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    Clinical Trial Results:
    A Randomized, Open-Label, Controlled, Phase II Trial of Combination Chemotherapy with or without Panitumumab as First-line Treatment of Subjects with Metastatic or Recurrent Head and Neck Cancer, and Cross-over Second-line Panitumumab Monotherapy of Subjects who Fail the Combination Chemotherapy Only Arm

    Summary
    EudraCT number
    2007-005722-79
    Trial protocol
    CZ   FR   SK   ES   AT   LT   BE  
    Global end of trial date
    06 Mar 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    20 Jun 2016
    First version publication date
    31 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    20050236
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00454779
    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 Jun 2012
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Mar 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To estimate the effect of panitumumab on progression-free survival based on investigators’ tumor response assessments when added to combination chemotherapy in the first-line treatment of metastatic or recurrent squamous cell carcinoma of the head and neck (SCCHN).
    Protection of trial subjects
    This study was conducted in accordance with applicable FDA 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
    29 Jan 2007
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy
    Long term follow-up duration
    24 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 10
    Country: Number of subjects enrolled
    Belgium: 16
    Country: Number of subjects enrolled
    Czech Republic: 2
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Lithuania: 1
    Country: Number of subjects enrolled
    Slovakia: 2
    Country: Number of subjects enrolled
    Spain: 9
    Country: Number of subjects enrolled
    United States: 68
    Worldwide total number of subjects
    113
    EEA total number of subjects
    45
    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)
    88
    From 65 to 84 years
    25
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Subjects were enrolled from 29 January 2007 to 1 September 2010.

    Pre-assignment
    Screening details
    A total of 148 subjects were screened; 113 subjects were randomized to first-line treatment (56 in the panitumumab plus chemotherapy arm and 57 in the chemotherapy alone arm) and 35 were considered screen failures.

    Period 1
    Period 1 title
    First-line Treatment Phase
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Panitumumab + Chemotherapy
    Arm description
    During the first-line treatment phase, subjects received panitumumab 9 mg/kg as an intravenous infusion before docetaxel 75 mg/m² and cisplatin 75 mg/m² combination chemotherapy in cycles repeated every 21 days for a maximum of 6 cycles. Subjects who had complete response, partial response, or stable disease and completed 6 cycles of first-line treatment and those subjects who discontinued chemotherapy for intolerability prior to progression remained on first-line panitumumab monotherapy until disease progression, unacceptable toxicities, withdrawal of consent, or death, whichever occurred first.
    Arm type
    Experimental

    Investigational medicinal product name
    Panitumumab
    Investigational medicinal product code
    AMG 954
    Other name
    Vectibix®
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Panitumumab 9 mg/kg was administered intravenously over 1 hour every 21 ± 3 days.

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Docetaxel 75 mg/m² was administered by continuous intravenous infusion over 1 hour on day 1 of each cycle.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cisplatin 75 mg/m² was infused after docetaxel infusion over 1 hour ± 15 minutes on day 1 of each cycle.

    Arm title
    Chemotherapy Alone
    Arm description
    During the first-line treatment phase, subjects received docetaxel 75 mg/m² and cisplatin 75 mg/m² combination chemotherapy in cycles repeated every 21 days for a maximum of 6 cycles.
    Arm type
    Active comparator

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Docetaxel 75 mg/m² was administered by continuous intravenous infusion over 1 hour on day 1 of each cycle.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cisplatin 75 mg/m² was infused after docetaxel infusion over 1 hour ± 15 minutes on day 1 of each cycle.

    Number of subjects in period 1
    Panitumumab + Chemotherapy Chemotherapy Alone
    Started
    56
    57
    Received Study Medication
    56
    55
    Completed
    51
    49
    Not completed
    5
    8
         Consent withdrawn by subject
    2
    4
         Ongoing
    1
    -
         Ended follow-up prior to analysis
    1
    1
         Lost to follow-up
    1
    -
         Lack of efficacy
    -
    2
         Protocol deviation
    -
    1
    Period 2
    Period 2 title
    Second-line Treatment Phase
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Panitumumab Monotherapy
    Arm description
    Eligible subjects in the chemotherapy alone arm who were determined to have disease progression before or after completing 6 cycles of chemotherapy in first-line treatment received second-line panitumumab monotherapy in cycles repeated every 21 days until disease progression, unacceptable toxicities, withdrawal of consent, or death, whichever occurred first.
    Arm type
    Crossover

    Investigational medicinal product name
    Panitumumab
    Investigational medicinal product code
    AMG 954
    Other name
    Vectibix®
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Panitumumab 9 mg/kg was administered intravenously over 1 hour every 21 ± 3 days.

    Number of subjects in period 2 [1]
    Panitumumab Monotherapy
    Started
    30
    Completed
    27
    Not completed
    3
         Consent withdrawn by subject
    1
         Ongoing
    1
         Ended follow-up prior to analysis
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Only eligible subjects in the chemotherapy alone arm who were determined to have disease progression before or after completing 6 cycles of chemotherapy in first-line treatment received second-line panitumumab monotherapy.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Panitumumab + Chemotherapy
    Reporting group description
    During the first-line treatment phase, subjects received panitumumab 9 mg/kg as an intravenous infusion before docetaxel 75 mg/m² and cisplatin 75 mg/m² combination chemotherapy in cycles repeated every 21 days for a maximum of 6 cycles. Subjects who had complete response, partial response, or stable disease and completed 6 cycles of first-line treatment and those subjects who discontinued chemotherapy for intolerability prior to progression remained on first-line panitumumab monotherapy until disease progression, unacceptable toxicities, withdrawal of consent, or death, whichever occurred first.

    Reporting group title
    Chemotherapy Alone
    Reporting group description
    During the first-line treatment phase, subjects received docetaxel 75 mg/m² and cisplatin 75 mg/m² combination chemotherapy in cycles repeated every 21 days for a maximum of 6 cycles.

