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    Clinical Trial Results:
    A Phase II, Multicenter, Randomized, Double-Blind Study to Evaluate the Efficacy and Safety of RO5520985 (Vanucizumab) Plus FOLFOX Versus Bevacizumab Plus FOLFOX in Patients With Previously Untreated Metastatic Colorectal Cancer

    Summary
    EudraCT number
    		 2013-005108-32
    Trial protocol
    		 BE   AT   ES   IT   GB  
    Global end of trial date
    01 Feb 2017

    Results information
    Results version number
    		 v1
    This version publication date
    29 Jul 2017
    First version publication date
    29 Jul 2017
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    BP29262
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02141295
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche Ltd
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, 4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    29 Jul 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Jul 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Feb 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of Study BP29262 is to estimate the efficacy of RO5520985 in combination with oxaliplatin, folinic acid, and 5 fluorouracil (mFOLFOX-6) vs. bevacizumab in combination with mFOLFOX-6, as measured by progression-free survival (PFS).
    Protection of trial subjects
    This study was fully adhered to the principles outlined in “Guideline for Good Clinical Practice” International Conference on Harmonization (ICH) Tripartite Guideline (January 1997) or with local law.
    Background therapy
    		 mFOLFOX Both arms received mFOLFOX as background therapy. In the induction therapy, participants received oxaliplatin at a dose of 85 mg/m^2 as IV infusion; folinic acid at a dose of 400 mg/m^2 as IV infusion; and 5-FU at a dose of 400 mg/m^2 as starting IV bolus followed by 2400 mg/m^2 as IV infusion every 2 weeks for up to 8 cycles (approximately 4 months). Subsequently, in the maintenance therapy participants received folinic acid at a dose of 400 mg/m^2 as IV infusion; and 5-FU at a dose of 400 mg/m^2 as starting IV bolus followed by 2400 mg/m^2 as IV infusion every 2 weeks until disease progression, unacceptable toxicities, consent withdrawal or Investigator's decision for a maximum of 24 months.
    Evidence for comparator
    		 Bevacizumab
    Actual start date of recruitment
    30 Jun 2014
    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
    Spain: 105
    Country: Number of subjects enrolled
    United Kingdom: 7
    Country: Number of subjects enrolled
    Austria: 5
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    United States: 59
    Country: Number of subjects enrolled
    Australia: 5
    Worldwide total number of subjects
    189
    EEA total number of subjects
    125
    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)
    101
    From 65 to 84 years
    88
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Participants with previously untreated metastatic colorectal cancer (mCRC) as defined by RECIST v1.1 were enrolled globally from 7 countries.

    Period 1
    Period 1 title
    Overall study (part 2) (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
    		 Vanucizumab + mFOLFOX-6
    Arm description
    		 In the induction therapy participants received vanucizumab at a dose of 2000 mg as IV infusion; oxaliplatin at a dose of 85 mg/m^2 as IV infusion; folinic acid at a dose of 400 mg/m^2 as IV infusion; and 5-FU at a dose of 400 mg/m^2 as starting IV bolus followed by 2400 mg/m^2 as IV infusion every 2 weeks for up to 8 cycles (approximately 4 months). Subsequently, in the maintenance therapy participants received vanucizumab at a dose of 2000 mg as IV infusion; folinic acid at a dose of 400 mg/m^2 as IV infusion; and 5-FU at a dose of 400 mg/m^2 as starting IV bolus followed by 2400 mg/m^2 as IV infusion every 2 weeks until disease progression, unacceptable toxicities, consent withdrawal or Investigator's decision for a maximum of 24 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vanucizumab
    Investigational medicinal product code
    Other name
    RO5520985
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    2000 mg as IV infusion

    Investigational medicinal product name
    Oxaliplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    85 mg/m^2 as IV infusion

    Investigational medicinal product name
    5-FU
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    400 mg/m^2 as starting IV bolus followed by 2400 mg/m^2 as IV infusion

    Investigational medicinal product name
    Folinic acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    400 mg/m^2 as IV infusion

    Arm title
    		 Bevacizumab + mFOLFOX-6
    Arm description
    		 In the induction therapy participants received bevacizumab at a dose of 5 milligram per kilogram (mg/kg) as IV infusion; oxaliplatin at a dose of 85 mg/m^2 as IV infusion; folinic acid at a dose of 400 mg/m^2 as IV infusion; and 5-FU at a dose of 400 mg/m^2 as starting IV bolus followed by 2400 mg/m^2 as IV infusion every 2 weeks for up to 8 cycles (approximately 4 months). Subsequently, in the maintenance therapy participants received bevacizumab at a dose of 5 milligram per kilogram (mg/kg) as IV infusion; folinic acid at a dose of 400 mg/m^2 as IV infusion; and 5-FU at a dose of 400 mg/m^2 as starting IV bolus followed by 2400 mg/m^2 as IV infusion every 2 weeks until disease progression, unacceptable toxicities, consent withdrawal or Investigator's decision for a maximum of 24 months.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 milligram per kilogram (mg/kg) as IV infusion

    Investigational medicinal product name
    Oxaliplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    85 mg/m^2 as IV infusion

    Investigational medicinal product name
    5-FU
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    400 mg/m^2 as starting IV bolus followed by 2400 mg/m^2 as IV infusion

    Investigational medicinal product name
    Folinic acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    400 mg/m^2 as IV infusion

    Number of subjects in period 1
    		Vanucizumab + mFOLFOX-6 Bevacizumab + mFOLFOX-6
    Started
    94
    95
    Completed
    17
    21
    Not completed
    77
    74
         Physician decision
    17
    12
         Consent withdrawn by subject
    9
    4
         Adverse event, non-fatal
    16
    10
         TBC
    5
    9
         Non-compliance
    1
    -
         Study terminated by sponsor
    -
    1
         Progressive disease
    29
    38

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Vanucizumab + mFOLFOX-6
    Reporting group description
    		 In the induction therapy participants received vanucizumab at a dose of 2000 mg as IV infusion; oxaliplatin at a dose of 85 mg/m^2 as IV infusion; folinic acid at a dose of 400 mg/m^2 as IV infusion; and 5-FU at a dose of 400 mg/m^2 as starting IV bolus followed by 2400 mg/m^2 as IV infusion every 2 weeks for up to 8 cycles (approximately 4 months). Subsequently, in the maintenance therapy participants received vanucizumab at a dose of 2000 mg as IV infusion; folinic acid at a dose of 400 mg/m^2 as IV infusion; and 5-FU at a dose of 400 mg/m^2 as starting IV bolus followed by 2400 mg/m^2 as IV infusion every 2 weeks until disease progression, unacceptable toxicities, consent withdrawal or Investigator's decision for a maximum of 24 months.

