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    Clinical Trial Results:
    A Phase 3, Multicenter, Randomized, Open-label Trial to Evaluate the Survival Benefit of Panitumumab and Best Supportive Care, Compared to Best Supportive Care Alone, in Subjects With Chemorefractory Wild-type KRAS Metastatic Colorectal Cancer

    Summary
    EudraCT number
    		 2010-022951-49
    Trial protocol
    		 GR   EE   LV   LT  
    Global end of trial date
    11 Nov 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Nov 2017
    First version publication date
    23 Nov 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    20100007
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01412957
    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
    24 Jul 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Nov 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study was to evaluate the benefit of panitumumab in addition to best supportive care compared to best supportive care alone in patients with chemorefractory wild-type KRAS (Kirsten rat sarcoma viral oncogene homolog) metastatic colorectal cancer.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines. Essential documents will be retained in accordance with ICH GCP. 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
    08 Nov 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy
    Long term follow-up duration
    		 2 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    China: 34
    Country: Number of subjects enrolled
    India: 23
    Country: Number of subjects enrolled
    Korea, Republic of: 79
    Country: Number of subjects enrolled
    Malaysia: 16
    Country: Number of subjects enrolled
    Philippines: 10
    Country: Number of subjects enrolled
    Croatia: 59
    Country: Number of subjects enrolled
    Estonia: 27
    Country: Number of subjects enrolled
    Greece: 2
    Country: Number of subjects enrolled
    Latvia: 11
    Country: Number of subjects enrolled
    Lithuania: 14
    Country: Number of subjects enrolled
    Romania: 48
    Country: Number of subjects enrolled
    Serbia: 10
    Country: Number of subjects enrolled
    Brazil: 14
    Country: Number of subjects enrolled
    Canada: 7
    Country: Number of subjects enrolled
    Chile: 7
    Country: Number of subjects enrolled
    Mexico: 16
    Worldwide total number of subjects
    377
    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)
    241
    From 65 to 84 years
    136
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 377 participants were randomized at 66 centers in Europe, Asia, North and South America from 8 November 2011 until 30 July 2013. Results are reported as of the final analysis data cut-off date of 24 July 2015.

    Pre-assignment
    Screening details
    		 Participants were stratified according to geographic region (Europe vs Asia vs rest of the world) and Eastern Cooperative Oncology Group (ECOG) performance status (0 or 1 vs 2) and randomized (1:1 ratio) to 1 of 2 treatment groups.

    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 + BSC
    Arm description
    		 Participants received panitumumab administered intravenously 6 mg/kg every 14 days plus best supportive care (BSC) until disease progression, withdrawal of consent, death, or intolerance of study drug.
    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
    The starting panitumumab dose was 6 mg/kg; panitumumab was administered by intravenous infusion on day 1 of every 14-day cycle.

    Arm title
    		 BSC Alone
    Arm description
    		 Participants received best supportive care until disease progression, withdrawal of consent, or death.
    Arm type
    		 Best Supportive Care

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Panitumumab + BSC BSC Alone
    Started
    189
    188
    Completed
    189
    188

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Panitumumab + BSC
    Reporting group description
    		 Participants received panitumumab administered intravenously 6 mg/kg every 14 days plus best supportive care (BSC) until disease progression, withdrawal of consent, death, or intolerance of study drug.

    Reporting group title
    BSC Alone
    Reporting group description
    		 Participants received best supportive care until disease progression, withdrawal of consent, or death.