    Reporting group values
    Panitumumab + Chemotherapy Chemotherapy Alone Total
    Number of subjects
    56 57 113
    Age categorical
    Units: Subjects
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    58.2 ( 8.6 ) 58.9 ( 7.4 ) -
    Gender, Male/Female
    Units: Participants
        Female
    9 5 14
        Male
    47 52 99
    Eastern Cooperative Oncology Group (ECOG) Performance Status
    Grade 0: Fully active, able to carry on all pre-disease performance without restriction; Grade 1: Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house or office work; Grade 2: Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours; Grade 3: Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours; Grade 4: Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair; Grade 5: Dead.
    Units: Subjects
        ECOG Performance Status: 0
    21 20 41
        ECOG Performance Status: 1
    35 37 72
    Disease Status
    Units: Subjects
        newly diagnosed/previously untreated
    8 7 15
        Recurrent
    48 50 98

    End points

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    End points reporting groups
    Reporting group title
    Panitumumab + Chemotherapy
    Reporting group description
    During the first-line treatment phase, subjects received panitumumab 9 mg/kg as an intravenous infusion before docetaxel 75 mg/m² and cisplatin 75 mg/m² combination chemotherapy in cycles repeated every 21 days for a maximum of 6 cycles. Subjects who had complete response, partial response, or stable disease and completed 6 cycles of first-line treatment and those subjects who discontinued chemotherapy for intolerability prior to progression remained on first-line panitumumab monotherapy until disease progression, unacceptable toxicities, withdrawal of consent, or death, whichever occurred first.

    Reporting group title
    Chemotherapy Alone
    Reporting group description
    During the first-line treatment phase, subjects received docetaxel 75 mg/m² and cisplatin 75 mg/m² combination chemotherapy in cycles repeated every 21 days for a maximum of 6 cycles.
    Reporting group title
    Panitumumab Monotherapy
    Reporting group description
    Eligible subjects in the chemotherapy alone arm who were determined to have disease progression before or after completing 6 cycles of chemotherapy in first-line treatment received second-line panitumumab monotherapy in cycles repeated every 21 days until disease progression, unacceptable toxicities, withdrawal of consent, or death, whichever occurred first.

    Primary: Progression Free Survival (PFS) During the First-line Treatment Phase

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    End point title
    Progression Free Survival (PFS) During the First-line Treatment Phase
    End point description
    The time from the date of randomization to the date of first disease progression determined by the investigators per a modified version of the Response Evaluation Criteria in Solid Tumors (RECIST v1.0) guidelines, or death within 60 days after the last evaluable tumor assessment or randomization date (whichever is later) during the first-line treatment phase. Subjects not meeting the criteria by the cutoff date were censored at the last evaluable tumor assessment during the first-line treatment phase. This analysis was performed in the Primary Analysis Set: all randomized subjects < 70 years of age who provided informed consent and received at least 1 dose of first-line treatment.
    End point type
    Primary
    End point timeframe
    Every 6 weeks until disease progression or death, up to 67 months
    End point values
    Panitumumab + Chemotherapy Chemotherapy Alone
    Number of subjects analysed
    52
    51
    Units: Months
        median (confidence interval 95%)
    6.9 (4.7 to 8.3)
    5.5 (4.1 to 6.8)
    Statistical analysis title
    Primary Analysis
    Statistical analysis description
    The primary analysis reflects the Cox proportional hazards model stratified by the interactive voice response system (IVRS) randomization factors: ECOG performance score (0 vs. 1) and disease status (newly diagnosed/previously untreated vs. recurrent). The hazard ratio is presented as panitumumab plus chemotherapy:chemotherapy alone. A value < 1.0 indicates a lower average event rate and longer time to event for panitumumab plus chemotherapy relative to chemotherapy alone.
    Comparison groups
    Panitumumab + Chemotherapy v Chemotherapy Alone
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    other [1]
    P-value
    = 0.051
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.629
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.395
         upper limit
    1.002
    Notes
    [1] - A formal hypothesis was not tested in this trial. This study provided an estimate and corresponding 2-sided 95% confidence interval (CI) of the relative efficacy of panitumumab plus combination chemotherapy vs combination chemotherapy only as measured by the PFS hazard ratio for combination chemotherapy with panitumumab relative to combination chemotherapy only in the first-line treatment of metastatic or recurrent SCCHN.
    Statistical analysis title
    Secondary Analysis
    Statistical analysis description
    The secondary analysis reflects a log-rank test stratified by IVRS randomization factors: ECOG performance score (0 vs. 1) and disease status (newly diagnosed/previously untreated vs. recurrent).
    Comparison groups
    Panitumumab + Chemotherapy v Chemotherapy Alone
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.048
    Method
    Logrank
    Confidence interval

    Secondary: Overall Objective Response Rate (ORR) During the First-line Treatment Phase

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    End point title
    Overall Objective Response Rate (ORR) During the First-line Treatment Phase
    End point description
    Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by the investigator using magnetic resonance imaging (MRI): Complete Response (CR), the disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter (SLD) of target lesions from Baseline; An objective response is defined as a best tumor response of CR or PR. An overall objective response of CR or PR must be confirmed at least 4 weeks after the criteria for response are first met. ORR is the percentage of subjects with an overall objective response among the analysis population. This analysis was performed in the Evaluable for Local Tumor Response Analysis Set: subset of subjects in the Primary Analysis Set with at least one unidimensionally measurable lesion at Baseline using a modified RECIST v1.0 per investigators’ review.
    End point type
    Secondary
    End point timeframe
    Every 6 weeks until disease progression or death, up to 67 months
    End point values
    Panitumumab + Chemotherapy Chemotherapy Alone
    Number of subjects analysed
    52
    51
    Units: Percentage of Participants
        arithmetic mean (confidence interval 95%)
    44.23 (30.73 to 57.73)
    37.25 (23.99 to 50.52)
    Statistical analysis title
    Weighted Difference in Rates
    Statistical analysis description
    The difference in rates and confidence intervals are calculated using the Mantel-Haenszel weights within strata defined by IVRS randomization factors: ECOG performance score (0 vs. 1) and disease status (newly diagnosed/previously untreated vs recurrent).
    Comparison groups
    Panitumumab + Chemotherapy v Chemotherapy Alone
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    6.23
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -11.67
         upper limit
    24.12
    Statistical analysis title
    Treatment Odds Ratio
    Statistical analysis description
    The odds ratio is defined as the odds of having an objective response in the panitumumab plus chemotherapy arm relative to the odds in the chemotherapy alone arm. It is calculated from a logistic regression model with treatment indicator and randomization factors (recorded on the case report form [CRF]) as covariates: ECOG performance status (0 vs. 1/2) and disease status (newly diagnosed/previously untreated vs previously treated).
    Comparison groups
    Panitumumab + Chemotherapy v Chemotherapy Alone
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.37
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.57
         upper limit
    3.33

