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    Clinical Trial Results:
    A Randomized, Multicenter, Phase 2 Study to Compare the Efficacy of Panitumumab in Combination With mFOLFOX6 to the Efficacy of Bevacizumab in Combination With mFOLFOX6 in Patients With Previously Untreated, KRAS Wild-Type, Unresectable, Metastatic Colorectal Cancer

    Summary
    EudraCT number
    		 2008-004281-71
    Trial protocol
    		 DE   BE   ES   IT  
    Global end of trial date
    07 Jul 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Jul 2017
    First version publication date
    08 Jul 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    20070509
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00819780
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Amgen Inc
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, CA, United States, 91320
    Public contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Scientific contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.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
    11 Feb 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Jul 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to estimate the treatment effect on progression-free survival (PFS) of panitumumab relative to bevacizumab in combination with mFOLFOX6 chemotherapy as first-line therapy for metastatic colorectal cancer (mCRC) in patients with tumors expressing wild-type Kirsten Rat Sarcoma-2 Virus (KRAS).
    Protection of trial subjects
    This study was conducted in accordance with Food and Drug Administration and International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines. All subjects provided written informed consent before undergoing any study-related procedures, including screening procedures. The study protocol, amendments, and the informed consent form (ICF) were reviewed by the Institutional Review Boards (IRBs) and Independent Ethics Committees (IECs). No subjects were recruited into the study and no investigational product (IP) was shipped until the IRB/IEC gave written approval of the protocol and ICF and Amgen received copies of these approvals.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Apr 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Safety
    Long term follow-up duration
    		 36 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 36
    Country: Number of subjects enrolled
    United States: 88
    Country: Number of subjects enrolled
    Belgium: 20
    Country: Number of subjects enrolled
    Germany: 57
    Country: Number of subjects enrolled
    Italy: 23
    Country: Number of subjects enrolled
    Spain: 61
    Worldwide total number of subjects
    285
    EEA total number of subjects
    161
    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)
    170
    From 65 to 84 years
    115
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 60 centers in North America and Europe. The first participant was enrolled on 24 April 2009 and the last participant was enrolled on 09 December 2011.

    Pre-assignment
    Screening details
    		 Six hundred and fifty-eight patients were screened and 285 enrolled in the study. Randomization was stratified by prior adjuvant oxaliplatin therapy (yes vs no).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Panitumumab Plus mFOLFOX6
    Arm description
    		 Participants received 6 mg/kg panitumumab administered by intravenous (IV) infusion and modified FOLFOX6 (mFOLFOX6) chemotherapy regimen consisting of oxaliplatin (85 mg/m²), leucovorin (400 mg/m²) and 5-fluorouracil (5-FU; 2400 mg/m²) administered on Day 1 of every 14-day cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Panitumumab
    Investigational medicinal product code
    Other name
    Vectibix
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Panitumumab was administered by intravenous (IV) infusion at a dose of 6 mg/kg on day 1 of every 14-day cycle, before the administration of chemotherapy.

    Arm title
    		 Bevacizumab Plus mFOLFOX6
    Arm description
    		 Participants received 5 mg/kg bevacizumab administered by IV infusion and the mFOLFOX6 regimen consisting of oxaliplatin (85 mg/m²), leucovorin (400 mg/m²), followed by 5-FU (2400 mg/m²) administered on Day 1 of every 14-day cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab was administered by IV infusion at a dose of 5 mg/kg on day 1 of every 14-day cycle, before the administration of chemotherapy.

    Number of subjects in period 1
    		Panitumumab Plus mFOLFOX6 Bevacizumab Plus mFOLFOX6
    Started
    142
    143
    Received Treatment
    139
    139
    Completed
    139
    139
    Not completed
    3
    4
         Did not receive study drug
    3
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Panitumumab Plus mFOLFOX6
    Reporting group description
    		 Participants received 6 mg/kg panitumumab administered by intravenous (IV) infusion and modified FOLFOX6 (mFOLFOX6) chemotherapy regimen consisting of oxaliplatin (85 mg/m²), leucovorin (400 mg/m²) and 5-fluorouracil (5-FU; 2400 mg/m²) administered on Day 1 of every 14-day cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death.

    Reporting group title
    Bevacizumab Plus mFOLFOX6
    Reporting group description
    		 Participants received 5 mg/kg bevacizumab administered by IV infusion and the mFOLFOX6 regimen consisting of oxaliplatin (85 mg/m²), leucovorin (400 mg/m²), followed by 5-FU (2400 mg/m²) administered on Day 1 of every 14-day cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death.

    Reporting group values
    		 Panitumumab Plus mFOLFOX6 Bevacizumab Plus mFOLFOX6 Total
    Number of subjects
    		 142 143 285
    Age Categorical
    Units: Subjects
        < 65 years
    		 80 90 170
        ≥ 65 years
    		 62 53 115
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.6 ± 10.4 60.5 ± 9.8 -
    Gender Categorical
    Units: Subjects
        Female
    		 56 47 103
        Male
    		 86 96 182
    Race/Ethnicity
    Units: Subjects
        White or Caucasian
    		 131 127 258
        Black or African American
    		 9 6 15
        Hispanic or Latino
    		 2 5 7
        Asian
    		 0 4 4
        Japanese
    		 0 1 1
    Prior Adjuvant Oxaliplatin Therapy
    Units: Subjects
        Yes
    		 14 14 28
        No
    		 128 129 257

    End points

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    End points reporting groups
    Reporting group title
    Panitumumab Plus mFOLFOX6
    Reporting group description
    		 Participants received 6 mg/kg panitumumab administered by intravenous (IV) infusion and modified FOLFOX6 (mFOLFOX6) chemotherapy regimen consisting of oxaliplatin (85 mg/m²), leucovorin (400 mg/m²) and 5-fluorouracil (5-FU; 2400 mg/m²) administered on Day 1 of every 14-day cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death.