    Reporting group values
    		 Panitumumab + BSC BSC Alone Total
    Number of subjects
    		 189 188 377
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 114 127 241
        From 65-84 years
    		 75 61 136
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 60.2 ± 10.7 58.7 ± 11.1 -
    Gender, Male/Female
    Units: Subjects
        Female
    		 82 79 161
        Male
    		 107 109 216
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino
    		 23 22 45
        Not Hispanic or Latino
    		 166 166 332
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    		 0 3 3
        Asian
    		 79 82 161
        White
    		 107 102 209
        Other
    		 3 1 4
    Geographic Region
    Units: Subjects
        Europe
    		 86 85 171
        Asia
    		 80 82 162
        Rest of world
    		 23 21 44
    Eastern Cooperative Oncology Group (ECOG) Performance Status
    A scale to assess a patient's disease status. 0 = Fully active, able to carry out all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity, ambulatory and able to carry out work of a light nature; 2 = Ambulatory and capable of all self care, unable to carry out any work activities. Up and about > 50% of waking hours; 3 = Capable of only limited self-care, confined to bed or chair > 50% of waking hours; 4 = Completely disabled, confined to bed or chair; 5 = Dead.
    Units: Subjects
        Grade 0
    		 71 65 136
        Grade 1
    		 100 107 207
        Grade 2
    		 18 16 34
    Location of Primary Tumor
    Units: Subjects
        Colon
    		 108 106 214
        Rectum
    		 81 81 162
        Missing
    		 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    Panitumumab + BSC
    Reporting group description
    		 Participants received panitumumab administered intravenously 6 mg/kg every 14 days plus best supportive care (BSC) until disease progression, withdrawal of consent, death, or intolerance of study drug.

    Reporting group title
    BSC Alone
    Reporting group description
    		 Participants received best supportive care until disease progression, withdrawal of consent, or death.

    Primary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Overall survival was defined as the time from the randomization date to the date of death. Participants who had not died by the analysis data cut-off date were censored at their last contact date and participants with survival data obtained after the planned analysis data cut-off date had survival censored at the cut-off date. The Intent to Treat (ITT) Analysis Set included all randomized participants; participants in the ITT Analysis Set were required to have wild-type KRAS exon 2 (codons 12 and 13, alleles G12A, G12D, G12R, G12C, G12S, G12V, or G13D) per protocol.
    End point type
    Primary
    End point timeframe
    From randomization to the last on-study or long-term follow-up visit, as of the data cut-off date of 24 July 2015. The median follow-up time was 34.4 weeks (panitumumab plus BSC: 40.3 weeks; BSC alone: 25.3 weeks).
    End point values
    		 Panitumumab + BSC BSC Alone
    Number of subjects analysed
    189
    188
    Units: months
        median (confidence interval 95%)
    10.0 (8.7 to 11.3)
    7.4 (5.8 to 9.3)
    Statistical analysis title
    		 Primary Analysis
    Statistical analysis description
    The primary hypothesis was that panitumumab plus BSC would improve overall survival compared to BSC alone. A comparison between treatments was performed using the log-rank test stratified by the randomization factors at a 5% significance level.
    Comparison groups
    Panitumumab + BSC v BSC Alone
    Number of subjects included in analysis
    377
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0086 [1]
    Method
    		 Logrank
    Confidence interval
    Notes
    [1] - Log-rank test stratified by randomization factors: geographic region (Europe vs Asia vs rest of world) and ECOG performance status (0 or 1 vs 2).

    Secondary: Progression-free Survival

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    End point title
    		 Progression-free Survival
    End point description
    Progression-free survival (PFS) was defined as the time from the randomization date to the date of disease progression per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 or death. Progressive disease (PD): At least a 20% increase in the size of target lesions compared with the smallest size since treatment started and an absolute increase of at least 5 mm, any new lesions or an increase in size of non-target lesions thought be ≥ 20% and an absolute increase of at least 5 mm, or significant increase in pleural effusions, ascites or other fluid collections with cytologic proof of malignancy. Participants who were alive and did not meet the criteria for progression by the analysis data cut-off date were censored at their last evaluable disease assessment date.
    End point type
    Secondary
    End point timeframe
    From randomization to the last on-study or long-term follow-up visit, as of the data cut-off date of 24 July 2015. The median follow-up time was 34.4 weeks (panitumumab plus BSC: 40.3 weeks; BSC alone: 25.3 weeks).
    End point values
    		 Panitumumab + BSC BSC Alone
    Number of subjects analysed
    189
    188
    Units: months
        median (confidence interval 95%)
    3.6 (3.4 to 5.3)
    1.7 (1.6 to 1.9)
    Statistical analysis title
    		 Primary Analysis
    Statistical analysis description
    PFS in the ITT Analysis Set was tested at a significance level of 5% conditional on a significant treatment effect on overall survival in the ITT Analysis Set.
    Comparison groups
    Panitumumab + BSC v BSC Alone
    Number of subjects included in analysis
    377
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [2]
    Method
    		 Logrank
    Confidence interval
    Notes
    [2] - Log-rank test stratified by randomization factors: geographic region (Europe vs Asia vs rest of world) and ECOG performance status (0 or 1 vs 2).