    Secondary: Rate of Disease Control (RDC) During the First-line Treatment Phase

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    End point title
    Rate of Disease Control (RDC) During the First-line Treatment Phase
    End point description
    Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), the disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter (SLD) of target lesions from baseline; Disease Progression (PD), >=20% increase in the SLD of target lesions from nadir; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. An overall response of CR or PR must be confirmed at least 4 weeks after the criteria for response are first met. A best overall response of SD requires a visit response of SD or better no earlier than 35 days after randomization. RDC is the percentage of subjects with a best overall response of CR, PR or SD among the analysis population (Evaluable for Local Tumor Response Analysis Set).
    End point type
    Secondary
    End point timeframe
    Every 6 weeks until disease progression or death, up to 67 months
    End point values
    Panitumumab + Chemotherapy Chemotherapy Alone
    Number of subjects analysed
    52
    51
    Units: Percentage of Participants
        arithmetic mean (confidence interval 95%)
    80.77 (70.06 to 91.48)
    72.55 (60.3 to 84.8)
    Statistical analysis title
    Treatment Odds Ratio
    Statistical analysis description
    The odds ratio is defined as the odds of having an objective response in the panitumumab plus chemotherapy arm relative to the odds in the chemotherapy alone arm. It is calculated from a logistic regression model with treatment indicator and randomization factors (recorded on the case report form) as covariates: ECOG performance status (0 vs. 1/2) and disease status (newly diagnosed/previously untreated vs. previously treated).
    Comparison groups
    Panitumumab + Chemotherapy v Chemotherapy Alone
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.76
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.62
         upper limit
    5.26
    Statistical analysis title
    Weighted Difference in Rates
    Statistical analysis description
    The difference in rates and confidence intervals are calculated using the Mantel-Haenszel weights within strata defined by randomization factors recorded in the IVRS: ECOG performance score (0 vs. 1) and disease status (newly diagnosed/previously untreated vs. recurrent).
    Comparison groups
    Panitumumab + Chemotherapy v Chemotherapy Alone
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    7.78
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.29
         upper limit
    23.85

    Secondary: Duration of Response (DOR) During the First-line Treatment Phase

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    End point title
    Duration of Response (DOR) During the First-line Treatment Phase
    End point description
    Calculated only for the subset of subjects with an overall response of CR or PR while on first-line treatment (subsequently confirmed at least 4 weeks thereafter) assessed by the investigator, and defined as the time from the first CR or PR to the first observed disease progression according to a modified RECIST v1.0. Subjects not meeting the criteria for progression by the analysis data cutoff date were censored at their last evaluable disease assessment date. Analyzed in the Evaluable for Local Tumor Response Analysis Set; Subjects With Objective Responses.
    End point type
    Secondary
    End point timeframe
    Every 6 weeks until disease progression or death, up to 67 months
    End point values
    Panitumumab + Chemotherapy Chemotherapy Alone
    Number of subjects analysed
    23
    19
    Units: Months
        median (confidence interval 95%)
    8 (5.7 to 11.1)
    5.1 (4.4 to 7.2)
    No statistical analyses for this end point

    Secondary: Time to Response (TTR) During the First-line Treatment Phase

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    End point title
    Time to Response (TTR) During the First-line Treatment Phase
    End point description
    Time from the date of randomization to the first CR or PR during first line treatment phase (subsequently confirmed at least 4 weeks thereafter), analyzed in the Evaluable for Local Tumor Response Analysis Set; Subjects With Objective Responses.
    End point type
    Secondary
    End point timeframe
    Every 6 weeks until disease progression or death, up to 67 months
    End point values
    Panitumumab + Chemotherapy Chemotherapy Alone
    Number of subjects analysed
    23
    19
    Units: Weeks
        arithmetic mean (standard deviation)
    8.8 ( 3.9 )
    10.6 ( 6.1 )
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) For the First-line Treatment

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    End point title
    Overall Survival (OS) For the First-line Treatment
    End point description
    Time from the date of randomization to the date of death during the entire study, analyzed in the Primary Analysis Set.
    End point type
    Secondary
    End point timeframe
    Until death, up to 67 months
    End point values
    Panitumumab + Chemotherapy Chemotherapy Alone
    Number of subjects analysed
    52
    51
    Units: Months
        median (confidence interval 95%)
    12.9 (9.4 to 18.5)
    13.8 (11.8 to 22.9)
    Statistical analysis title
    Primary Analysis
    Statistical analysis description
    The primary analysis reflects the Cox proportional hazards model stratified by IVRS randomization factors: ECOG performance score (0 vs. 1) and disease status (newly diagnosed/previously untreated vs. recurrent). Hazard ratio is presented as panitumumab plus chemotherapy:chemotherapy alone. A value < 1.0 indicates a lower average event rate and longer time to event for panitumumab plus chemotherapy relative to chemotherapy alone.
    Comparison groups
    Panitumumab + Chemotherapy v Chemotherapy Alone
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.663
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.103
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.709
         upper limit
    1.717
    Statistical analysis title
    Secondary Analysis
    Statistical analysis description
    The secondary analysis reflects a log-rank test stratified by IVRS randomization factors: ECOG performance score (0 vs. 1) and disease status (newly diagnosed/previously untreated vs. recurrent).
    Comparison groups
    Panitumumab + Chemotherapy v Chemotherapy Alone
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.666
    Method
    Logrank
    Confidence interval

    Secondary: Progression Free Survival (PFS) During the Second-line Treatment Phase

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    End point title
    Progression Free Survival (PFS) During the Second-line Treatment Phase
    End point description
    The time from the first dose of panitumumab monotherapy to the date of first disease progression determined by the investigator per modified RECIST v1.0, or death within 60 days after the last evaluable tumor assessment or the second-line first dose date (whichever is later) during the second-line treatment phase. Subjects not meeting the criteria by the cutoff date were censored at the last evaluable tumor assessment during the second-line treatment phase. This endpoint was analyzed in the Evaluable Subset for Second-line Panitumumab Monotherapy: subjects who were randomized to docetaxel and cisplatin chemotherapy alone treatment for their first-line treatments and treated subsequently with at least 1 dose of panitumumab monotherapy.
    End point type
    Secondary
    End point timeframe
    From the first dose of panitumumab monotherapy, every 6 weeks until disease progression or death, up to 57 months
    End point values
    Panitumumab Monotherapy
    Number of subjects analysed
    30
    Units: Months
        median (confidence interval 95%)
    4.2 (1.5 to 7.6)
    No statistical analyses for this end point