    Reporting group title
    Bevacizumab + mFOLFOX-6
    Reporting group description
    		 In the induction therapy participants received bevacizumab at a dose of 5 milligram per kilogram (mg/kg) as IV infusion; oxaliplatin at a dose of 85 mg/m^2 as IV infusion; folinic acid at a dose of 400 mg/m^2 as IV infusion; and 5-FU at a dose of 400 mg/m^2 as starting IV bolus followed by 2400 mg/m^2 as IV infusion every 2 weeks for up to 8 cycles (approximately 4 months). Subsequently, in the maintenance therapy participants received bevacizumab at a dose of 5 milligram per kilogram (mg/kg) as IV infusion; folinic acid at a dose of 400 mg/m^2 as IV infusion; and 5-FU at a dose of 400 mg/m^2 as starting IV bolus followed by 2400 mg/m^2 as IV infusion every 2 weeks until disease progression, unacceptable toxicities, consent withdrawal or Investigator's decision for a maximum of 24 months.

    Reporting group values
    		 Vanucizumab + mFOLFOX-6 Bevacizumab + mFOLFOX-6 Total
    Number of subjects
    		 94 95 189
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    		 48 53 101
        From 65-84 years
    		 46 42 88
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.7 ± 11 62.3 ± 10.6 -
    Gender Categorical
    Units: Subjects
        Female
    		 38 57 95
        Male
    		 56 38 94
    Subject analysis sets

    Subject analysis set title
    Safety run-in (part 1)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    8 eligible participants received 2000 milligrams (mg) vanucizumab + mFOLFOX-6 every two weeks for up to 8 cycles in order to confirm the dose and schedule for the overall study.

    Subject analysis sets values
    		 Safety run-in (part 1)
    Number of subjects
    8
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    4
        From 65-84 years
    4
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    63.3 ± 10.8
    Gender Categorical
    Units: Subjects
        Female
    3
        Male
    5

    End points

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    End points reporting groups
    Reporting group title
    Vanucizumab + mFOLFOX-6
    Reporting group description
    		 In the induction therapy participants received vanucizumab at a dose of 2000 mg as IV infusion; oxaliplatin at a dose of 85 mg/m^2 as IV infusion; folinic acid at a dose of 400 mg/m^2 as IV infusion; and 5-FU at a dose of 400 mg/m^2 as starting IV bolus followed by 2400 mg/m^2 as IV infusion every 2 weeks for up to 8 cycles (approximately 4 months). Subsequently, in the maintenance therapy participants received vanucizumab at a dose of 2000 mg as IV infusion; folinic acid at a dose of 400 mg/m^2 as IV infusion; and 5-FU at a dose of 400 mg/m^2 as starting IV bolus followed by 2400 mg/m^2 as IV infusion every 2 weeks until disease progression, unacceptable toxicities, consent withdrawal or Investigator's decision for a maximum of 24 months.

    Reporting group title
    Bevacizumab + mFOLFOX-6
    Reporting group description
    		 In the induction therapy participants received bevacizumab at a dose of 5 milligram per kilogram (mg/kg) as IV infusion; oxaliplatin at a dose of 85 mg/m^2 as IV infusion; folinic acid at a dose of 400 mg/m^2 as IV infusion; and 5-FU at a dose of 400 mg/m^2 as starting IV bolus followed by 2400 mg/m^2 as IV infusion every 2 weeks for up to 8 cycles (approximately 4 months). Subsequently, in the maintenance therapy participants received bevacizumab at a dose of 5 milligram per kilogram (mg/kg) as IV infusion; folinic acid at a dose of 400 mg/m^2 as IV infusion; and 5-FU at a dose of 400 mg/m^2 as starting IV bolus followed by 2400 mg/m^2 as IV infusion every 2 weeks until disease progression, unacceptable toxicities, consent withdrawal or Investigator's decision for a maximum of 24 months.

    Subject analysis set title
    Safety run-in (part 1)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    8 eligible participants received 2000 milligrams (mg) vanucizumab + mFOLFOX-6 every two weeks for up to 8 cycles in order to confirm the dose and schedule for the overall study.

    Primary: Progression-free Survival (PFS), time to event

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    End point title
    		 Progression-free Survival (PFS), time to event
    End point description
    Efficacy of vanucizumab was evaluated in terms of PFS as Investigator-Assessed Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1).
    End point type
    Primary
    End point timeframe
    Baseline, every 8 weeks, up to approximately 29 months
    End point values
    		 Vanucizumab + mFOLFOX-6 Bevacizumab + mFOLFOX-6
    Number of subjects analysed
    94
    95
    Units: Number of days
        median (confidence interval 95%)
    343 (304 to 386)
    333 (263 to 388)
    Statistical analysis title
    		 Stratified analysis (metastatic sites from IVRS)
    Statistical analysis description
    Kaplan-Meier methods were used to estimate median PFS for each treatment arm and the 95% CIs for median PFS were computed using the Brookmeyer and Crowley method. The stratified Cox proportional hazard was used to estimate the hazard ratio (i.e., the magnitude of the treatment effect) and the corresponding 95% confidence interval. The stratification factors are number of metastatic sites (1 vs. >1) and country/region (USA vs rest of the world).
    Comparison groups
    Bevacizumab + mFOLFOX-6 v Vanucizumab + mFOLFOX-6
    Number of subjects included in analysis
    189
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7581 [1]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 1.44
    Notes
    [1] - log-rank

    Secondary: Percentage of Participants With Objective Response (ORR) as Assessed Using RECIST v. 1.1

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    End point title
    		 Percentage of Participants With Objective Response (ORR) as Assessed Using RECIST v. 1.1
    End point description
    Efficacy of vanucizumab was evaluated in terms of Percentage of Participants With ORR as Investigator-Assessed Using RECIST v. 1.1. Best Overall Confirmed Response.
    End point type
    Secondary
    End point timeframe
    Baseline (within 28 days prior to Day 1), then every 8 weeks until progressive disease (PD), start of other anticancer therapy, withdrawal of consent, or death (up to approximately 29 months)
    End point values
    		 Vanucizumab + mFOLFOX-6 Bevacizumab + mFOLFOX-6
    Number of subjects analysed
    94
    95
    Units: Percentage of participants
    number (confidence interval 95%)
        Responders, total
    41.5 (31.53 to 51.45)
    45.3 (35.25 to 55.27)
        Complete response (CR)
    0 (0 to 3.85)
    3.2 (0.66 to 8.95)
        Partial response (PR)
    41.5 (31.41 to 52.12)
    42.1 (32.04 to 52.67)
    No statistical analyses for this end point