    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
    A secondary efficacy endpoint was overall survival in participants with wild-type rat sarcoma viral oncogene homolog (RAS) (without mutation in exons 2 [codons 12 and 13], 3 [codons 59 and 61], and 4 [codons 117 and 146] of KRAS and neuroblastoma RAS viral oncogene (NRAS)). In participants with wild-type RAS, RAS mutation status was defined by KRAS exon 2 mutation status per clinical trial assay testing and mutation status of KRAS exon 3 and 4 and NRAS exons 2, 3 and 4 per Sanger bi-directional sequencing. Overall survival was defined as the time from the randomization date to the date of death. Participants who had not died by the analysis data cut-off date were censored at their last contact date and participants with survival data obtained after the planned analysis data cut-off date had survival censored at the cut-off date.
    End point type
    Secondary
    End point timeframe
    From randomization to the last on-study or long-term follow-up visit, as of the data cut-off date of 24 July 2015. The median follow-up time was 36.1 weeks (panitumumab plus BSC: 43.7 weeks; BSC alone: 23.6 weeks).
    End point values
    		 Panitumumab + BSC BSC Alone
    Number of subjects analysed
    142
    128
    Units: months
        median (confidence interval 95%)
    10.0 (8.7 to 11.6)
    6.9 (5.2 to 7.9)
    Statistical analysis title
    		 Primary Analysis
    Statistical analysis description
    Overall survival in the Wild-type RAS Efficacy Analysis Set was compared at a significance level of 5% conditional on a significant treatment effect for progression-free survival in the ITT Analysis Set.
    Comparison groups
    Panitumumab + BSC v BSC Alone
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0152 [3]
    Method
    		 Logrank
    Confidence interval
    Notes
    [3] - Log-rank test stratified by randomization factors: geographic region (Europe vs Asia vs rest of world) and ECOG performance status (0 or 1 vs 2).

    Secondary: Progression Free Survival (PFS) in Participants with Wild-type RAS

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    End point title
    		 Progression Free Survival (PFS) in Participants with Wild-type RAS
    End point description
    PFS was defined as the time from the randomization date to the date of disease progression per RECIST version 1.1 or death. Progressive disease (PD): At least a 20% increase in the size of target lesions compared with the smallest size since treatment started and an absolute increase of at least 5 mm, any new lesions, or an increase in size of non-target lesions thought be ≥ 20% with an absolute increase of at least 5 mm, or significant increase in pleural effusions, ascites or other fluid collections with cytologic proof of malignancy. Participants who were alive and did not meet the criteria for progression by the analysis data cut-off date were censored at their last evaluable disease assessment date. The Wild-type RAS Efficacy Analysis Set consists of a subset of participants in the ITT Analysis Set without mutation in exon 2, 3, and 4 of KRAS or NRAS).
    End point type
    Secondary
    End point timeframe
    From randomization to the last on-study or long-term follow-up visit, as of the data cut-off date of 24 July 2015. The median follow-up time was 36.1 weeks (panitumumab plus BSC: 43.7 weeks; BSC alone: 23.6 weeks).
    End point values
    		 Panitumumab + BSC BSC Alone
    Number of subjects analysed
    142
    128
    Units: months
        median (confidence interval 95%)
    5.2 (3.5 to 5.3)
    1.7 (1.6 to 2.2)
    Statistical analysis title
    		 Primary Analysis
    Statistical analysis description
    PFS in the Wild-type RAS Efficacy Analysis Set was to be compared at a significance level of 5% if overall survival in the wild-type RAS Efficacy Anaysis Set demonstrated a significant treatment effect.
    Comparison groups
    Panitumumab + BSC v BSC Alone
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [4]
    Method
    		 Logrank
    Confidence interval
    Notes
    [4] - Log-rank test stratified by randomization factors: geographic region (Europe vs Asia vs rest of world) and ECOG performance status (0 or 1 vs 2).