    Secondary: Overall Objective Response Rate (ORR) During the Second-line Treatment Phase

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    End point title
    Overall Objective Response Rate (ORR) During the Second-line Treatment Phase
    End point description
    Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by the investigator using MRI: Complete Response (CR), the disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter (SLD) of target lesions from baseline; Overall Response (OR) = CR + PR. An overall response of CR or PR must be confirmed at least 4 weeks after the criteria for response are first met. ORR is the percentage of subjects with an overall objective response among the Evaluable for Local Tumor Response Analysis Set for Second-line Panitumumab Monotherapy population.
    End point type
    Secondary
    End point timeframe
    Every 6 weeks until disease progression or death, up to 57 months
    End point values
    Panitumumab Monotherapy
    Number of subjects analysed
    30
    Units: Percentage of Participants
        arithmetic mean (confidence interval 95%)
    13.33 (1.17 to 25.5)
    No statistical analyses for this end point

    Secondary: Rate of Disease Control (RDC) During the Second-line Treatment Phase

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    End point title
    Rate of Disease Control (RDC) During the Second-line Treatment Phase
    End point description
    Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), the disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter (SLD) of target lesions from Baseline; Disease Progression (PD), >=20% increase in the SLD of target lesions from nadir; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. An overall response of CR or PR must be confirmed at least 4 weeks after the criteria for response are first met. A best overall response of SD requires a visit response of SD or better no earlier than 35 days after the first dose date in second-line treatment. RDC is the percentage of subjects with a best overall response of CR, PR or SD among the Evaluable for Local Tumor Response Analysis Set for Second-line Panitumumab Monotherapy population.
    End point type
    Secondary
    End point timeframe
    Every 6 weeks until disease progression or death, up to 57 months
    End point values
    Panitumumab Monotherapy
    Number of subjects analysed
    30
    Units: Percentage of Participants
        arithmetic mean (confidence interval 95%)
    53.33 (35.48 to 71.19)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) During the Second-line Treatment Phase

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    End point title
    Duration of Response (DOR) During the Second-line Treatment Phase
    End point description
    Time from the first CR or PR in the second-line treatment phase to the first observed disease progression by a modified RECIST v1.0 per Investigator assessment. Subjects not meeting the criteria for progression by the analysis data cutoff date were censored at their last evaluable disease assessment date. Analyzed in the Evaluable for Local Tumor Response Analysis Set for Second-line Panitumumab Monotherapy: Subjects With Objective Responses. "99999" indicates values not estimable due to the low number of events.
    End point type
    Secondary
    End point timeframe
    Every 6 weeks until disease progression or death, up to 57 months
    End point values
    Panitumumab Monotherapy
    Number of subjects analysed
    4
    Units: Months
        median (confidence interval 95%)
    99999 (5.1 to 99999)
    No statistical analyses for this end point

    Secondary: Time to Response (TTR) During the Second-line Treatment Phase

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    End point title
    Time to Response (TTR) During the Second-line Treatment Phase
    End point description
    Time from the first dose of panitumumab monotherapy to the first CR or PR during second-line treatment phase (subsequently confirmed at least 4 weeks thereafter) analyzed in the Evaluable for Local Tumor Response Analysis Set for Second-line Panitumumab Monotherapy: Subjects With Objective Responses.
    End point type
    Secondary
    End point timeframe
    Every 6 weeks until disease progression or death, up to 57 months
    End point values
    Panitumumab Monotherapy
    Number of subjects analysed
    4
    Units: Weeks
        arithmetic mean (standard deviation)
    10.6 ( 5.6 )
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) for Second-line Treatment

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    End point title
    Overall Survival (OS) for Second-line Treatment
    End point description
    Time from the first dose of panitumumab monotherapy to the date of death during the second-line treatment phase, analyzed in the Evaluable Subset for Second-line Panitumumab Monotherapy population.
    End point type
    Secondary
    End point timeframe
    Until death, up to 57 months
    End point values
    Panitumumab Monotherapy
    Number of subjects analysed
    30
    Units: Months
        median (confidence interval 95%)
    8.5 (6.5 to 13.2)
    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 in each part of the study. The median time frame is 4.5, 4.4 and 3.7 months by treatment group respectively.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    First-line: Panitumumab Plus Chemotherapy
    Reporting group description
    During the first-line treatment phase, subjects received panitumumab 9 mg/kg as an intravenous infusion before docetaxel 75 mg/m² and cisplatin 75 mg/m² combination chemotherapy in cycles repeated every 21 days for a maximum of 6 cycles.

    Reporting group title
    First-line: Chemotherapy Alone
    Reporting group description
    During the first-line treatment phase, subjects received docetaxel 75 mg/m² and cisplatin 75 mg/m² combination chemotherapy in cycles repeated every 21 days for a maximum of 6 cycles.

    Reporting group title
    Second-line: Panitumumab Monotherapy
    Reporting group description
    Eligible subjects in the chemotherapy alone arm who were determined to have disease progression before or after completing 6 cycles of chemotherapy in first-line treatment received second-line panitumumab monotherapy in cycles repeated every 21 days until disease progression, unacceptable toxicities, withdrawal of consent, or death, whichever occurred first.