    Secondary: Duration of Objective Response, as Assessed Using RECIST v. 1.1

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    End point title
    		 Duration of Objective Response, as Assessed Using RECIST v. 1.1
    End point description
    Efficacy of vanucizumab was evaluated in terms of duration of objective response as assessed using RECIST v. 1.1. This was computed using the PFS definition with death on study (deaths that occurred outside the 30 days window from the last study treatment are excluded).
    End point type
    Secondary
    End point timeframe
    Baseline (within 28 days prior to Day 1), then every 8 weeks until PD, start of other anticancer therapy, withdrawal of consent, or death (up to approximately 29 months)
    End point values
    		 Vanucizumab + mFOLFOX-6 Bevacizumab + mFOLFOX-6
    Number of subjects analysed
    94
    95
    Units: days
        median (confidence interval 95%)
    282 (274 to 453)
    315 (220 to 392)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    Efficacy of vanucizumab was evaluated in terms of OS as the time from randomization until death from any cause. 99999 = data not estimable because there were only few deaths in both treatment arms (immature data).
    End point type
    Secondary
    End point timeframe
    Baseline until death from any cause (maximum up to approximately 3.5 years)
    End point values
    		 Vanucizumab + mFOLFOX-6 Bevacizumab + mFOLFOX-6
    Number of subjects analysed
    94
    95
    Units: days
        median (confidence interval 95%)
    622 (622 to 99999)
    630 (630 to 99999)
    Statistical analysis title
    		 Stratified analysis (metastatic sites from IVRS)
    Statistical analysis description
    Kaplan-Meier methods were used to estimate median OS for each treatment arm and the 95% CIs for median OS were computed using the Brookmeyer and Crowley method. The stratified Cox proportional hazard was used to estimate the hazard ratio (i.e., the magnitude of the treatment effect) and the corresponding 95% confidence interval. The stratification factors are number of metastatic sites (1 vs. >1) and country/region (USA vs rest of the world).
    Comparison groups
    Vanucizumab + mFOLFOX-6 v Bevacizumab + mFOLFOX-6
    Number of subjects included in analysis
    189
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.5626
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 1.6

    Secondary: Percentage of Participants With Adverse Events (AEs)

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    End point title
    		 Percentage of Participants With Adverse Events (AEs)
    End point description
    Safety is evaluated in terms of percentage of participants with at least one serious adverse event and percentage of participants with at least one adverse event.
    End point type
    Secondary
    End point timeframe
    Up to approximately 29 months
    End point values
    		 Vanucizumab + mFOLFOX-6 Bevacizumab + mFOLFOX-6 Safety run-in (part 1)
    Number of subjects analysed
    93
    95
    8
    Units: Percentage of participants
    number (not applicable)
        Serious Adverse events
    44.1
    42.1
    37.5
        Adverse events
    100
    100
    100
    No statistical analyses for this end point

    Secondary: Number of Participants With Human Anti-human Antibodies (HAHAs) Against Vanucizumab

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    End point title
    		 Number of Participants With Human Anti-human Antibodies (HAHAs) Against Vanucizumab [2]
    End point description
    Safety is evaluated in terms of number of participants with Human Anti-human Antibodies (HAHAs) Against Vanucizumab.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hours [hrs]) on Day 1 Cycle 1 (D1C1), D1C5, D1C9, D1C13 (cycle length=14 days), end of study (EoS, within 28 to 42 days after last dose, latest at 29 months)
    Notes
    [2] - 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: This end point was only evaluated in the arm where patients were administered Vanucizumab. Given that the immunogenicity of Bevacizumab is already known and well characterized, no immunogenicity was evaluated for Bevacizumab.
    End point values
    		 Vanucizumab + mFOLFOX-6 Safety run-in (part 1)
    Number of subjects analysed
    93
    8
    Units: Number of Participants
    1
    2
    No statistical analyses for this end point

    Secondary: Area Under the Plasma Concentration-Time Curve (AUC) of Vanucizumab

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    End point title
    		 Area Under the Plasma Concentration-Time Curve (AUC) of Vanucizumab [3]
    End point description
    PK profile of vanucizumab was evaluated in terms of AUC, values are reported for cycle 8 of part 1 (safety run-in) and part 2 of the study.
    End point type
    Secondary
    End point timeframe
    Part 1 (C1, C6), Part 2 (C1, C8): D1 (Pre-dose [0 hrs], EoI [at 0.5-1.5 hrs], 1, 2, 4 hrs post infusion start), D2, D4, D6, D8 (cycle length=14 days); Part 1 (C2 to C5, C7 to C8), Part 2 (C2 to C7): D1 (pre-dose, EoI), at PD/ EoS (latest at 29 months)
    Notes
    [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: This PK end point was only evaluated in the arm where patients were administered Vanucizumab. Given that the PK of Bevacizumab with chemotherapy is already known and well characterized, no PK end point were evaluated for Bevacizumab.
    End point values
    		 Vanucizumab + mFOLFOX-6 Safety run-in (part 1)
    Number of subjects analysed
    45
    3
    Units: hr*ug/ml
    geometric mean (geometric coefficient of variation)
        Cycle 8
    82100 ± 31.6
    112000 ± 11.2
    No statistical analyses for this end point

    Secondary: Maximum Observed Plasma Concentration (Cmax) of Vanucizumab

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    End point title
    		 Maximum Observed Plasma Concentration (Cmax) of Vanucizumab [4]
    End point description
    PK profile of vanucizumab was evaluated in terms of Cmax, values are reported for cycle 8 for both part 1 (safety run-in) and part 2 of the study.
    End point type
    Secondary
    End point timeframe
    Part 1 (C1, C6), Part 2 (C1, C8): D1 (Pre-dose [0 hrs], EoI [at 0.5-1.5 hrs], 1, 2, 4 hrs post infusion start), D2, D4, D6, D8 (cycle length=14 days); Part 1 (C2 to C5, C7 to C8), Part 2 (C2 to C7): D1 (pre-dose, EoI), at PD/ EoS (latest at 29 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: This PK end point was only evaluated in the arm where patients were administered Vanucizumab. Given that the PK of Bevacizumab with chemotherapy is already known and well characterized, no PK end point were evaluated for Bevacizumab.
    End point values
    		 Vanucizumab + mFOLFOX-6 Safety run-in (part 1)
    Number of subjects analysed
    64
    6
    Units: ug/ml
        geometric mean (geometric coefficient of variation)
    794 ± 38.2
    685 ± 17.6
    No statistical analyses for this end point