    Reporting group title
    Bevacizumab Plus mFOLFOX6
    Reporting group description
    		 Participants received 5 mg/kg bevacizumab administered by IV infusion and the mFOLFOX6 regimen consisting of oxaliplatin (85 mg/m²), leucovorin (400 mg/m²), followed by 5-FU (2400 mg/m²) administered on Day 1 of every 14-day cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death.

    Primary: Progression-free Survival (PFS)

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    End point title
    		 Progression-free Survival (PFS)
    End point description
    PFS was defined as the time from the date of randomization to the date of first disease progression, or death within 60 days after the last evaluable tumor assessment or randomization date (whichever was later). Participants not meeting the criteria by the cutoff date were censored at the last evaluable tumor assessment date. Tumor response was evaluated by the investigator per modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 every 8 weeks until radiographic disease progression. Progression is defined as at least a 20% increase in the size of target lesions, unequivocal progression of existing non-target lesions, or any new lesions. PFS was analyzed in the intent-to-treat (ITT) analysis set, which includes all randomized participants.
    End point type
    Primary
    End point timeframe
    From randomization until the data cutoff date of 11 February 2015; median follow-up time was 103 weeks.
    End point values
    		 Panitumumab Plus mFOLFOX6 Bevacizumab Plus mFOLFOX6
    Number of subjects analysed
    142
    143
    Units: months
        median (confidence interval 95%)
    10.9 (9.4 to 12.8)
    10.1 (9 to 12.6)
    Statistical analysis title
    		 Primary Analysis of Progression-free Survival Time
    Comparison groups
    Bevacizumab Plus mFOLFOX6 v Panitumumab Plus mFOLFOX6
    Number of subjects included in analysis
    285
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2924 [1]
    Method
    		 Stratified Cox proportional hazards
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.868
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.667
         upper limit
    		 1.13
    Notes
    [1] - The Cox proportional hazard model is stratified by prior adjuvant oxaliplatin therapy

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Overall survival was defined as the time from randomization to the date of death, with participants alive or lost to follow-up at the analysis data cutoff date censored at their last contact date.
    End point type
    Secondary
    End point timeframe
    From randomization until the data cutoff date of 11 February 2015; median follow-up time was 103 weeks.
    End point values
    		 Panitumumab Plus mFOLFOX6 Bevacizumab Plus mFOLFOX6
    Number of subjects analysed
    142
    143
    Units: months
        median (confidence interval 95%)
    31.6 (24.3 to 41.2)
    23.9 (20.9 to 29)
    Statistical analysis title
    		 Primary Analysis of Survival Time
    Comparison groups
    Panitumumab Plus mFOLFOX6 v Bevacizumab Plus mFOLFOX6
    Number of subjects included in analysis
    285
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0385 [2]
    Method
    		 Stratified Cox proportional hazards
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.742
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.559
         upper limit
    		 0.984
    Notes
    [2] - The Cox proportional hazard model is stratified by prior adjuvant oxaliplatin therapy

    Secondary: Percentage of Participants With an Objective Response

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    End point title
    		 Percentage of Participants With an Objective Response
    End point description
    Objective response was defined as having a confirmed complete response (CR) or partial response (PR) during first-line treatment, based on the investigator’s review of scans using a modified-RECIST v1.0. A complete or partial response was confirmed no less than 4-weeks after the criteria for response were first met. Complete Response: Disappearance of all target and non-target lesions and no new lesions. Partial Response: At least a 30% decrease in the sum of the longest diameter (SLD) of target lesions and no progression of non-target lesions and no new lesions, or the disappearance of all target lesions with persistence of one or more non-target lesion(s) not qualifying for either CR or progressive disease and no new lesions. Response was analyzed in the Evaluable for Local Tumor Response Analysis Set, defined as the subset of participants in the ITT Analysis Set who had at least 1 unidimensionally measurable lesion per modified RECIST 1.0 per the local investigator.
    End point type
    Secondary
    End point timeframe
    From randomization until the data cutoff date of 11 February 2015; median follow-up time was 103 weeks.
    End point values
    		 Panitumumab Plus mFOLFOX6 Bevacizumab Plus mFOLFOX6
    Number of subjects analysed
    142 [3]
    142 [4]
    Units: percentage of participants
        number (confidence interval 95%)
    59.15 (50.6 to 67.32)
    52.11 (43.58 to 60.56)
    Notes
    [3] - Evaluable for Local Tumor Response Analysis Set
    [4] - Evaluable for Local Tumor Response Analysis Set
    Statistical analysis title
    		 Analysis of Objective Response
    Comparison groups
    Panitumumab Plus mFOLFOX6 v Bevacizumab Plus mFOLFOX6
    Number of subjects included in analysis
    284
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2804 [5]
    Method
    		 Stratified exact test
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 2.2
    Notes
    [5] - Stratified by prior adjuvant oxaliplatin therapy

    Secondary: Duration of Response

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    End point title
    		 Duration of Response
    End point description
    For participants with a confirmed objective response, the time from first confirmed objective response to radiologic disease progression per modified RECIST 1.0 criteria or death. For participants who responded and did not progress or die, duration of response was censored at their last evaluable disease assessment date.
    End point type
    Secondary
    End point timeframe
    From randomization until the data cutoff date of 11 February 2015; median follow-up time was 103 weeks.
    End point values
    		 Panitumumab Plus mFOLFOX6 Bevacizumab Plus mFOLFOX6
    Number of subjects analysed
    84 [6]
    74 [7]
    Units: months
        median (confidence interval 95%)
    11.1 (8.8 to 13.2)
    9.2 (7.5 to 10.2)
    Notes
    [6] - Evaluable for Local Tumor Response Analysis Set: Responders
    [7] - Evaluable for Local Tumor Response Analysis Set: Responders
    No statistical analyses for this end point