    Serious adverse events
    First-line: Panitumumab Plus Chemotherapy First-line: Chemotherapy Alone Second-line: Panitumumab Monotherapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    34 / 56 (60.71%)
    27 / 55 (49.09%)
    10 / 30 (33.33%)
         number of deaths (all causes)
    9
    3
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    HEAD AND NECK CANCER
         subjects affected / exposed
    2 / 56 (3.57%)
    0 / 55 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MALIGNANT ASCITES
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    NEOPLASM MALIGNANT
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    NEOPLASM PROGRESSION
         subjects affected / exposed
    1 / 56 (1.79%)
    1 / 55 (1.82%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    TUMOUR HAEMORRHAGE
         subjects affected / exposed
    2 / 56 (3.57%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    TUMOUR ULCERATION
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    ARTERIAL HAEMORRHAGE
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPOTENSION
         subjects affected / exposed
    5 / 56 (8.93%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CHILLS
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DEVICE DISLOCATION
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GENERAL PHYSICAL HEALTH DETERIORATION
         subjects affected / exposed
    3 / 56 (5.36%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    LOCALISED OEDEMA
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MALAISE
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MUCOSAL INFLAMMATION
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    OEDEMA PERIPHERAL
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PYREXIA
         subjects affected / exposed
    2 / 56 (3.57%)
    4 / 55 (7.27%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    ASPIRATION
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DYSPNOEA
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HAEMOPTYSIS
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPOXIA
         subjects affected / exposed
    2 / 56 (3.57%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    INTERSTITIAL LUNG DISEASE
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA ASPIRATION
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    RESPIRATORY FAILURE
         subjects affected / exposed
    1 / 56 (1.79%)
    1 / 55 (1.82%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Psychiatric disorders
    CONFUSIONAL STATE
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 55 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MENTAL STATUS CHANGES
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    BLOOD CREATINE INCREASED
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HEPATIC ENZYME INCREASED
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    INTERNATIONAL NORMALISED RATIO INCREASED
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    TRANSAMINASES INCREASED
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    ARTERIAL INJURY
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    FEEDING TUBE COMPLICATION
         subjects affected / exposed
    1 / 56 (1.79%)
    1 / 55 (1.82%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HUMERUS FRACTURE
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    POST PROCEDURAL DISCHARGE
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    POST PROCEDURAL HAEMORRHAGE
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    STERNAL FRACTURE
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    ACUTE MYOCARDIAL INFARCTION
         subjects affected / exposed
    1 / 56 (1.79%)
    1 / 55 (1.82%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ARTERIOSCLEROSIS CORONARY ARTERY
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ATRIAL FIBRILLATION
         subjects affected / exposed
    2 / 56 (3.57%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CARDIAC FAILURE CONGESTIVE
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    ATAXIA
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 55 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CEREBROVASCULAR ACCIDENT
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 55 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    CONVULSION
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 55 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DIZZINESS
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 55 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PRESYNCOPE
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SYNCOPE
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    1 / 56 (1.79%)
    3 / 55 (5.45%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    FEBRILE NEUTROPENIA
         subjects affected / exposed
    3 / 56 (5.36%)
    4 / 55 (7.27%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    NEUTROPENIA
         subjects affected / exposed
    3 / 56 (5.36%)
    3 / 55 (5.45%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PANCYTOPENIA
         subjects affected / exposed
    2 / 56 (3.57%)
    1 / 55 (1.82%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    THROMBOCYTOPENIA
         subjects affected / exposed
    2 / 56 (3.57%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    2 / 56 (3.57%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ABDOMINAL WALL DISORDER
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 55 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    APHAGIA
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    APHTHOUS STOMATITIS
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CONSTIPATION
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    6 / 56 (10.71%)
    2 / 55 (3.64%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    8 / 9
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DUODENAL ULCER PERFORATION
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DYSPHAGIA
         subjects affected / exposed
    0 / 56 (0.00%)
    3 / 55 (5.45%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    2 / 56 (3.57%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HAEMATEMESIS
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ILEUS
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    INTESTINAL OBSTRUCTION
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    NAUSEA
         subjects affected / exposed
    2 / 56 (3.57%)
    4 / 55 (7.27%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    OESOPHAGEAL STENOSIS
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 55 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ORAL CAVITY FISTULA
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    TONGUE HAEMORRHAGE
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 55 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    VOMITING
         subjects affected / exposed
    2 / 56 (3.57%)
    4 / 55 (7.27%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    2 / 2