    Secondary: Minimum Observed Plasma Concentration (Clast) of Vanucizumab

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    End point title
    		 Minimum Observed Plasma Concentration (Clast) of Vanucizumab [5]
    End point description
    PK profile of vanucizumab was evaluated in terms of Clast, values are reported for cycle 8 of both part 1 (safety run-in) and part 2 of the study.
    End point type
    Secondary
    End point timeframe
    Part 1 (C1, C6), Part 2 (C1, C8): D1 (Pre-dose [0 hrs]), D2, D4, D6, D8 (cycle length=14 days); Part 1 (C2 to C5, C7 to C8), Part 2 (C2 to C7): D1 (pre-dose), at PD/ EoS (latest at 29 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: This PK end point was only evaluated in the arm where patients were administered Vanucizumab. Given that the PK of Bevacizumab with chemotherapy is already known and well characterized, no PK end point were evaluated for Bevacizumab.
    End point values
    		 Vanucizumab + mFOLFOX-6
    Number of subjects analysed
    64
    Units: ug/ml
    geometric mean (geometric coefficient of variation)
        Cycle 8
    361 ± 39.8
    No statistical analyses for this end point

    Secondary: Time to Reach Cmax (Tmax) of Vanucizumab

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    End point title
    		 Time to Reach Cmax (Tmax) of Vanucizumab [6]
    End point description
    PK profile of vanucizumab was evaluated in terms of Tmax for cycles 8 for both part 1 (safety run-in) and part 2 of the study.
    End point type
    Secondary
    End point timeframe
    Part 1 (C1, C6), Part 2 (C1, C8): D1 (Pre-dose [0 hrs], EoI [at 0.5-1.5 hrs], 1, 2, 4 hrs post infusion start), D2, D4, D6, D8 (cycle length=14 days); Part 1 (C2 to C5, C7 to C8), Part 2 (C2 to C7): D1 (pre-dose, EoI), at PD/ EoS (latest at 29 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: This PK end point was only evaluated in the arm where patients were administered Vanucizumab. Given that the PK of Bevacizumab with chemotherapy is already known and well characterized, no PK end point were evaluated for Bevacizumab.
    End point values
    		 Vanucizumab + mFOLFOX-6 Safety run-in (part 1)
    Number of subjects analysed
    64
    6
    Units: hr
    median (full range (min-max))
        Cycle 8
    1.58 (0.5 to 4.77)
    4.04 (0.5 to 5.25)
    No statistical analyses for this end point

    Secondary: Plasma Terminal Half-Life (t1/2) of Vanucizumab

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    End point title
    		 Plasma Terminal Half-Life (t1/2) of Vanucizumab [7]
    End point description
    PK profile of vanucizumab was evaluated in terms of t1/2, values are reported for cycle 8 of both part 1 (safety run-in) and part 2 of the study.
    End point type
    Secondary
    End point timeframe
    Part 1 (C1, C6), Part 2 (C1, C8): D1 (Pre-dose [0 hrs], EoI [at 0.5-1.5 hrs], 1, 2, 4 hrs post infusion start), D2, D4, D6, D8 (cycle length=14 days); Part 1 (C2 to C5, C7 to C8), Part 2 (C2 to C7): D1 (pre-dose, EoI), at PD/ EoS (latest at 29 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: This PK end point was only evaluated in the arm where patients were administered Vanucizumab. Given that the PK of Bevacizumab with chemotherapy is already known and well characterized, no PK end point were evaluated for Bevacizumab.
    End point values
    		 Vanucizumab + mFOLFOX-6 Safety run-in (part 1)
    Number of subjects analysed
    37
    3
    Units: hr
        geometric mean (geometric coefficient of variation)
    157 ± 30.3
    202 ± 12.4
    No statistical analyses for this end point

    Secondary: Plasma Clearance at Steady State (CLss) of Vanucizumab

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    End point title
    		 Plasma Clearance at Steady State (CLss) of Vanucizumab [8]
    End point description
    PK profile of vanucizumab was evaluated in terms of CLss, values are reported for cycle 8 of both part 1 (safety run-in) and part 2 of the study.
    End point type
    Secondary
    End point timeframe
    Part 1 (C1, C6), Part 2 (C1, C8): D1 (Pre-dose [0 hrs], EoI [at 0.5-1.5 hrs], 1, 2, 4 hrs post infusion start), D2, D4, D6, D8 (cycle length=14 days); Part 1 (C2 to C5, C7 to C8), Part 2 (C2 to C7): D1 (pre-dose, EoI), at PD/ EoS (latest at 29 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: This PK end point was only evaluated in the arm where patients were administered Vanucizumab. Given that the PK of Bevacizumab with chemotherapy is already known and well characterized, no PK end point were evaluated for Bevacizumab.
    End point values
    		 Vanucizumab + mFOLFOX-6 Safety run-in (part 1)
    Number of subjects analysed
    37
    3
    Units: ml/hr
        geometric mean (geometric coefficient of variation)
    18 ± 29
    15.3 ± 26.7
    No statistical analyses for this end point

    Secondary: Volume of Distribution at Steady State (Vss) of Vanucizumab

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    End point title
    		 Volume of Distribution at Steady State (Vss) of Vanucizumab [9]
    End point description
    PK profile of vanucizumab was evaluated in terms of Vss, values are reported for cycle 8 of both part 1 (safety run-in) and part 2 of the study.
    End point type
    Secondary
    End point timeframe
    Part 1 (C1, C6), Part 2 (C1, C8): D1 (Pre-dose [0 hrs], EoI [at 0.5-1.5 hrs], 1, 2, 4 hrs post infusion start), D2, D4, D6, D8 (cycle length=14 days); Part 1 (C2 to C5, C7 to C8), Part 2 (C2 to C7): D1 (pre-dose, EoI), at PD/ EoS (latest at 29 months)
    Notes
    [9] - 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: This PK end point was only evaluated in the arm where patients were administered Vanucizumab. Given that the PK of Bevacizumab with chemotherapy is already known and well characterized, no PK end point were evaluated for Bevacizumab.
    End point values
    		 Vanucizumab + mFOLFOX-6 Safety run-in (part 1)
    Number of subjects analysed
    37
    3
    Units: ml
        geometric mean (geometric coefficient of variation)
    4140 ± 29.7
    4400 ± 25.1
    No statistical analyses for this end point