    Secondary: Time to Disease Progression

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    End point title
    		 Time to Disease Progression
    End point description
    Time to progression (TTP) is defined as the time from randomization to the date of radiologic disease progression per modified RECIST 1.0 criteria. Participants not meeting criteria for disease progression by the analysis data cutoff date were censored at their last evaluable disease assessment date. Progression is defined as at least a 20% increase in the size of target lesions, unequivocal progression of existing non-target lesions, or any new lesions.
    End point type
    Secondary
    End point timeframe
    From randomization until the data cutoff date of 11 February 2015; median follow-up time was 103 weeks.
    End point values
    		 Panitumumab Plus mFOLFOX6 Bevacizumab Plus mFOLFOX6
    Number of subjects analysed
    142
    143
    Units: months
        median (confidence interval 95%)
    11.2 (9.8 to 13.1)
    11.1 (9.3 to 12.7)
    Statistical analysis title
    		 Analysis of Time to Disease Progression
    Comparison groups
    Panitumumab Plus mFOLFOX6 v Bevacizumab Plus mFOLFOX6
    Number of subjects included in analysis
    285
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3164 [8]
    Method
    		 Stratified Cox proportional hazards
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.662
         upper limit
    		 1.143
    Notes
    [8] - The Cox proportional hazard model is stratified by prior adjuvant oxaliplatin therapy

    Secondary: Time to Initial Objective Response

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    End point title
    		 Time to Initial Objective Response
    End point description
    For participants with a confirmed objective response, the time from randomization to the date of first confirmed objective response. Assessments are based on the investigator’s review of scans using a modified-RECIST v1.0. An objective response is defined as a best tumor response of complete or partial response. A complete or partial response was confirmed no less than 4-weeks after the criteria for response were first met.
    End point type
    Secondary
    End point timeframe
    From randomization until the data cutoff date of 11 February 2015; median follow-up time was 103 weeks.
    End point values
    		 Panitumumab Plus mFOLFOX6 Bevacizumab Plus mFOLFOX6
    Number of subjects analysed
    84 [9]
    74 [10]
    Units: months
        median (inter-quartile range (Q1-Q3))
    1.84 (1.69 to 2.3)
    1.84 (1.71 to 3.65)
    Notes
    [9] - Evaluable for Local Tumor Response Analysis Set: Responders
    [10] - Evaluable for Local Tumor Response Analysis Set: Responders
    No statistical analyses for this end point

    Secondary: Resection Rate

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    End point title
    		 Resection Rate
    End point description
    The resection rate was defined as the percentage of participants with a surgical procedure that resulted in partial reduction or complete eradication of all metastatic disease.
    End point type
    Secondary
    End point timeframe
    From randomization until the data cutoff date of 11 February 2015; median follow-up time was 103 weeks.
    End point values
    		 Panitumumab Plus mFOLFOX6 Bevacizumab Plus mFOLFOX6
    Number of subjects analysed
    142
    143
    Units: percentage of participants
        number (confidence interval 95%)
    13.38 (8.25 to 20.1)
    11.19 (6.53 to 17.53)
    No statistical analyses for this end point

    Secondary: Progression-free Survival (PFS) in Participants With Wild-type Rat Sarcoma Viral Oncogene Homolog (RAS)

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    End point title
    		 Progression-free Survival (PFS) in Participants With Wild-type Rat Sarcoma Viral Oncogene Homolog (RAS)
    End point description
    PFS was defined as the time from the date of randomization to the date of first disease progression, or death within 60 days after the last evaluable tumor assessment or randomization date (whichever was later). Participants not meeting the criteria by the cutoff date were censored at the last evaluable tumor assessment date. Tumor response was evaluated by the investigator per modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 every 8 weeks until radiographic disease progression. Progression is defined as at least a 20% increase in the size of target lesions, unequivocal progression of existing non-target lesions, or any new lesions. The Wild-type RAS Efficacy Analysis Set was defined as a subset of Wild-type KRAS Exon 2 Efficacy Analysis Set including all randomized participants with wild-type KRAS exon 2, 3, 4, NRAS exon 2, 3, and 4.
    End point type
    Secondary
    End point timeframe
    From randomization until the data cutoff date of 11 February 2015; median follow-up time was 126 weeks.
    End point values
    		 Panitumumab Plus mFOLFOX6 Bevacizumab Plus mFOLFOX6
    Number of subjects analysed
    88 [11]
    82 [12]
    Units: months
        median (confidence interval 95%)
    12.8 (10.7 to 15.1)
    10.1 (9 to 12.7)
    Notes
    [11] - Wild-type RAS Efficacy Analysis Set
    [12] - Wild-type RAS Efficacy Analysis Set
    Statistical analysis title
    		 Analysis of Progression-free Survival Time
    Comparison groups
    Panitumumab Plus mFOLFOX6 v Bevacizumab Plus mFOLFOX6
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0292 [13]
    Method
    		 Stratified Cox proportional hazards
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.679
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 0.962
    Notes
    [13] - The Cox proportional hazard model is stratified by prior adjuvant oxaliplatin therapy

    Secondary: Progression-free Survival (PFS) in Participants With Wild-type RAS / V-raf Murine Sarcoma Viral Oncogene Homolog B1 (BRAF)