    Secondary: Objective Response Rate

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    End point title
    		 Objective Response Rate
    End point description
    Objective response rate (ORR) is defined as the percentage of participants with either a complete response (CR) or partial response (PR) per RECIST version 1.1. Radiographic tumor assessments and investigator’s assessment of response were performed at Week 4, Week 8, and then every 8 weeks until disease progression (radiographic or clinical progression). CR: Disappearance of all target and non-target lesions and no new lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR: At least a 30% decrease in the size of target lesions with 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 lesions not qualifying for either CR or PD and no new lesions.
    End point type
    Secondary
    End point timeframe
    Response was assessed at Week 4, Week 8, and then every 8 weeks until the data cut-off date of 24 July 2015. The median follow-up time was 34.4 weeks (panitumumab plus BSC: 40.3 weeks; BSC alone: 25.3 weeks).
    End point values
    		 Panitumumab + BSC BSC Alone
    Number of subjects analysed
    189
    188
    Units: percentage of participants
        number (confidence interval 95%)
    26.98 (20.80 to 33.91)
    1.60 (0.33 to 4.59)
    Statistical analysis title
    		 Primary Analysis
    Statistical analysis description
    ORR was not formally tested and the p-values are descriptive only. An exact test was used to test the hypothesis that the common odds ratio for panitumumab plus BSC relative to BSC alone for the objective response is equal to 1.0 stratified by the randomization factors.
    Comparison groups
    Panitumumab + BSC v BSC Alone
    Number of subjects included in analysis
    377
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [5]
    Method
    		 Stratified exact test
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    24.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 7.47
         upper limit
    		 123.77
    Notes
    [5] - Stratified by randomization factors: geographic region (Europe vs Asia vs rest of world) and ECOG performance status (0 or 1 vs 2).

    Secondary: Objective Response Rate in Participants with Wild-type RAS

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    End point title
    		 Objective Response Rate in Participants with Wild-type RAS
    End point description
    Objective response rate is defined as the percentage of participants with either a complete response (CR) or partial response (PR) per RECIST version 1.1. Radiographic tumor assessments and investigator’s assessment of response were performed at Week 4, Week 8, and then every 8 weeks until disease progression (radiographic or clinical progression). CR: Disappearance of all target and non-target lesions and no new lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR: At least a 30% decrease in the size of target lesions with 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 lesions not qualifying for either CR or PD and no new lesions. The Wild-type RAS Efficacy Analysis Set was used for the analysis.
    End point type
    Secondary
    End point timeframe
    Response was assessed at Week 4, Week 8, and then every 8 weeks until the data cut-off date of 24 July 2015. The median follow-up time was 36.1 weeks (panitumumab plus BSC: 43.7 weeks; BSC alone: 23.6 weeks).
    End point values
    		 Panitumumab + BSC BSC Alone
    Number of subjects analysed
    142
    128
    Units: percentage of participants
        number (confidence interval 95%)
    30.99 (23.50 to 39.28)
    2.34 (0.49 to 6.70)
    Statistical analysis title
    		 Primary Analysis
    Statistical analysis description
    ORR was not formally tested and the p-values are descriptive only. An exact test was used to test the hypothesis that the common odds ratio for panitumumab plus BSC relative to BSC alone for the objective response is equal to 1.0 stratified by the randomization factors.
    Comparison groups
    Panitumumab + BSC v BSC Alone
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [6]
    Method
    		 Stratified exact test
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    20
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.89
         upper limit
    		 101.62
    Notes
    [6] - Stratified by randomization factors: geographic region (Europe vs Asia vs rest of world) and ECOG performance status (0 or 1 vs 2).