    Secondary: Cmax Accumulation Ratio (AR) of Vanucizumab

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    End point title
    		 Cmax Accumulation Ratio (AR) of Vanucizumab [10]
    End point description
    PK profile of vanucizumab was evaluated in terms of Cmax Ratio, values are reported for cycle 8 of both part 1 (safety run-in) and part 2 of the study.
    End point type
    Secondary
    End point timeframe
    Part 1 (C1, C6), Part 2 (C1, C8): D1 (Pre-dose [0 hrs], EoI [at 0.5-1.5 hrs], 1, 2, 4 hrs post infusion start), D2, D4, D6, D8 (cycle length=14 days); Part 1 (C2 to C5, C7 to C8), Part 2 (C2 to C7): D1 (pre-dose, EoI), at PD/ EoS (latest at 29 months)
    Notes
    [10] - 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: This PK end point was only evaluated in the arm where patients were administered Vanucizumab. Given that the PK of Bevacizumab with chemotherapy is already known and well characterized, no PK end point were evaluated for Bevacizumab.
    End point values
    		 Vanucizumab + mFOLFOX-6 Safety run-in (part 1)
    Number of subjects analysed
    64
    5
    Units: N/A
        geometric mean (geometric coefficient of variation)
    1.63 ± 36.2
    1.51 ± 27.2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 28 days after the last dose of study drug (maximum treatment time = approximately 29 months).
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Vanucizumab + mFOLFOX-6
    Reporting group description
    		 In the induction therapy participants received vanucizumab at a dose of 2000 mg as IV infusion; oxaliplatin at a dose of 85 mg/m^2 as IV infusion; folinic acid at a dose of 400 mg/m^2 as IV infusion; and 5-FU at a dose of 400 mg/m^2 as starting IV bolus followed by 2400 mg/m^2 as IV infusion every 2 weeks for up to 8 cycles (approximately 4 months). Subsequently, in the maintenance therapy participants received vanucizumab at a dose of 2000 mg as IV infusion; folinic acid at a dose of 400 mg/m^2 as IV infusion; and 5-FU at a dose of 400 mg/m^2 as starting IV bolus followed by 2400 mg/m^2 as IV infusion every 2 weeks until disease progression, unacceptable toxicities, consent withdrawal or Investigator's decision for a maximum of 24 months.

    Reporting group title
    Bevacizumab + mFOLFOX-6
    Reporting group description
    		 In the induction therapy participants received bevacizumab at a dose of 5 milligram per kilogram (mg/kg) as IV infusion; oxaliplatin at a dose of 85 mg/m^2 as IV infusion; folinic acid at a dose of 400 mg/m^2 as IV infusion; and 5-FU at a dose of 400 mg/m^2 as starting IV bolus followed by 2400 mg/m^2 as IV infusion every 2 weeks for up to 8 cycles (approximately 4 months). Subsequently, in the maintenance therapy participants received bevacizumab at a dose of 5 milligram per kilogram (mg/kg) as IV infusion; folinic acid at a dose of 400 mg/m^2 as IV infusion; and 5-FU at a dose of 400 mg/m^2 as starting IV bolus followed by 2400 mg/m^2 as IV infusion every 2 weeks until disease progression, unacceptable toxicities, consent withdrawal or Investigator's decision for a maximum of 24 months.

    Reporting group title
    Safety run-in
    Reporting group description
    		 8 eligible participants received 2000 milligrams (mg) vanucizumab + mFOLFOX-6 every two weeks for up to 8 cycles in order to confirm the dose and schedule for the overall study.