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    End point title
    		 Progression-free Survival (PFS) in Participants With Wild-type RAS / V-raf Murine Sarcoma Viral Oncogene Homolog B1 (BRAF)
    End point description
    PFS was defined as the time from the date of randomization to the date of first disease progression, or death within 60 days after the last evaluable tumor assessment or randomization date (whichever was later). Participants not meeting the criteria by the cutoff date were censored at the last evaluable tumor assessment date. Tumor response was evaluated by the investigator per modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 every 8 weeks until radiographic disease progression. Progression is defined as at least a 20% increase in the size of target lesions, unequivocal progression of existing non-target lesions, or any new lesions. The Wild-type RAS/BRAF Efficacy Analysis Set was defined as a subset of Wild-type KRAS Exon 2 Efficacy Analysis Set with wild-type KRAS exon 2, 3, and 4, NRAS exon 2, 3, 4, and BRAF exon 15.
    End point type
    Secondary
    End point timeframe
    From randomization until the data cutoff date of 11 February 2015; median follow-up time was 135 weeks.
    End point values
    		 Panitumumab Plus mFOLFOX6 Bevacizumab Plus mFOLFOX6
    Number of subjects analysed
    77 [14]
    79 [15]
    Units: months
        median (confidence interval 95%)
    13.1 (11.6 to 16.2)
    10.1 (9 to 12.7)
    Notes
    [14] - Wild-type RAS/BRAF Efficacy Analysis Set
    [15] - Wild-type RAS/BRAF Efficacy Analysis Set
    Statistical analysis title
    		 Analysis of Progression-free Survival Time
    Comparison groups
    Panitumumab Plus mFOLFOX6 v Bevacizumab Plus mFOLFOX6
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0075 [16]
    Method
    		 Stratified Cox proportional hazards
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.607
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.421
         upper limit
    		 0.875
    Notes
    [16] - The Cox proportional hazard model is stratified by prior adjuvant oxaliplatin therapy

    Secondary: Overall Survival in Participants With Wild-type RAS

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    End point title
    		 Overall Survival in Participants With Wild-type RAS
    End point description
    Overall survival was defined as the time from randomization to the date of death, with participants alive or lost to follow-up at the analysis data cutoff date censored at their last contact date. The Wild-type RAS Efficacy Analysis Set was defined as a subset of Wild-type KRAS Exon 2 Efficacy Analysis Set including all randomized participants with wild-type KRAS exon 2, 3, 4, NRAS exon 2, 3, and 4.
    End point type
    Secondary
    End point timeframe
    From randomization until the data cutoff date of 11 February 2015; median follow-up time was 126 weeks.
    End point values
    		 Panitumumab Plus mFOLFOX6 Bevacizumab Plus mFOLFOX6
    Number of subjects analysed
    88 [17]
    82 [18]
    Units: months
        median (confidence interval 95%)
    36.9 (27.9 to 46.1)
    28.9 (23.3 to 32)
    Notes
    [17] - Wild-type RAS Efficacy Analysis Set
    [18] - Wild-type RAS Efficacy Analysis Set
    Statistical analysis title
    		 Analysis of Survival Time
    Comparison groups
    Panitumumab Plus mFOLFOX6 v Bevacizumab Plus mFOLFOX6
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1541 [19]
    Method
    		 Stratified Cox proportional hazards
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.763
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.526
         upper limit
    		 1.107
    Notes
    [19] - The Cox proportional hazard model is stratified by prior adjuvant Oxaliplatin therapy

    Secondary: Overall Survival in Participants With Wild-type RAS / BRAF

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    End point title
    		 Overall Survival in Participants With Wild-type RAS / BRAF
    End point description
    Overall survival was defined as the time from randomization to the date of death, with participants alive or lost to follow-up at the analysis data cutoff date censored at their last contact date. The Wild-type RAS/BRAF Efficacy Analysis Set was defined as a subset of Wild-type KRAS Exon 2 Efficacy Analysis Set with wild-type KRAS exon 2, 3, and 4, NRAS exon 2, 3, 4, and BRAF exon 15.
    End point type
    Secondary
    End point timeframe
    From randomization until the data cutoff date of 11 February 2015; median follow-up time was 135 weeks.
    End point values
    		 Panitumumab Plus mFOLFOX6 Bevacizumab Plus mFOLFOX6
    Number of subjects analysed
    77 [20]
    79 [21]
    Units: months
        median (confidence interval 95%)
    41.3 (31.6 to 46.7)
    28.9 (23.9 to 33.1)
    Notes
    [20] - Wild-type RAS/BRAF Efficacy Analysis Set
    [21] - Wild-type RAS/BRAF Efficacy Analysis Set
    Statistical analysis title
    		 Analysis of Survival Time
    Comparison groups
    Panitumumab Plus mFOLFOX6 v Bevacizumab Plus mFOLFOX6
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0809 [22]
    Method
    		 Stratified Cox proportional hazards
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.704
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.475
         upper limit
    		 1.044
    Notes
    [22] - The Cox proportional hazard model is stratified by prior adjuvant oxaliplatin therapy

    Secondary: Percentage of Participants With an Objective Response for Participants With Wild-type RAS

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    End point title
    		 Percentage of Participants With an Objective Response for Participants With Wild-type RAS
    End point description
    Objective response was defined as having a confirmed complete response (CR) or partial response (PR) during first-line treatment, based on the investigator’s review of scans using a modified-RECIST v1.0. A complete or partial response was confirmed no less than 4-weeks after the criteria for response were first met. Complete Response: Disappearance of all target and non-target lesions and no new lesions. Partial Response: At least a 30% decrease in the sum of the longest diameter (SLD) of target lesions and no progression of non-target lesions and no new lesions, or the disappearance of all target lesions with persistence of one or more non-target lesion(s) not qualifying for either CR or progressive disease and no new lesions. The Wild-type RAS Investigator Tumor Response Analysis Set was defined as the subset of participants in the Wild-type RAS Efficacy Analysis Set who had at least 1 unidimensionally measurable lesion per modified RECIST 1.0 per the local investigator.
    End point type
    Secondary
    End point timeframe
    From randomization until the data cutoff date of 11 February 2015; median follow-up time was 126 weeks
    End point values
    		 Panitumumab Plus mFOLFOX6 Bevacizumab Plus mFOLFOX6
    Number of subjects analysed
    88 [23]
    81 [24]
    Units: percentage of participants
        number (confidence interval 95%)
    63.64 (52.69 to 73.63)
    58.02 (46.54 to 68.91)
    Notes
    [23] - Wild-type RAS Investigator Tumor Response Analysis Set
    [24] - Wild-type RAS Investigator Tumor Response Analysis Set
    Statistical analysis title
    		 Analysis of Objective Response
    Comparison groups
    Panitumumab Plus mFOLFOX6 v Bevacizumab Plus mFOLFOX6
    Number of subjects included in analysis
    169
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7088 [25]
    Method
    		 Stratified exact test
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 2.34
    Notes
    [25] - Stratified by prior exposure to oxaliplatin