    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
    The severity of each AE was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 (Grade 1 = Mild; 2 = Moderate (discomfort enough to cause interference with usual activity); 3 = Severe (incapacitating with inability to work or do usual activity); 4 = Life-threatening and 5 = Fatal), with the exception of the skin-or nail-related AEs which were graded using a CTCAE version 3.0 with modifications. A serious AE was defined as an AE that met at least 1 of the following criteria: • fatal, • life-threatening, • required in-patient hospitalization or prolongation of existing hospitalization, • resulted in persistent or significant disability/incapacity, • congenital anomaly/birth defect, and/or • other medically important serious event. Treatment-related AEs (TRAEs) are those the investigator considered there was reasonable possibility that the event might have been caused by study drug.
    End point type
    Secondary
    End point timeframe
    From first dose until 30 days after last dose; median safety reporting periods were 4.2 months and 2.2 months for panitumumab plus BSC arm and BSC alone arm, respectively.
    End point values
    		 Panitumumab + BSC BSC Alone
    Number of subjects analysed
    189
    188
    Units: participants
        Any adverse event (AE)|
    184
    115
        AE with worst grade of 3|
    71
    30
        AE with worst grade of 4|
    17
    5
        AE with worst grade of 5|
    8
    15
        Serious adverse event (SAE)|
    48
    37
        AE leading to discontinuation of panitumumab|
    19
    0
        Treatment-related adverse event (TRAE)|
    166
    7
        Treatment-related AE with worst grade of 3|
    42
    1
        Treatment-related AE with worst grade of 4|
    4
    1
        Treatment-related AE with worst grade of 5|
    0
    1
        Serious treatment-related AE|
    2
    3
        TRAE leading to discontinuation of panitumumab|
    1
    0
    No statistical analyses for this end point

    Secondary: Maximum Post-baseline Change from Baseline in Corrected QT (QTc) Interval

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    End point title
    		 Maximum Post-baseline Change from Baseline in Corrected QT (QTc) Interval
    End point description
    QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle as measured by electrocardiogram (ECG). QTc is the QT interval corrected for heart rate. ECGs were collected at the following time points from participants randomized to panitumumab arm at a limited number of sites: Week 1 prior to first panitumumab infusion (Baseline) and within 30 minutes following the end of the first infusion of panitumumab (Cmax), Week 7 after 3 doses of panitumumab (steady state), and the safety follow-up visit. ECGs were submitted for independent central review to calculate the reported QTc interval using both the Bazett correction (QTcB) and the Fridericia correction (QTcF). The QTc Analysis Set consists of a subset of participants in the Safety Analysis Set who received at least one panitumumab dose and were enrolled at one of the sites participating in QTc evaluation and had baseline and at least 1 post-baseline QTc assessment.
    End point type
    Secondary
    End point timeframe
    Baseline (pre-dose), Week 1 and Week 7 (post-dose) and 4 weeks after the last dose (Safety Follow-up visit)
    End point values
    		 Panitumumab + BSC BSC Alone
    Number of subjects analysed
    53
    0 [7]
    Units: msec
    arithmetic mean (standard deviation)
        QTcF
    14.58 ± 13.60
    ±
        QTcB
    12.57 ± 12.15
    ±
    Notes
    [7] - QTC was only analyzed in participants who received panitumumab
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose until 30 days after last dose; median safety reporting periods were 4.2 months and 2.2 months for panitumumab plus BSC arm and BSC alone arm, respectively.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Panitumumab + BSC
    Reporting group description
    		 Participants received panitumumab administered intravenously 6 mg/kg every 14 days plus best supportive care (BSC) until disease progression, withdrawal of consent, death, or intolerance of study drug.

    Reporting group title
    BSC Alone
    Reporting group description
    		 Participants received best supportive care until disease progression, withdrawal of consent, or death.