    4 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    CHOLECYSTITIS
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HEPATIC FAILURE
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Skin and subcutaneous tissue disorders
    ACNE
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    ACUTE PRERENAL FAILURE
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RENAL FAILURE
         subjects affected / exposed
    0 / 56 (0.00%)
    3 / 55 (5.45%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RENAL FAILURE ACUTE
         subjects affected / exposed
    2 / 56 (3.57%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    MUSCULAR WEAKNESS
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 55 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MUSCULOSKELETAL CHEST PAIN
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RHABDOMYOLYSIS
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    ABDOMINAL ABSCESS
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BETA HAEMOLYTIC STREPTOCOCCAL INFECTION
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BRONCHITIS
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 55 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CELLULITIS
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CLOSTRIDIUM DIFFICILE COLITIS
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    FUNGAEMIA
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    NEUTROPENIC SEPSIS
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ORAL INFECTION
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    OSTEOMYELITIS
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    4 / 56 (7.14%)
    6 / 55 (10.91%)
    3 / 30 (10.00%)
         occurrences causally related to treatment / all
    3 / 5
    4 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA STAPHYLOCOCCAL
         subjects affected / exposed
    2 / 56 (3.57%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    PSEUDOMONAL SEPSIS
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PSEUDOMONAS INFECTION
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SEPSIS
         subjects affected / exposed
    3 / 56 (5.36%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    3 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    SEPTIC SHOCK
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    STAPHYLOCOCCAL INFECTION
         subjects affected / exposed
    1 / 56 (1.79%)
    2 / 55 (3.64%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    STAPHYLOCOCCAL SEPSIS
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    STENOTROPHOMONAS INFECTION
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    UROSEPSIS
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    WOUND INFECTION
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DEHYDRATION
         subjects affected / exposed
    8 / 56 (14.29%)
    2 / 55 (3.64%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    6 / 10
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ELECTROLYTE IMBALANCE
         subjects affected / exposed
    2 / 56 (3.57%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    FAILURE TO THRIVE
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 55 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPERNATRAEMIA
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPOCALCAEMIA
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPOKALAEMIA
         subjects affected / exposed
    1 / 56 (1.79%)
    1 / 55 (1.82%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPOMAGNESAEMIA
         subjects affected / exposed
    1 / 56 (1.79%)
    2 / 55 (3.64%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPONATRAEMIA
         subjects affected / exposed
    1 / 56 (1.79%)
    1 / 55 (1.82%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MALNUTRITION
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 55 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    First-line: Panitumumab Plus Chemotherapy First-line: Chemotherapy Alone Second-line: Panitumumab Monotherapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    54 / 56 (96.43%)
    53 / 55 (96.36%)
    26 / 30 (86.67%)
    Vascular disorders
    HYPERTENSION
         subjects affected / exposed
    3 / 56 (5.36%)
    2 / 55 (3.64%)
    0 / 30 (0.00%)
         occurrences all number
    5
    2
    0
    HYPOTENSION
         subjects affected / exposed
    6 / 56 (10.71%)
    2 / 55 (3.64%)
    2 / 30 (6.67%)
         occurrences all number
    6
    3
    2
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    13 / 56 (23.21%)
    5 / 55 (9.09%)
    3 / 30 (10.00%)
         occurrences all number
    25
    6
    4
    CHILLS
         subjects affected / exposed
    5 / 56 (8.93%)
    3 / 55 (5.45%)
    2 / 30 (6.67%)
         occurrences all number
    6
    3
    2
    FACE OEDEMA
         subjects affected / exposed
    4 / 56 (7.14%)
    1 / 55 (1.82%)
    1 / 30 (3.33%)
         occurrences all number
    5
    1
    1
    LOCALISED OEDEMA
         subjects affected / exposed
    1 / 56 (1.79%)
    1 / 55 (1.82%)
    2 / 30 (6.67%)
         occurrences all number
    1
    1
    2
    FATIGUE
         subjects affected / exposed
    28 / 56 (50.00%)
    28 / 55 (50.91%)
    5 / 30 (16.67%)
         occurrences all number
    50
    43
    5
    MUCOSAL INFLAMMATION
         subjects affected / exposed
    15 / 56 (26.79%)
    7 / 55 (12.73%)
    1 / 30 (3.33%)
         occurrences all number
    24
    7
    2
    OEDEMA
         subjects affected / exposed
    4 / 56 (7.14%)
    1 / 55 (1.82%)
    0 / 30 (0.00%)
         occurrences all number
    4
    1
    0
    OEDEMA PERIPHERAL
         subjects affected / exposed
    4 / 56 (7.14%)
    10 / 55 (18.18%)
    2 / 30 (6.67%)
         occurrences all number
    4
    12
    2
    PAIN
         subjects affected / exposed
    4 / 56 (7.14%)
    1 / 55 (1.82%)
    1 / 30 (3.33%)
         occurrences all number
    4
    1
    1
    PYREXIA
         subjects affected / exposed
    8 / 56 (14.29%)
    8 / 55 (14.55%)
    3 / 30 (10.00%)
         occurrences all number
    12
    8
    3
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    8 / 56 (14.29%)
    5 / 55 (9.09%)
    3 / 30 (10.00%)
         occurrences all number
    10
    8
    3
    DYSPNOEA
         subjects affected / exposed
    11 / 56 (19.64%)
    9 / 55 (16.36%)
    2 / 30 (6.67%)
         occurrences all number
    14
    10
    2
    EPISTAXIS
         subjects affected / exposed
    6 / 56 (10.71%)
    2 / 55 (3.64%)
    1 / 30 (3.33%)
         occurrences all number
    7
    2
    1
    HAEMOPTYSIS
         subjects affected / exposed
    3 / 56 (5.36%)
    1 / 55 (1.82%)
    0 / 30 (0.00%)
         occurrences all number
    3
    2
    0
    HICCUPS
         subjects affected / exposed
    2 / 56 (3.57%)
    6 / 55 (10.91%)
    0 / 30 (0.00%)
         occurrences all number
    2
    6
    0
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    3 / 56 (5.36%)
    4 / 55 (7.27%)
    2 / 30 (6.67%)
         occurrences all number