    Secondary: Percentage of Participants With an Objective Response for Participants With Wild-type RAS / BRAF

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    End point title
    		 Percentage of Participants With an Objective Response for Participants With Wild-type RAS / BRAF
    End point description
    Objective response was defined as having a confirmed complete response (CR) or partial response (PR) during first-line treatment, based on the investigator’s review of scans using a modified-RECIST v1.0. A complete or partial response was confirmed no less than 4-weeks after the criteria for response were first met. Complete Response: Disappearance of all target and non-target lesions and no new lesions. Partial Response: At least a 30% decrease in the sum of the longest diameter (SLD) of target lesions and no progression of non-target lesions and no new lesions, or the disappearance of all target lesions with persistence of one or more non-target lesion(s) not qualifying for either CR or progressive disease and no new lesions. The Wild-type RAS/BRAF Investigator Tumor Response Analysis Set was defined as the subset of participants in the Wild-type RAS/BRAF Efficacy Analysis Set who had at least 1 unidimensionally measurable lesion per modified RECIST 1.0 per the local investigator.
    End point type
    Secondary
    End point timeframe
    From randomization until the data cutoff date of 11 February 2015; median follow-up time was 135 weeks
    End point values
    		 Panitumumab Plus mFOLFOX6 Bevacizumab Plus mFOLFOX6
    Number of subjects analysed
    77 [26]
    78 [27]
    Units: percentage of participants
        number (confidence interval 95%)
    63.64 (51.88 to 74.3)
    58.97 (47.25 to 69.99)
    Notes
    [26] - Wild-type RAS/BRAF Investigator Tumor Response Analysis Set
    [27] - Wild-type RAS/BRAF Investigator Tumor Response Analysis Set
    Statistical analysis title
    		 Analysis of Objective Response
    Comparison groups
    Panitumumab Plus mFOLFOX6 v Bevacizumab Plus mFOLFOX6
    Number of subjects included in analysis
    155
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7613 [28]
    Method
    		 Stratified exact test
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.58
         upper limit
    		 2.38
    Notes
    [28] - Stratified by prior exposure to oxaliplatin

    Secondary: Number of Participants With Adverse Events (AEs)

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    End point title
    		 Number of Participants With Adverse Events (AEs)
    End point description
    Severity was graded using Common Terminology Criteria for Adverse Events (CTCAE) v3.0, with the exception of some dermatology/skin adverse events that were graded using CTCAE v3.0 with modifications. Fatal adverse events are classified as grade 5. Serious adverse events include any event that is fatal, life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, a congenital anomaly/birth defect, or other significant medical hazard. Treatment-related AEs were those that the investigator considered a reasonable possibility that might have been caused by study drug.
    End point type
    Secondary
    End point timeframe
    The time frame for adverse event reporting is from the first dose date to 30 days since the last dose date. The median time frame is 8.0 months for Panitumumab plus mFOLFOX6 arm and 7.3 months for Bevacizumab plus mFOLFOX6 arm.
    End point values
    		 Panitumumab Plus mFOLFOX6 Bevacizumab Plus mFOLFOX6
    Number of subjects analysed
    139 [29]
    139 [30]
    Units: participants
        Any adverse event (AE)
    139
    139
        AE with worst grade of 3
    88
    79
        AE with worst grade of 4
    31
    28
        AE with worst grade of 5
    7
    9
        Serious adverse event (SAE)
    62
    54
        AE leading to discontinuation of study drug
    41
    37
        Any treatment-related adverse event (TRAE)
    138
    136
        Treatment-related AE with worst grade of 3
    92
    77
        Treatment-related AE with worst grade of 4
    24
    25
        Treatment-related AE with worst grade of 5
    3
    2
        Serious treatment-related adverse event
    37
    28
        TRAE leading to discontinuation of study drug
    30
    30
    Notes
    [29] - Safety Analysis Set
    [30] - Safety Analysis Set
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The time frame for adverse event reporting is from the first dose date to 30 days since the last dose date. The median time frame is 8.0 months for Panitumumab plus mFOLFOX6 arm and 7.3 months for Bevacizumab plus mFOLFOX6 arm.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Bevacizumab Plus mFOLFOX6
    Reporting group description
    		 Participants received 5 mg/kg bevacizumab administered by IV infusion and the mFOLFOX6 regimen consisting of oxaliplatin (85 mg/m²), leucovorin (400 mg/m²), followed by 5-FU (2400 mg/m²) administered on Day 1 of every 14-day cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death.

    Reporting group title
    Panitumumab Plus mFOLFOX6
    Reporting group description
    		 Participants received 6 mg/kg panitumumab administered by intravenous (IV) infusion and modified FOLFOX6 (mFOLFOX6) chemotherapy regimen consisting of oxaliplatin (85 mg/m²), leucovorin (400 mg/m²) and 5-fluorouracil (5-FU; 2400 mg/m²) administered on Day 1 of every 14-day cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death.