    Serious adverse events
    		 Vanucizumab + mFOLFOX-6 Bevacizumab + mFOLFOX-6 Safety run-in
    Total subjects affected by serious adverse events
         subjects affected / exposed
    41 / 93 (44.09%)
    40 / 95 (42.11%)
    3 / 8 (37.50%)
         number of deaths (all causes)
    16
    21
    3
         number of deaths resulting from adverse events
    0
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    INFECTED NEOPLASM
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 95 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumor obstruction
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 95 (1.05%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    AORTIC THROMBOSIS
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 95 (1.05%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 95 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    2 / 93 (2.15%)
    1 / 95 (1.05%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    VASOSPASM
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 95 (1.05%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 95 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COMPLICATION ASSOCIATED WITH DEVICE
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 95 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GENERAL PHYSICAL HEALTH DETERIORATION
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 95 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    NON−CARDIAC CHEST PAIN
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 95 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    OEDEMA PERIPHERAL
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 95 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 93 (4.30%)
    4 / 95 (4.21%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 95 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    FEMALE GENITAL TRACT FISTULA
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 95 (1.05%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    ACUTE RESPIRATORY FAILURE
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 95 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    EPISTAXIS
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 95 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PLEURAL EFFUSION
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 95 (1.05%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    2 / 93 (2.15%)
    0 / 95 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 95 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    DEVICE DISLOCATION
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 95 (1.05%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DEVICE OCCLUSION
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 95 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 95 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GASTROINTESTINAL ANASTOMOTIC LEAK
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 95 (1.05%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PELVIC FRACTURE
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 95 (1.05%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SPINAL FRACTURE
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 95 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    TOXICITY TO VARIOUS AGENTS
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 95 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 95 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 95 (1.05%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 95 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cardiac disorder
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 95 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 95 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 95 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial Ischaemia
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 95 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Guillain-Barre syndrome
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 95 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 95 (1.05%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SPINAL CORD COMPRESSION
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 95 (1.05%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    TRANSIENT ISCHAEMIC ATTACK
         subjects affected / exposed
    1 / 93 (1.08%)
    2 / 95 (2.11%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 95 (1.05%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile Neutropenia
         subjects affected / exposed
    0 / 93 (0.00%)
    5 / 95 (5.26%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 93 (1.08%)
    2 / 95 (2.11%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 95 (1.05%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 93 (1.08%)
    3 / 95 (3.16%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal ulcer
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 95 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 95 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 93 (1.08%)
    1 / 95 (1.05%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 93 (1.08%)
    3 / 95 (3.16%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 95 (1.05%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterovesical fistula
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 95 (1.05%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 95 (1.05%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal perforation
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 95 (1.05%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 95 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    2 / 93 (2.15%)
    3 / 95 (3.16%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    3 / 93 (3.23%)
    2 / 95 (2.11%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    1 / 93 (1.08%)
    1 / 95 (1.05%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    3 / 93 (3.23%)
    1 / 95 (1.05%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 95 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 95 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 95 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    3 / 93 (3.23%)
    1 / 95 (1.05%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 95 (1.05%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    BILE DUCT STONE
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 95 (1.05%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal colic
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 95 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 95 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 95 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    CERVICAL SPINAL STENOSIS
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 95 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PATHOLOGICAL FRACTURE
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 95 (1.05%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 95 (1.05%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DIARRHOEA INFECTIOUS
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 95 (1.05%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 95 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ENTEROCOCCAL BACTERAEMIA
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 95 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 93 (0.00%)
    2 / 95 (2.11%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 95 (1.05%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PYELONEPHRITIS ACUTE
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 95 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 95 (1.05%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 93 (0.00%)
    2 / 95 (2.11%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Splenic abscess
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 95 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 95 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 95 (1.05%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 93 (1.08%)
    4 / 95 (4.21%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 93 (1.08%)
    1 / 95 (1.05%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    FAILURE TO THRIVE
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 95 (1.05%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPOKALAEMIA
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 95 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Vanucizumab + mFOLFOX-6 Bevacizumab + mFOLFOX-6 Safety run-in
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    90 / 93 (96.77%)
    94 / 95 (98.95%)
    8 / 8 (100.00%)
    Vascular disorders
    Embolism venous
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 95 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Hypertension
         subjects affected / exposed
    41 / 93 (44.09%)
    26 / 95 (27.37%)
    5 / 8 (62.50%)
         occurrences all number
    65
    49
    9
    Hypotension
         subjects affected / exposed
    0 / 93 (0.00%)
    6 / 95 (6.32%)