    7
    4
    4
    PLEURAL EFFUSION
         subjects affected / exposed
    2 / 56 (3.57%)
    3 / 55 (5.45%)
    0 / 30 (0.00%)
         occurrences all number
    2
    3
    0
    PRODUCTIVE COUGH
         subjects affected / exposed
    1 / 56 (1.79%)
    2 / 55 (3.64%)
    2 / 30 (6.67%)
         occurrences all number
    1
    2
    2
    RHINORRHOEA
         subjects affected / exposed
    4 / 56 (7.14%)
    1 / 55 (1.82%)
    0 / 30 (0.00%)
         occurrences all number
    4
    1
    0
    Psychiatric disorders
    ANXIETY
         subjects affected / exposed
    8 / 56 (14.29%)
    6 / 55 (10.91%)
    3 / 30 (10.00%)
         occurrences all number
    10
    7
    4
    DEPRESSION
         subjects affected / exposed
    7 / 56 (12.50%)
    4 / 55 (7.27%)
    0 / 30 (0.00%)
         occurrences all number
    7
    4
    0
    INSOMNIA
         subjects affected / exposed
    5 / 56 (8.93%)
    4 / 55 (7.27%)
    1 / 30 (3.33%)
         occurrences all number
    7
    4
    1
    Investigations
    HAEMOGLOBIN DECREASED
         subjects affected / exposed
    3 / 56 (5.36%)
    1 / 55 (1.82%)
    0 / 30 (0.00%)
         occurrences all number
    4
    1
    0
    WEIGHT DECREASED
         subjects affected / exposed
    13 / 56 (23.21%)
    11 / 55 (20.00%)
    6 / 30 (20.00%)
         occurrences all number
    21
    12
    7
    Injury, poisoning and procedural complications
    LACERATION
         subjects affected / exposed
    3 / 56 (5.36%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    4
    0
    0
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    13 / 56 (23.21%)
    7 / 55 (12.73%)
    4 / 30 (13.33%)
         occurrences all number
    17
    8
    5
    DYSGEUSIA
         subjects affected / exposed
    5 / 56 (8.93%)
    6 / 55 (10.91%)
    1 / 30 (3.33%)
         occurrences all number
    11
    6
    1
    HEADACHE
         subjects affected / exposed
    5 / 56 (8.93%)
    8 / 55 (14.55%)
    2 / 30 (6.67%)
         occurrences all number
    5
    9
    2
    NEUROPATHY PERIPHERAL
         subjects affected / exposed
    9 / 56 (16.07%)
    11 / 55 (20.00%)
    1 / 30 (3.33%)
         occurrences all number
    15
    15
    1
    PARAESTHESIA
         subjects affected / exposed
    2 / 56 (3.57%)
    3 / 55 (5.45%)
    0 / 30 (0.00%)
         occurrences all number
    2
    4
    0
    PERIPHERAL SENSORY NEUROPATHY
         subjects affected / exposed
    2 / 56 (3.57%)
    5 / 55 (9.09%)
    2 / 30 (6.67%)
         occurrences all number
    2
    6
    3
    POLYNEUROPATHY
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    2 / 30 (6.67%)
         occurrences all number
    0
    1
    2
    SOMNOLENCE
         subjects affected / exposed
    3 / 56 (5.36%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    4
    0
    0
    SYNCOPE
         subjects affected / exposed
    3 / 56 (5.36%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    3
    0
    0
    TREMOR
         subjects affected / exposed
    3 / 56 (5.36%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    3
    0
    0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    22 / 56 (39.29%)
    27 / 55 (49.09%)
    7 / 30 (23.33%)
         occurrences all number
    58
    87
    7
    FEBRILE NEUTROPENIA
         subjects affected / exposed
    0 / 56 (0.00%)
    3 / 55 (5.45%)
    0 / 30 (0.00%)
         occurrences all number
    0
    3
    0
    LEUKOPENIA
         subjects affected / exposed
    7 / 56 (12.50%)
    5 / 55 (9.09%)
    0 / 30 (0.00%)
         occurrences all number
    8
    9
    0
    NEUTROPENIA
         subjects affected / exposed
    9 / 56 (16.07%)
    9 / 55 (16.36%)
    1 / 30 (3.33%)
         occurrences all number
    13
    16
    1
    THROMBOCYTOPENIA
         subjects affected / exposed
    5 / 56 (8.93%)
    5 / 55 (9.09%)
    1 / 30 (3.33%)
         occurrences all number
    8
    14
    1
    Ear and labyrinth disorders
    TINNITUS
         subjects affected / exposed
    0 / 56 (0.00%)
    4 / 55 (7.27%)
    2 / 30 (6.67%)
         occurrences all number
    0
    5
    2
    VERTIGO
         subjects affected / exposed
    0 / 56 (0.00%)
    4 / 55 (7.27%)
    1 / 30 (3.33%)
         occurrences all number
    0
    4
    1
    Eye disorders
    CONJUNCTIVITIS
         subjects affected / exposed
    8 / 56 (14.29%)
    0 / 55 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    13
    0
    2
    DRY EYE
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    1
    0
    2
    LACRIMATION INCREASED
         subjects affected / exposed
    2 / 56 (3.57%)
    4 / 55 (7.27%)
    0 / 30 (0.00%)
         occurrences all number
    2
    4
    0
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    7 / 56 (12.50%)
    3 / 55 (5.45%)
    0 / 30 (0.00%)
         occurrences all number
    7
    6
    0
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    2 / 56 (3.57%)
    3 / 55 (5.45%)
    1 / 30 (3.33%)
         occurrences all number
    2
    3
    1
    CONSTIPATION
         subjects affected / exposed
    15 / 56 (26.79%)
    9 / 55 (16.36%)
    3 / 30 (10.00%)
         occurrences all number
    19
    11
    3
    DIARRHOEA
         subjects affected / exposed
    25 / 56 (44.64%)
    16 / 55 (29.09%)
    5 / 30 (16.67%)
         occurrences all number
    51
    20
    5
    DRY MOUTH
         subjects affected / exposed
    2 / 56 (3.57%)
    3 / 55 (5.45%)
    2 / 30 (6.67%)
         occurrences all number
    2
    3
    2
    DYSPEPSIA
         subjects affected / exposed
    4 / 56 (7.14%)
    6 / 55 (10.91%)
    1 / 30 (3.33%)
         occurrences all number
    4
    6
    1
    DYSPHAGIA
         subjects affected / exposed
    9 / 56 (16.07%)
    4 / 55 (7.27%)
    5 / 30 (16.67%)
         occurrences all number
    11
    4
    6
    MOUTH ULCERATION
         subjects affected / exposed
    4 / 56 (7.14%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    4
    0
    0
    NAUSEA
         subjects affected / exposed
    34 / 56 (60.71%)
    33 / 55 (60.00%)
    4 / 30 (13.33%)
         occurrences all number
    60
    45
    4
    RECTAL HAEMORRHAGE
         subjects affected / exposed
    3 / 56 (5.36%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    3
    0
    0
    STOMATITIS
         subjects affected / exposed
    9 / 56 (16.07%)
    3 / 55 (5.45%)
    1 / 30 (3.33%)
         occurrences all number
    12
    4
    1
    VOMITING
         subjects affected / exposed
    15 / 56 (26.79%)
    18 / 55 (32.73%)
    2 / 30 (6.67%)
         occurrences all number
    28
    26
    2
    Skin and subcutaneous tissue disorders
    ACNE
         subjects affected / exposed
    7 / 56 (12.50%)
    0 / 55 (0.00%)
    3 / 30 (10.00%)
         occurrences all number
    23
    0
    4
    ALOPECIA
         subjects affected / exposed
    18 / 56 (32.14%)
    14 / 55 (25.45%)
    0 / 30 (0.00%)
         occurrences all number
    22
    18
    0
    DECUBITUS ULCER
         subjects affected / exposed