    Serious adverse events
    		 Bevacizumab Plus mFOLFOX6 Panitumumab Plus mFOLFOX6
    Total subjects affected by serious adverse events
         subjects affected / exposed
    54 / 139 (38.85%)
    62 / 139 (44.60%)
         number of deaths (all causes)
    9
    7
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colorectal cancer
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Tumour associated fever
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    4 / 139 (2.88%)
    4 / 139 (2.88%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intra-abdominal haematoma
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis superficial
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Adverse drug reaction
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 139 (1.44%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 139 (2.88%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    2 / 7
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis in device
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary embolism
         subjects affected / exposed
    6 / 139 (4.32%)
    7 / 139 (5.04%)
         occurrences causally related to treatment / all
    4 / 6
    5 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary venous thrombosis
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Psychiatric disorders
    Mood altered
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Panic attack
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Substance abuse
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Eastern Cooperative Oncology Group performance status worsened
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Face injury
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound haemorrhage
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 139 (0.72%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 139 (1.44%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    4 / 139 (2.88%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    3 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Convulsion
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertebrobasilar insufficiency
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (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
    Febrile neutropenia
         subjects affected / exposed
    3 / 139 (2.16%)
    3 / 139 (2.16%)
         occurrences causally related to treatment / all
    3 / 3
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 139 (0.72%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 139 (1.44%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    1 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 139 (1.44%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    2 / 139 (1.44%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 139 (0.00%)
    2 / 139 (1.44%)
         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 / 139 (0.72%)
    9 / 139 (6.47%)
         occurrences causally related to treatment / all
    1 / 1
    10 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 139 (0.00%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal perforation
         subjects affected / exposed
    2 / 139 (1.44%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    3 / 139 (2.16%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    2 / 139 (1.44%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    2 / 139 (1.44%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal perforation
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Stomatitis
         subjects affected / exposed
    0 / 139 (0.00%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal perforation
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 139 (1.44%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug eruption
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nail bed inflammation
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 139 (0.72%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    1 / 139 (0.72%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric obstruction
         subjects affected / exposed
    1 / 139 (0.72%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Groin pain
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Trismus
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epididymitis
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster oticus
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    2 / 139 (1.44%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion site infection
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningoencephalitis herpetic
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perirectal abscess
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 139 (2.16%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    1 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 139 (1.44%)
    3 / 139 (2.16%)
         occurrences causally related to treatment / all
    0 / 3
    3 / 4
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    Subcutaneous abscess
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 139 (1.44%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 139 (0.00%)
    3 / 139 (2.16%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    1 / 139 (0.72%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    2 / 139 (1.44%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Bevacizumab Plus mFOLFOX6 Panitumumab Plus mFOLFOX6
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    139 / 139 (100.00%)
    139 / 139 (100.00%)
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    11 / 139 (7.91%)
    5 / 139 (3.60%)
         occurrences all number
    12
    6
    Hypertension
         subjects affected / exposed
    36 / 139 (25.90%)
    7 / 139 (5.04%)
         occurrences all number
    50
    9
    Haematoma
         subjects affected / exposed
    7 / 139 (5.04%)
    1 / 139 (0.72%)
         occurrences all number
    7
    2
    Hypotension
         subjects affected / exposed
    6 / 139 (4.32%)
    7 / 139 (5.04%)
         occurrences all number
    7
    9
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    12 / 139 (8.63%)
    11 / 139 (7.91%)
         occurrences all number
    16
    12
    Asthenia
         subjects affected / exposed
    44 / 139 (31.65%)
    50 / 139 (35.97%)
         occurrences all number
    101
    107
    Fatigue
         subjects affected / exposed
    66 / 139 (47.48%)
    50 / 139 (35.97%)
         occurrences all number
    158
    164
    Mucosal inflammation
         subjects affected / exposed
    21 / 139 (15.11%)
    50 / 139 (35.97%)
         occurrences all number
    32
    113
    Oedema peripheral
         subjects affected / exposed
    9 / 139 (6.47%)
    19 / 139 (13.67%)
         occurrences all number
    9
    22
    Pyrexia
         subjects affected / exposed
    30 / 139 (21.58%)
    21 / 139 (15.11%)
         occurrences all number
    53
    24
    Temperature intolerance
         subjects affected / exposed
    11 / 139 (7.91%)
    7 / 139 (5.04%)
         occurrences all number
    14
    8
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    19 / 139 (13.67%)
    16 / 139 (11.51%)
         occurrences all number
    25
    24
    Dysphonia
         subjects affected / exposed
    8 / 139 (5.76%)
    4 / 139 (2.88%)
         occurrences all number
    8
    4
    Cough
         subjects affected / exposed
    13 / 139 (9.35%)
    18 / 139 (12.95%)
         occurrences all number
    15
    21
    Dyspnoea exertional
         subjects affected / exposed
    6 / 139 (4.32%)
    7 / 139 (5.04%)
         occurrences all number
    6
    8
    Epistaxis
         subjects affected / exposed
    32 / 139 (23.02%)
    29 / 139 (20.86%)
         occurrences all number
    43
    42
    Oropharyngeal pain
         subjects affected / exposed
    12 / 139 (8.63%)
    4 / 139 (2.88%)
         occurrences all number
    15
    4
    Pulmonary embolism
         subjects affected / exposed
    8 / 139 (5.76%)
    7 / 139 (5.04%)
         occurrences all number
    8
    7
    Rhinorrhoea
         subjects affected / exposed
    13 / 139 (9.35%)
    4 / 139 (2.88%)
         occurrences all number
    16
    4
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    8 / 139 (5.76%)
    10 / 139 (7.19%)
         occurrences all number
    8
    10
    Insomnia
         subjects affected / exposed
    20 / 139 (14.39%)
    15 / 139 (10.79%)
         occurrences all number
    22
    16
    Investigations
    Platelet count decreased
         subjects affected / exposed
    5 / 139 (3.60%)
    10 / 139 (7.19%)
         occurrences all number
    9
    12
    Weight decreased
         subjects affected / exposed
    16 / 139 (11.51%)
    32 / 139 (23.02%)
         occurrences all number
    19
    67
    Weight increased
         subjects affected / exposed
    2 / 139 (1.44%)
    8 / 139 (5.76%)
         occurrences all number
    2
    11
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    6 / 139 (4.32%)
    10 / 139 (7.19%)
         occurrences all number
    8
    15