    1 / 8 (12.50%)
         occurrences all number
    0
    6
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    40 / 93 (43.01%)
    42 / 95 (44.21%)
    3 / 8 (37.50%)
         occurrences all number
    90
    127
    6
    Chest discomfort
         subjects affected / exposed
    2 / 93 (2.15%)
    0 / 95 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    2
    0
    1
    Chest pain
         subjects affected / exposed
    5 / 93 (5.38%)
    3 / 95 (3.16%)
    0 / 8 (0.00%)
         occurrences all number
    5
    3
    0
    Fatigue
         subjects affected / exposed
    26 / 93 (27.96%)
    21 / 95 (22.11%)
    1 / 8 (12.50%)
         occurrences all number
    31
    25
    1
    Mass
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 95 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Mucosal inflammation
         subjects affected / exposed
    21 / 93 (22.58%)
    31 / 95 (32.63%)
    4 / 8 (50.00%)
         occurrences all number
    40
    66
    6
    Oedema peripheral
         subjects affected / exposed
    10 / 93 (10.75%)
    2 / 95 (2.11%)
    3 / 8 (37.50%)
         occurrences all number
    11
    2
    5
    Pyrexia
         subjects affected / exposed
    16 / 93 (17.20%)
    15 / 95 (15.79%)
    1 / 8 (12.50%)
         occurrences all number
    22
    21
    1
    Temperature intolerance
         subjects affected / exposed
    11 / 93 (11.83%)
    10 / 95 (10.53%)
    1 / 8 (12.50%)
         occurrences all number
    15
    16
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    10 / 93 (10.75%)
    9 / 95 (9.47%)
    1 / 8 (12.50%)
         occurrences all number
    12
    12
    1
    Dysphonia
         subjects affected / exposed
    12 / 93 (12.90%)
    9 / 95 (9.47%)
    1 / 8 (12.50%)
         occurrences all number
    12
    12
    2
    Dyspnoea
         subjects affected / exposed
    10 / 93 (10.75%)
    10 / 95 (10.53%)
    1 / 8 (12.50%)
         occurrences all number
    11
    12
    1
    Epistaxis
         subjects affected / exposed
    19 / 93 (20.43%)
    28 / 95 (29.47%)
    2 / 8 (25.00%)
         occurrences all number
    26
    36
    2
    Hiccups
         subjects affected / exposed
    4 / 93 (4.30%)
    2 / 95 (2.11%)
    1 / 8 (12.50%)
         occurrences all number
    4
    3
    1
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    3 / 93 (3.23%)
    6 / 95 (6.32%)
    1 / 8 (12.50%)
         occurrences all number
    3
    6
    1
    Rhinorrhoea
         subjects affected / exposed
    4 / 93 (4.30%)
    5 / 95 (5.26%)
    0 / 8 (0.00%)
         occurrences all number
    5
    5
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    9 / 93 (9.68%)
    8 / 95 (8.42%)
    1 / 8 (12.50%)
         occurrences all number
    9
    8
    1
    Depression
         subjects affected / exposed
    6 / 93 (6.45%)
    1 / 95 (1.05%)
    1 / 8 (12.50%)
         occurrences all number
    6
    1
    1
    Insomnia
         subjects affected / exposed
    11 / 93 (11.83%)
    12 / 95 (12.63%)
    0 / 8 (0.00%)
         occurrences all number
    11
    13
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 93 (3.23%)
    5 / 95 (5.26%)
    0 / 8 (0.00%)
         occurrences all number
    4
    5
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 93 (3.23%)
    7 / 95 (7.37%)
    0 / 8 (0.00%)
         occurrences all number
    7
    7
    0
    GAMMA−GLUTAMYLTRANSFERASE INCREASED
         subjects affected / exposed
    1 / 93 (1.08%)
    4 / 95 (4.21%)
    1 / 8 (12.50%)
         occurrences all number
    1
    5
    1
    Lipase increased
         subjects affected / exposed
    2 / 93 (2.15%)
    8 / 95 (8.42%)
    0 / 8 (0.00%)
         occurrences all number
    2
    8
    0
    Platelet count decreased
         subjects affected / exposed
    10 / 93 (10.75%)
    4 / 95 (4.21%)
    0 / 8 (0.00%)
         occurrences all number
    25
    6
    0
    Weight decreased
         subjects affected / exposed
    11 / 93 (11.83%)
    13 / 95 (13.68%)
    0 / 8 (0.00%)
         occurrences all number
    12
    13
    0
    Weight increased
         subjects affected / exposed
    4 / 93 (4.30%)
    2 / 95 (2.11%)
    1 / 8 (12.50%)
         occurrences all number
    4
    2
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    3 / 93 (3.23%)
    3 / 95 (3.16%)
    1 / 8 (12.50%)
         occurrences all number
    4
    3
    2
    Infusion related reaction
         subjects affected / exposed
    19 / 93 (20.43%)
    12 / 95 (12.63%)
    1 / 8 (12.50%)
         occurrences all number
    26
    17
    1
    Nervous system disorders
    Aphonia
         subjects affected / exposed
    5 / 93 (5.38%)
    2 / 95 (2.11%)
    0 / 8 (0.00%)
         occurrences all number
    5
    2
    0
    Dizziness
         subjects affected / exposed
    10 / 93 (10.75%)
    12 / 95 (12.63%)
    1 / 8 (12.50%)
         occurrences all number
    12
    17
    1
    Dysaesthesia
         subjects affected / exposed
    15 / 93 (16.13%)
    22 / 95 (23.16%)
    1 / 8 (12.50%)
         occurrences all number
    32
    79
    3
    Dysgeusia
         subjects affected / exposed
    16 / 93 (17.20%)
    22 / 95 (23.16%)
    5 / 8 (62.50%)
         occurrences all number
    16
    26
    6
    Headache
         subjects affected / exposed
    15 / 93 (16.13%)
    18 / 95 (18.95%)
    2 / 8 (25.00%)
         occurrences all number
    16
    29
    2
    Hypoaesthesia
         subjects affected / exposed
    0 / 93 (0.00%)
    3 / 95 (3.16%)
    1 / 8 (12.50%)
         occurrences all number
    0
    3
    2
    Neuropathy peripheral
         subjects affected / exposed
    16 / 93 (17.20%)
    26 / 95 (27.37%)
    3 / 8 (37.50%)
         occurrences all number
    29
    62
    8
    Neurotoxicity
         subjects affected / exposed
    8 / 93 (8.60%)
    2 / 95 (2.11%)
    0 / 8 (0.00%)
         occurrences all number
    14
    2
    0
    Paraesthesia
         subjects affected / exposed
    15 / 93 (16.13%)
    17 / 95 (17.89%)
    1 / 8 (12.50%)
         occurrences all number
    17
    24
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    32 / 93 (34.41%)
    27 / 95 (28.42%)
    2 / 8 (25.00%)
         occurrences all number
    79
    70
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 93 (6.45%)
    12 / 95 (12.63%)
    3 / 8 (37.50%)
         occurrences all number
    7
    19
    3
    Leukopenia
         subjects affected / exposed
    1 / 93 (1.08%)
    3 / 95 (3.16%)
    1 / 8 (12.50%)
         occurrences all number
    1
    3
    1
    Neutropenia
         subjects affected / exposed
    39 / 93 (41.94%)
    42 / 95 (44.21%)
    4 / 8 (50.00%)
         occurrences all number
    52
    63
    6
    Thrombocytopenia
         subjects affected / exposed
    4 / 93 (4.30%)
    8 / 95 (8.42%)
    3 / 8 (37.50%)
         occurrences all number
    6
    8
    4
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 95 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Eyelid oedema
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 95 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Lacrimation increase
         subjects affected / exposed
    4 / 93 (4.30%)
    5 / 95 (5.26%)
    2 / 8 (25.00%)
         occurrences all number
    5
    6
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    26 / 93 (27.96%)
    18 / 95 (18.95%)
    2 / 8 (25.00%)
         occurrences all number
    33
    19
    3
    Abdominal pain lower
         subjects affected / exposed
    7 / 93 (7.53%)
    3 / 95 (3.16%)
    0 / 8 (0.00%)
         occurrences all number
    8
    3
    0
    Abdominal pain upper
         subjects affected / exposed
    6 / 93 (6.45%)
    12 / 95 (12.63%)
    0 / 8 (0.00%)
         occurrences all number
    9
    12
    0
    Constipation
         subjects affected / exposed
    24 / 93 (25.81%)
    29 / 95 (30.53%)
    3 / 8 (37.50%)
         occurrences all number
    35
    48
    5
    Diarrhoea
         subjects affected / exposed
    54 / 93 (58.06%)
    54 / 95 (56.84%)
    6 / 8 (75.00%)
         occurrences all number
    102
    127
    8
    Dry mounth
         subjects affected / exposed
    4 / 93 (4.30%)
    5 / 95 (5.26%)
    0 / 8 (0.00%)
         occurrences all number
    4
    6
    0
    Dyspepsia
         subjects affected / exposed
    11 / 93 (11.83%)
    8 / 95 (8.42%)
    0 / 8 (0.00%)
         occurrences all number
    14
    12
    0
    Flatulence
         subjects affected / exposed
    5 / 93 (5.38%)
    2 / 95 (2.11%)
    0 / 8 (0.00%)
         occurrences all number
    6
    2
    0
    Gingival bleeding
         subjects affected / exposed
    0 / 93 (0.00%)
    3 / 95 (3.16%)
    1 / 8 (12.50%)
         occurrences all number
    0
    3
    1
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 95 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Hypoaesthesia oral
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 95 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Nausea
         subjects affected / exposed