    Serious adverse events
    		 Panitumumab + BSC BSC Alone
    Total subjects affected by serious adverse events
         subjects affected / exposed
    48 / 189 (25.40%)
    37 / 188 (19.68%)
         number of deaths (all causes)
    8
    15
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon cancer
         subjects affected / exposed
    3 / 189 (1.59%)
    3 / 188 (1.60%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 3
    0 / 3
    Colorectal cancer
         subjects affected / exposed
    1 / 189 (0.53%)
    3 / 188 (1.60%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    1 / 3
    Colorectal cancer metastatic
         subjects affected / exposed
    2 / 189 (1.06%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Colorectal cancer recurrent
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastases to central nervous system
         subjects affected / exposed
    2 / 189 (1.06%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to ovary
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 189 (0.53%)
    2 / 188 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 189 (0.00%)
    3 / 188 (1.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 189 (0.00%)
    2 / 188 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 188 (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
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Injury, poisoning and procedural complications
    Humerus fracture
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Pyloric stenosis
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 188 (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 myocardial infarction
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial ischaemia
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 188 (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
    Brain oedema
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 189 (0.00%)
    2 / 188 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lateral medullary syndrome
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 189 (1.06%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Speech disorder
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 189 (0.53%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 189 (0.53%)
    2 / 188 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone marrow toxicity
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Diplopia
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    3 / 189 (1.59%)
    3 / 188 (1.60%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal necrosis
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrointestinal obstruction
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    3 / 189 (1.59%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    3 / 189 (1.59%)
    3 / 188 (1.60%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nausea
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stenosis
         subjects affected / exposed
    1 / 189 (0.53%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    1 / 189 (0.53%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 189 (0.53%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 188 (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
    Acne
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    1 / 189 (0.53%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive uropathy
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric obstruction
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract inflammation
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Spinal pain
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 188 (0.53%)
         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
    2 / 189 (1.06%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Urinary tract infection
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Panitumumab + BSC BSC Alone
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    174 / 189 (92.06%)
    75 / 188 (39.89%)
    Investigations
    Weight decreased
         subjects affected / exposed
    13 / 189 (6.88%)
    5 / 188 (2.66%)
         occurrences all number
    19
    6
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    14 / 189 (7.41%)
    16 / 188 (8.51%)
         occurrences all number
    28
    21
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    28 / 189 (14.81%)
    14 / 188 (7.45%)
         occurrences all number
    42
    20
    Pyrexia
         subjects affected / exposed
    16 / 189 (8.47%)
    9 / 188 (4.79%)
         occurrences all number
    21
    12
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    29 / 189 (15.34%)
    18 / 188 (9.57%)
         occurrences all number
    38
    24
    Constipation
         subjects affected / exposed
    16 / 189 (8.47%)
    12 / 188 (6.38%)
         occurrences all number
    17
    13
    Diarrhoea
         subjects affected / exposed
    25 / 189 (13.23%)
    7 / 188 (3.72%)
         occurrences all number
    44
    7
    Dyspepsia
         subjects affected / exposed
    10 / 189 (5.29%)
    2 / 188 (1.06%)
         occurrences all number
    10
    2
    Nausea
         subjects affected / exposed
    11 / 189 (5.82%)
    10 / 188 (5.32%)
         occurrences all number
    18
    13
    Stomatitis
         subjects affected / exposed
    12 / 189 (6.35%)
    0 / 188 (0.00%)
         occurrences all number
    15
    0
    Vomiting
         subjects affected / exposed
    12 / 189 (6.35%)
    7 / 188 (3.72%)
         occurrences all number
    12
    8
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform
         subjects affected / exposed
    54 / 189 (28.57%)
    0 / 188 (0.00%)
         occurrences all number
    105
    0
    Acne
         subjects affected / exposed
    26 / 189 (13.76%)
    0 / 188 (0.00%)
         occurrences all number
    49
    0
    Dry skin
         subjects affected / exposed
    29 / 189 (15.34%)
    1 / 188 (0.53%)
         occurrences all number
    40
    1
    Erythema
         subjects affected / exposed
    23 / 189 (12.17%)
    0 / 188 (0.00%)
         occurrences all number
    35
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    20 / 189 (10.58%)
    0 / 188 (0.00%)
         occurrences all number
    25
    0
    Pruritus
         subjects affected / exposed
    47 / 189 (24.87%)
    0 / 188 (0.00%)
         occurrences all number
    80
    0
    Rash
         subjects affected / exposed
    73 / 189 (38.62%)
    2 / 188 (1.06%)
         occurrences all number
    142
    2
    Rash maculo-papular
         subjects affected / exposed
    10 / 189 (5.29%)
    0 / 188 (0.00%)
         occurrences all number
    35
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    14 / 189 (7.41%)
    10 / 188 (5.32%)
         occurrences all number
    20
    11
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    12 / 189 (6.35%)
    0 / 188 (0.00%)
         occurrences all number
    28
    0
    Paronychia
         subjects affected / exposed
    27 / 189 (14.29%)
    0 / 188 (0.00%)
         occurrences all number
    56
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    18 / 189 (9.52%)
    16 / 188 (8.51%)
         occurrences all number
    25
    16
    Hypoalbuminaemia
         subjects affected / exposed
    10 / 189 (5.29%)
    3 / 188 (1.60%)
         occurrences all number
    16
    3
    Hypocalcaemia
         subjects affected / exposed
    14 / 189 (7.41%)
    1 / 188 (0.53%)
         occurrences all number
    23
    1
    Hypokalaemia
         subjects affected / exposed
    11 / 189 (5.82%)
    1 / 188 (0.53%)
         occurrences all number
    17
    1
    Hypomagnesaemia
         subjects affected / exposed
    53 / 189 (28.04%)
    2 / 188 (1.06%)
         occurrences all number
    112
    2