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    18 / 139 (12.95%)
    17 / 139 (12.23%)
         occurrences all number
    22
    25
    Dysaesthesia
         subjects affected / exposed
    23 / 139 (16.55%)
    13 / 139 (9.35%)
         occurrences all number
    88
    32
    Dysgeusia
         subjects affected / exposed
    27 / 139 (19.42%)
    31 / 139 (22.30%)
         occurrences all number
    29
    40
    Headache
         subjects affected / exposed
    17 / 139 (12.23%)
    13 / 139 (9.35%)
         occurrences all number
    28
    15
    Neuropathy peripheral
         subjects affected / exposed
    46 / 139 (33.09%)
    46 / 139 (33.09%)
         occurrences all number
    133
    172
    Neurotoxicity
         subjects affected / exposed
    12 / 139 (8.63%)
    12 / 139 (8.63%)
         occurrences all number
    31
    35
    Paraesthesia
         subjects affected / exposed
    31 / 139 (22.30%)
    26 / 139 (18.71%)
         occurrences all number
    86
    64
    Peripheral sensory neuropathy
         subjects affected / exposed
    24 / 139 (17.27%)
    25 / 139 (17.99%)
         occurrences all number
    53
    93
    Polyneuropathy
         subjects affected / exposed
    16 / 139 (11.51%)
    18 / 139 (12.95%)
         occurrences all number
    38
    33
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    66 / 139 (47.48%)
    63 / 139 (45.32%)
         occurrences all number
    145
    171
    Leukopenia
         subjects affected / exposed
    10 / 139 (7.19%)
    10 / 139 (7.19%)
         occurrences all number
    12
    19
    Anaemia
         subjects affected / exposed
    20 / 139 (14.39%)
    25 / 139 (17.99%)
         occurrences all number
    31
    44
    Thrombocytopenia
         subjects affected / exposed
    17 / 139 (12.23%)
    34 / 139 (24.46%)
         occurrences all number
    59
    94
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    6 / 139 (4.32%)
    8 / 139 (5.76%)
         occurrences all number
    6
    9
    Vision blurred
         subjects affected / exposed
    3 / 139 (2.16%)
    8 / 139 (5.76%)
         occurrences all number
    4
    8
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    6 / 139 (4.32%)
    8 / 139 (5.76%)
         occurrences all number
    6
    8
    Abdominal pain
         subjects affected / exposed
    30 / 139 (21.58%)
    26 / 139 (18.71%)
         occurrences all number
    40
    33
    Abdominal pain upper
         subjects affected / exposed
    12 / 139 (8.63%)
    11 / 139 (7.91%)
         occurrences all number
    13
    13
    Ascites
         subjects affected / exposed
    7 / 139 (5.04%)
    0 / 139 (0.00%)
         occurrences all number
    7
    0
    Cheilitis
         subjects affected / exposed
    0 / 139 (0.00%)
    8 / 139 (5.76%)
         occurrences all number
    0
    10
    Constipation
         subjects affected / exposed
    46 / 139 (33.09%)
    44 / 139 (31.65%)
         occurrences all number
    59
    65
    Diarrhoea
         subjects affected / exposed
    85 / 139 (61.15%)
    84 / 139 (60.43%)
         occurrences all number
    205
    232
    Dyspepsia
         subjects affected / exposed
    16 / 139 (11.51%)
    15 / 139 (10.79%)
         occurrences all number
    18
    20
    Haemorrhoids
         subjects affected / exposed
    8 / 139 (5.76%)
    4 / 139 (2.88%)
         occurrences all number
    11
    4
    Nausea
         subjects affected / exposed
    85 / 139 (61.15%)
    76 / 139 (54.68%)
         occurrences all number
    165
    145
    Rectal haemorrhage
         subjects affected / exposed
    6 / 139 (4.32%)
    8 / 139 (5.76%)
         occurrences all number
    6
    8
    Stomatitis
         subjects affected / exposed
    31 / 139 (22.30%)
    47 / 139 (33.81%)
         occurrences all number
    65
    117
    Vomiting
         subjects affected / exposed
    38 / 139 (27.34%)
    44 / 139 (31.65%)
         occurrences all number
    68
    75
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 139 (0.72%)
    35 / 139 (25.18%)
         occurrences all number
    1
    193
    Alopecia
         subjects affected / exposed
    21 / 139 (15.11%)
    26 / 139 (18.71%)
         occurrences all number
    23
    29
    Dermatitis acneiform
         subjects affected / exposed
    2 / 139 (1.44%)
    27 / 139 (19.42%)
         occurrences all number
    2
    54
    Dry skin
         subjects affected / exposed
    12 / 139 (8.63%)
    56 / 139 (40.29%)
         occurrences all number
    14
    100
    Erythema
         subjects affected / exposed
    2 / 139 (1.44%)
    12 / 139 (8.63%)
         occurrences all number
    2
    17
    Exfoliative rash
         subjects affected / exposed
    2 / 139 (1.44%)
    11 / 139 (7.91%)
         occurrences all number
    4
    23
    Hypertrichosis
         subjects affected / exposed
    0 / 139 (0.00%)
    9 / 139 (6.47%)
         occurrences all number
    0
    9
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    14 / 139 (10.07%)
    22 / 139 (15.83%)
         occurrences all number
    29
    31
    Nail disorder
         subjects affected / exposed
    6 / 139 (4.32%)
    13 / 139 (9.35%)
         occurrences all number
    6
    42
    Pruritus
         subjects affected / exposed
    4 / 139 (2.88%)
    16 / 139 (11.51%)
         occurrences all number
    5
    25
    Rash
         subjects affected / exposed
    9 / 139 (6.47%)
    87 / 139 (62.59%)
         occurrences all number
    11
    274
    Skin fissures
         subjects affected / exposed
    1 / 139 (0.72%)
    31 / 139 (22.30%)
         occurrences all number
    5
    60
    Skin toxicity
         subjects affected / exposed
    0 / 139 (0.00%)
    10 / 139 (7.19%)
         occurrences all number
    0
    21
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    2 / 139 (1.44%)
    7 / 139 (5.04%)
         occurrences all number
    2
    9
    Proteinuria
         subjects affected / exposed
    11 / 139 (7.91%)
    16 / 139 (11.51%)
         occurrences all number
    19
    33
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    14 / 139 (10.07%)
    8 / 139 (5.76%)
         occurrences all number
    16
    10
    Back pain
         subjects affected / exposed
    14 / 139 (10.07%)
    13 / 139 (9.35%)
         occurrences all number
    18
    17
    Muscular weakness
         subjects affected / exposed
    7 / 139 (5.04%)
    3 / 139 (2.16%)
         occurrences all number
    8
    5
    Neck pain
         subjects affected / exposed
    7 / 139 (5.04%)
    2 / 139 (1.44%)
         occurrences all number
    7
    2
    Musculoskeletal pain
         subjects affected / exposed
    10 / 139 (7.19%)
    9 / 139 (6.47%)
         occurrences all number
    12
    11
    Musculoskeletal chest pain
         subjects affected / exposed
    7 / 139 (5.04%)
    3 / 139 (2.16%)
         occurrences all number
    7
    4
    Pain in extremity
         subjects affected / exposed
    18 / 139 (12.95%)
    12 / 139 (8.63%)
         occurrences all number
    28
    13
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    8 / 139 (5.76%)
    4 / 139 (2.88%)
         occurrences all number
    10
    5
    Nasopharyngitis
         subjects affected / exposed
    8 / 139 (5.76%)
    8 / 139 (5.76%)
         occurrences all number
    9
    8
    Conjunctivitis
         subjects affected / exposed
    4 / 139 (2.88%)
    17 / 139 (12.23%)
         occurrences all number
    16
    31
    Respiratory tract infection
         subjects affected / exposed
    6 / 139 (4.32%)
    9 / 139 (6.47%)
         occurrences all number
    9
    10
    Paronychia
         subjects affected / exposed
    2 / 139 (1.44%)
    25 / 139 (17.99%)
         occurrences all number
    3
    44
    Rhinitis
         subjects affected / exposed
    5 / 139 (3.60%)
    9 / 139 (6.47%)
         occurrences all number
    5
    11
    Upper respiratory tract infection
         subjects affected / exposed
    9 / 139 (6.47%)
    6 / 139 (4.32%)
         occurrences all number
    9
    8
    Urinary tract infection
         subjects affected / exposed
    9 / 139 (6.47%)
    11 / 139 (7.91%)
         occurrences all number
    13
    29
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    44 / 139 (31.65%)
    56 / 139 (40.29%)
         occurrences all number
    56
    111
    Dehydration
         subjects affected / exposed
    10 / 139 (7.19%)
    18 / 139 (12.95%)
         occurrences all number
    14
    27
    Hypocalcaemia
         subjects affected / exposed
    5 / 139 (3.60%)
    12 / 139 (8.63%)
         occurrences all number
    5
    23
    Hypoalbuminaemia
         subjects affected / exposed
    7 / 139 (5.04%)
    3 / 139 (2.16%)
         occurrences all number
    17
    7
    Hypokalaemia
         subjects affected / exposed
    17 / 139 (12.23%)
    38 / 139 (27.34%)
         occurrences all number
    27
    90
    Hypomagnesaemia
         subjects affected / exposed
    9 / 139 (6.47%)
    58 / 139 (41.73%)
         occurrences all number
    10
    192

