrences all number
    4
    5
    Flatulence
         subjects affected / exposed
    1 / 63 (1.59%)
    4 / 62 (6.45%)
         occurrences all number
    1
    4
    Rectal haemorrhage
         subjects affected / exposed
    4 / 63 (6.35%)
    0 / 62 (0.00%)
         occurrences all number
    4
    0
    Skin and subcutaneous tissue disorders
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    8 / 63 (12.70%)
    13 / 62 (20.97%)
         occurrences all number
    16
    23
    Rash
         subjects affected / exposed
    8 / 63 (12.70%)
    13 / 62 (20.97%)
         occurrences all number
    14
    20
    Alopecia
         subjects affected / exposed
    9 / 63 (14.29%)
    9 / 62 (14.52%)
         occurrences all number
    12
    12
    Dry skin
         subjects affected / exposed
    9 / 63 (14.29%)
    6 / 62 (9.68%)
         occurrences all number
    11
    6
    Nail disorder
         subjects affected / exposed
    6 / 63 (9.52%)
    4 / 62 (6.45%)
         occurrences all number
    6
    7
    Pruritus
         subjects affected / exposed
    4 / 63 (6.35%)
    5 / 62 (8.06%)
         occurrences all number
    5
    5
    Skin hyperpigmentation
         subjects affected / exposed
    7 / 63 (11.11%)
    3 / 62 (4.84%)
         occurrences all number
    7
    3
    Rash erythematous
         subjects affected / exposed
    1 / 63 (1.59%)
    4 / 62 (6.45%)
         occurrences all number
    2
    4
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    7 / 63 (11.11%)
    10 / 62 (16.13%)
         occurrences all number
    10
    11
    Dysuria
         subjects affected / exposed
    5 / 63 (7.94%)
    6 / 62 (9.68%)
         occurrences all number
    5
    7
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    12 / 63 (19.05%)
    10 / 62 (16.13%)
         occurrences all number
    13
    11
    Back pain
         subjects affected / exposed
    11 / 63 (17.46%)
    10 / 62 (16.13%)
         occurrences all number
    16
    15
    Pain in extremity
         subjects affected / exposed
    6 / 63 (9.52%)
    10 / 62 (16.13%)
         occurrences all number
    6
    12
    Musculoskeletal pain
         subjects affected / exposed
    6 / 63 (9.52%)
    8 / 62 (12.90%)
         occurrences all number
    6
    9
    Muscle spasms
         subjects affected / exposed
    5 / 63 (7.94%)
    4 / 62 (6.45%)
         occurrences all number
    7
    6
    Myalgia
         subjects affected / exposed
    6 / 63 (9.52%)
    3 / 62 (4.84%)
         occurrences all number
    7
    5
    Pain in jaw
         subjects affected / exposed
    3 / 63 (4.76%)
    4 / 62 (6.45%)
         occurrences all number
    3
    5
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 63 (9.52%)
    11 / 62 (17.74%)
         occurrences all number
    7
    15
    Urinary tract infection
         subjects affected / exposed
    8 / 63 (12.70%)
    9 / 62 (14.52%)
         occurrences all number
    11
    11
    Nasopharyngitis
         subjects affected / exposed
    11 / 63 (17.46%)
    4 / 62 (6.45%)
         occurrences all number
    13
    6
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    18 / 63 (28.57%)
    24 / 62 (38.71%)
         occurrences all number
    36
    32
    Hypokalemia
         subjects affected / exposed
    5 / 63 (7.94%)
    6 / 62 (9.68%)
         occurrences all number
    6
    7
    Hypomagnesaemia
         subjects affected / exposed
    5 / 63 (7.94%)
    1 / 62 (1.61%)
         occurrences all number
    6
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Oct 2011
    - Clarified several aspects of study conduct and background; - FOLFOX dose modification schema for participants experiencing hematologic toxicity was modified to reflect prevailing practices; -The use of head computed tomography or brain magnetic resonance imaging was pertained only to participants with suspected central nervous system metastases or carcinomatous meningitis.
    18 Sep 2012
    - Included new unplanned safety data from Study MEF4984g (a Phase II study of MEGF0444A, bevacizumab, and carboplatin/paclitaxel chemotherapy in advanced non-small cell lung cancer participants) and from the current Study MEF4982g. As a result of these analyses, any Grade greater than or equal to (>=) 3 bleeding adverse event was reported within 24 hours as a protocol-defined adverse event of special interest. Concomitant use of non-steroidal anti-inflammatory drugs was discouraged; - Included clinical safety and efficacy updates from the Phase 1 studies of MEGFO444A; - Included the required use of in-line filter for administration of MEGF0444A.
    21 Apr 2013
    - The Sponsor's plan to perform an interim analysis was added. The interim analysis was intended to provide a preliminary assessment of the activity of study regimen and not to terminate the trial if efficacy results appeared favourable; - The amendment clarified that only participants who discontinued study treatment for reasons other than disease progression continued tumor assessments until documentation of progressive disease, initiation of another anti-cancer therapy, withdrawal of consent, or death.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The protocol-specified primary analysis demonstrated no evidence of efficacy; and the Sponsor terminated the study.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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