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Oct 2012
    • Clarified that the investigator’s assessment of response will be used to determine tumor response and progression for the purposes of management of a subject and for the analysis of PFS and ORR endpoints. Tumor imaging studies will be submitted to a central repository location. • Specified that tumor radiographic imaging scans performed according to the Schedule of Assessments must be submitted to the central imaging vendor. • Specified additional collection of blood for biomarker development: blood collection for exploratory biomarker development (at study day 1 [prior to the panitumumab administration for subjects randomized to panitumumab plus BSC arm]), at time of each scheduled radiographic tumor imaging assessment (ie, at week 4 [+ 1 week], week 8 [± 1 week] and then every 8 weeks [± 1 week]) until disease progression, and at the safety follow-up visit. • Clarified that in case Amgen elects to have scans reviewed by an independent centralized radiology vendor, additional available imaging data may be requested from subjects who discontinue the treatment phase due to assessment of disease progression by the investigator that is not subsequently confirmed by the central radiology review. • Clarified that for the purposes of the PFS and ORR analyses, the determination of objective disease progression will be based on investigator’s assessments. In the case Amgen elects to have scans reviewed by an independent centralized radiology vendor, additional analyses of PFS and ORR will be provided based on the central review of the scans.
    25 Jul 2013
    • Expanded the codons examined in subjects with wild-type RAS to include exons 2 [codons 12 and 13], 3 [codons 59 and 61], and 4 [codons 117 and 146] of KRAS; specify that the NRAS gene will be examined; and specify that exon 2 (codons 12 and 13) will be examined in subjects with wild-type KRAS tumors. • Updated the background and rationale sections to provide the justification for incorporating additional RAS mutations into the study objectives • Corrected Section 7 and Schedule of Assessment to ensure biomarker blood samples are collected from both arms • Updated the planned method of statistical analyses to include an alternative definition for progression-free survival by excluding deaths occurring more than 60 days after the last evaluable tumor assessment or randomization date (whichever is later) as events which will also be considered as part of planned PFS analyses. • Added language to inform the investigator to report a serious adverse event that occurs outside the protocol-specified reporting period per EU CT-3 Guidance • Added pregnancy and lactation reporting procedures

    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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