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Jan 2010
    • Allowed local KRAS testing by other experienced laboratories using a validated test method per local regulatory guidelines • Updated inclusion/exclusion, dose adjustment, withholding, and discontinuation criteria to reflect recent changes in clinical practice • Clarified the exclusion criteria regarding the use of contraception during the study to be consistent with contraception use instructions described in the Risk and Discomfort section of panitumumab informed consent template and bevacizumab prescribing information • Updated the panitumumab background information to incorporate the latest information for the two large phase 3 studies, 20050203 and 20050181, of panitumumab in combination with first- and second-line chemotherapy, respectively, that were conducted in patients with mCRC • Clarified collection of antibody samples • Specified RECIST version utilized in this study as version 1.0 • Clarified adverse event reporting timelines • Deleted the main and the optional pharmacogenetic informed consent form templates from the appendix section of the protocol. The ICF templates were provided to the investigative sites separately.
    23 Feb 2012
    • Prospectively prespecified the study and analysis of a wider array of potentially prognostic and predictive biomarkers within the RAS/BRAF family oncogenes for efficacy and safety • Revised the definition of PFS, changing from “the time from the date of randomization to the date of progression or the date of death (any cause)” to “the time from randomization to the date of first disease progression, or death within 60 days after the last evaluable tumor assessment or randomization date (whichever is later). Subjects not meeting the criteria by the cutoff date are censored at the last evaluable tumor assessment date.” • Addition of a sensitivity analysis using the original PFS definition • Modification of the anti-panitumumab antibody follow-up instructions to clarify that, if a subject tests positive at the safety follow-up visit, additional serum samples would continue to be collected during the long term follow-up regardless of the baseline antibody test results • Clarified that data collection for subjects who remained on protocol-specified treatment following the completion of all planned study analyses was limited to treatment administration and serious adverse events up to and including the 30-day safety follow-up visit • Revised Section 8.1 to permit obtainment of survival data from public records for any subject for whom the survival status was not known even if a subject withdrew full consent per the FDA guidelines and local regional regulatory agencies • Revised the reasons for removal from study in Section 8.1 to differentiate between removal from treatment phase and removal from long-term follow-up observation phase • Revised the “Reporting Procedures for SAE” to allow for reporting other than by fax (eg, electronic reporting)

    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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