    51 / 93 (54.84%)
    55 / 95 (57.89%)
    6 / 8 (75.00%)
         occurrences all number
    90
    98
    6
    Odynophagia
         subjects affected / exposed
    2 / 93 (2.15%)
    0 / 95 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    2
    0
    1
    Oral pain
         subjects affected / exposed
    6 / 93 (6.45%)
    1 / 95 (1.05%)
    0 / 8 (0.00%)
         occurrences all number
    6
    1
    0
    Proctalgia
         subjects affected / exposed
    1 / 93 (1.08%)
    3 / 95 (3.16%)
    1 / 8 (12.50%)
         occurrences all number
    2
    4
    1
    Rectal haemorrhage
         subjects affected / exposed
    3 / 93 (3.23%)
    4 / 95 (4.21%)
    1 / 8 (12.50%)
         occurrences all number
    3
    4
    1
    Stomatitis
         subjects affected / exposed
    15 / 93 (16.13%)
    11 / 95 (11.58%)
    1 / 8 (12.50%)
         occurrences all number
    23
    15
    1
    Vomiting
         subjects affected / exposed
    29 / 93 (31.18%)
    27 / 95 (28.42%)
    1 / 8 (12.50%)
         occurrences all number
    39
    45
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    5 / 93 (5.38%)
    14 / 95 (14.74%)
    1 / 8 (12.50%)
         occurrences all number
    5
    14
    1
    Nail disorder
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 95 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    1
    PALMAR−PLANTAR ERYTHRODYSAESTHESIA SYNDROME
         subjects affected / exposed
    7 / 93 (7.53%)
    15 / 95 (15.79%)
    2 / 8 (25.00%)
         occurrences all number
    12
    21
    2
    Rash
         subjects affected / exposed
    5 / 93 (5.38%)
    8 / 95 (8.42%)
    0 / 8 (0.00%)
         occurrences all number
    8
    10
    0
    Skin hyperpigmentation
         subjects affected / exposed
    4 / 93 (4.30%)
    4 / 95 (4.21%)
    2 / 8 (25.00%)
         occurrences all number
    5
    5
    2
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    5 / 93 (5.38%)
    6 / 95 (6.32%)
    0 / 8 (0.00%)
         occurrences all number
    5
    8
    0
    Proteinuria
         subjects affected / exposed
    11 / 93 (11.83%)
    9 / 95 (9.47%)
    1 / 8 (12.50%)
         occurrences all number
    14
    15
    5
    Urinary tract pain
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 95 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 93 (4.30%)
    8 / 95 (8.42%)
    2 / 8 (25.00%)
         occurrences all number
    4
    10
    4
    Back pain
         subjects affected / exposed
    8 / 93 (8.60%)
    14 / 95 (14.74%)
    1 / 8 (12.50%)
         occurrences all number
    9
    16
    1
    Bone pain
         subjects affected / exposed
    1 / 93 (1.08%)
    5 / 95 (5.26%)
    1 / 8 (12.50%)
         occurrences all number
    1
    6
    2
    Musculoskeletal pain
         subjects affected / exposed
    9 / 93 (9.68%)
    7 / 95 (7.37%)
    1 / 8 (12.50%)
         occurrences all number
    12
    9
    1
    Myalgia
         subjects affected / exposed
    8 / 93 (8.60%)
    7 / 95 (7.37%)
    0 / 8 (0.00%)
         occurrences all number
    11
    10
    0
    Pain in extremitiy
         subjects affected / exposed
    2 / 93 (2.15%)
    6 / 95 (6.32%)
    2 / 8 (25.00%)
         occurrences all number
    2
    7
    2
    Pain in jaw
         subjects affected / exposed
    6 / 93 (6.45%)
    2 / 95 (2.11%)
    0 / 8 (0.00%)
         occurrences all number
    6
    4
    0
    Infections and infestations
    Ear infection
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 95 (1.05%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    1
    Furuncle
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 95 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Gingivitis
         subjects affected / exposed
    4 / 93 (4.30%)
    2 / 95 (2.11%)
    1 / 8 (12.50%)
         occurrences all number
    4
    3
    1
    Nasopharyngitis
         subjects affected / exposed
    7 / 93 (7.53%)
    8 / 95 (8.42%)
    2 / 8 (25.00%)
         occurrences all number
    8
    11
    2
    Oral candidiasis
         subjects affected / exposed
    5 / 93 (5.38%)
    1 / 95 (1.05%)
    1 / 8 (12.50%)
         occurrences all number
    5
    2
    1
    Periodontitis
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 95 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Rhinitis
         subjects affected / exposed
    0 / 93 (0.00%)
    3 / 95 (3.16%)
    1 / 8 (12.50%)
         occurrences all number
    0
    3
    2
    Sinusitis
         subjects affected / exposed
    3 / 93 (3.23%)
    1 / 95 (1.05%)
    1 / 8 (12.50%)
         occurrences all number
    4
    1
    1
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 93 (2.15%)
    13 / 95 (13.68%)
    1 / 8 (12.50%)
         occurrences all number
    2
    14
    1
    Urinary tract infection
         subjects affected / exposed
    10 / 93 (10.75%)
    10 / 95 (10.53%)
    2 / 8 (25.00%)
         occurrences all number
    11
    13
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    28 / 93 (30.11%)
    32 / 95 (33.68%)
    1 / 8 (12.50%)
         occurrences all number
    44
    66
    3
    Dehydration
         subjects affected / exposed
    8 / 93 (8.60%)
    7 / 95 (7.37%)
    1 / 8 (12.50%)
         occurrences all number
    10
    7
    1
    Hyperglycaemia
         subjects affected / exposed
    0 / 93 (0.00%)
    6 / 95 (6.32%)
    0 / 8 (0.00%)
         occurrences all number
    0
    10
    0
    Hyperuricaemia
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 95 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Hypokalaemia
         subjects affected / exposed
    8 / 93 (8.60%)
    10 / 95 (10.53%)
    0 / 8 (0.00%)
         occurrences all number
    9
    10
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Apr 2014
    Amended due to FDA request • An exclusion criterion for metastatic disease that involves major airways or blood vessels, or centrally located mediastinal tumor masses of large volume, was added. • An exclusion criterion for history of gross hemoptysis (defined as bright red blood or ≥ 1/2 teaspoon) within 2 months prior to randomization was added. • Further vanucizumab pharmacokinetic (PK) samples were added in Cycle 1 and Cycle 8.
    16 May 2014
    Amended due to request following VHP in Europe • For the Part I safety run-in, simultaneous (i.e., same day) treatment administration to several patients, for the first 6 patients, was no longer allowed. Treatment of the first 6 patients was sequential i.e., there was always at least 1 working day between the first vanucizumab administration of one enrolled patient and the first vanucizumab administration of the next enrolled patient.
    10 Jun 2014
    • The revisions in Protocol Version 2 (EU) and Protocol Version 1 (US) were combined into a harmonized Version 3.
    08 Sep 2015
    • The sample size was increased from 140 patients to approximately 190 patients in order to compensate for early patient discontinuations and thereby to ensure that the number of PFS events required for the core analysis (n = 80) would be reached.
    10 Feb 2016
    • Risk mitigation measures were implemented as described in the Dear Investigator Letter (DIL) of 24 December 2015. The reason for submission of the DIL was to inform investigators that  10% of patients across two studies with vanucizumab had experienced gastrointestinal (GI) perforations (including GI fistula and intra abdominal abscess) and to inform them about additional risk mitigation measures that were made effective immediately to ensure the utmost safety and well- being of the patients, including: – Re-consenting ongoing patients to inform them about the increased risk of GI perforation associated with the blinded study drug treatment. – Excluding patients with a history of peptic ulcer disease, diverticulitis, or colitis within 6 months prior to Day 1 of Cycle 1. – Excluding patients with abdominal surgery or interventions within 60 days prior to Day 1 of Cycle 1. – Excluding patients with colonic prosthesis (stent) implant in place. – Permanently discontinuing study drug treatment in patients with confirmed intestinal sub-occlusive syndrome/occlusive syndrome/intestinal obstruction. – Advising patients to immediately contact the study physician in case they experience clinical symptoms suggestive of intestinal sub-/occlusion/intestinal obstruction or GI perforation such as acute, persisting and/or increasing abdominal pain, nausea and vomiting, etc. in order to initiate the appropriate diagnostic and therapeutic measures for this condition. – Prohibiting concomitant chronic use of non steroidal anti inflammatory drugs (NSAIDs) while receiving study drugs. However, for the symptomatic relief of medical conditions (e.g. headache, fever) sporadic or short-term intake of oral NSAIDs was allowed, when co-administered with proton pump inhibitors to reduce potential gastrointestinal damage.

    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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