    3 / 56 (5.36%)
    0 / 55 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    3
    0
    1
    DERMATITIS
         subjects affected / exposed
    4 / 56 (7.14%)
    0 / 55 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    4
    0
    1
    DERMATITIS ACNEIFORM
         subjects affected / exposed
    13 / 56 (23.21%)
    0 / 55 (0.00%)
    3 / 30 (10.00%)
         occurrences all number
    33
    0
    4
    DRY SKIN
         subjects affected / exposed
    13 / 56 (23.21%)
    3 / 55 (5.45%)
    10 / 30 (33.33%)
         occurrences all number
    16
    3
    10
    ERYTHEMA
         subjects affected / exposed
    7 / 56 (12.50%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    11
    0
    0
    NAIL DISORDER
         subjects affected / exposed
    6 / 56 (10.71%)
    2 / 55 (3.64%)
    1 / 30 (3.33%)
         occurrences all number
    21
    3
    1
    PRURITUS
         subjects affected / exposed
    5 / 56 (8.93%)
    3 / 55 (5.45%)
    4 / 30 (13.33%)
         occurrences all number
    6
    3
    4
    RASH
         subjects affected / exposed
    21 / 56 (37.50%)
    2 / 55 (3.64%)
    13 / 30 (43.33%)
         occurrences all number
    42
    2
    24
    SKIN EXFOLIATION
         subjects affected / exposed
    4 / 56 (7.14%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    4
    0
    0
    SKIN FISSURES
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    1
    0
    2
    Renal and urinary disorders
    NOCTURIA
         subjects affected / exposed
    0 / 56 (0.00%)
    3 / 55 (5.45%)
    0 / 30 (0.00%)
         occurrences all number
    0
    3
    0
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    3 / 56 (5.36%)
    0 / 55 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    5
    0
    2
    BACK PAIN
         subjects affected / exposed
    5 / 56 (8.93%)
    2 / 55 (3.64%)
    1 / 30 (3.33%)
         occurrences all number
    5
    2
    1
    BONE PAIN
         subjects affected / exposed
    1 / 56 (1.79%)
    3 / 55 (5.45%)
    0 / 30 (0.00%)
         occurrences all number
    2
    4
    0
    MUSCLE SPASMS
         subjects affected / exposed
    2 / 56 (3.57%)
    0 / 55 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    2
    0
    2
    MUSCULAR WEAKNESS
         subjects affected / exposed
    1 / 56 (1.79%)
    3 / 55 (5.45%)
    0 / 30 (0.00%)
         occurrences all number
    1
    3
    0
    NECK PAIN
         subjects affected / exposed
    4 / 56 (7.14%)
    0 / 55 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    4
    0
    3
    PAIN IN EXTREMITY
         subjects affected / exposed
    4 / 56 (7.14%)
    1 / 55 (1.82%)
    1 / 30 (3.33%)
         occurrences all number
    6
    1
    1
    PAIN IN JAW
         subjects affected / exposed
    3 / 56 (5.36%)
    4 / 55 (7.27%)
    0 / 30 (0.00%)
         occurrences all number
    3
    5
    0
    Infections and infestations
    BRONCHITIS
         subjects affected / exposed
    3 / 56 (5.36%)
    1 / 55 (1.82%)
    1 / 30 (3.33%)
         occurrences all number
    3
    1
    1
    CANDIDIASIS
         subjects affected / exposed
    3 / 56 (5.36%)
    2 / 55 (3.64%)
    1 / 30 (3.33%)
         occurrences all number
    3
    3
    1
    CELLULITIS
         subjects affected / exposed
    1 / 56 (1.79%)
    1 / 55 (1.82%)
    2 / 30 (6.67%)
         occurrences all number
    2
    1
    2
    PARONYCHIA
         subjects affected / exposed
    2 / 56 (3.57%)
    0 / 55 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    3
    0
    2
    PNEUMONIA
         subjects affected / exposed
    4 / 56 (7.14%)
    1 / 55 (1.82%)
    0 / 30 (0.00%)
         occurrences all number
    4
    1
    0
    URINARY TRACT INFECTION
         subjects affected / exposed
    3 / 56 (5.36%)
    1 / 55 (1.82%)
    0 / 30 (0.00%)
         occurrences all number
    4
    1
    0
    Metabolism and nutrition disorders
    CACHEXIA
         subjects affected / exposed
    3 / 56 (5.36%)
    0 / 55 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    3
    0
    0
    DECREASED APPETITE
         subjects affected / exposed
    20 / 56 (35.71%)
    10 / 55 (18.18%)
    4 / 30 (13.33%)
         occurrences all number
    26
    12
    4
    DEHYDRATION
         subjects affected / exposed
    11 / 56 (19.64%)
    3 / 55 (5.45%)
    3 / 30 (10.00%)
         occurrences all number
    12
    3
    3
    HYPOALBUMINAEMIA
         subjects affected / exposed
    4 / 56 (7.14%)
    1 / 55 (1.82%)
    0 / 30 (0.00%)
         occurrences all number
    5
    1
    0
    HYPOCALCAEMIA
         subjects affected / exposed
    7 / 56 (12.50%)
    4 / 55 (7.27%)
    1 / 30 (3.33%)
         occurrences all number
    13
    17
    1
    HYPOKALAEMIA
         subjects affected / exposed
    17 / 56 (30.36%)
    6 / 55 (10.91%)
    0 / 30 (0.00%)
         occurrences all number
    29
    12
    0
    HYPOMAGNESAEMIA
         subjects affected / exposed
    23 / 56 (41.07%)
    13 / 55 (23.64%)
    5 / 30 (16.67%)
         occurrences all number
    84
    21
    17
    HYPONATRAEMIA
         subjects affected / exposed
    5 / 56 (8.93%)
    3 / 55 (5.45%)
    0 / 30 (0.00%)
         occurrences all number
    8
    5
    0
    HYPOPHOSPHATAEMIA
         subjects affected / exposed
    4 / 56 (7.14%)
    3 / 55 (5.45%)
    2 / 30 (6.67%)
         occurrences all number
    4
    3
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Dec 2007
    - Added global language from protocol template and increased enrollment period to allow for EU expansion  - Incorporated information from the EXTREME trial into the background and sample size calculation section. This change resulted in a reduction of the sample size from 150 to 110. - Added a requirement for first-cycle G-CSF prophylaxis. - Inclusion and exclusion criteria were modified to minimize identified burdens to enrollment and to be consistent with other internal/external head and neck trials.
    10 Aug 2009
    - Subjects ≥ 70 years of age were excluded. This is based on an observation that prior to Amendment 2, more deaths that occurred within 60 days of last protocol treatment arm occurred among older subjects (50% of deaths within 60 days of the last protocol-defined treatment among 13% of randomized subjects across arms). - A mid cycle (day 11 visit) was added to check subjects’ vital signs, key laboratory values, and to document adverse events - The entry criterion for creatinine clearance was increased to ≥ 60 mL/min - Added an additional safety data review once each additional group of 10 randomized subjects all had the opportunity to complete 2 cycles of treatment.
    11 Jan 2012
    - Revised the definition of PFS to “the time from the date of randomization to the date of first disease progression determined by the investigators per modified RECIST v1.0, or death within 60 days after the last evaluable tumor assessment or randomization date (whichever was later) during the first-line treatment phase.” Subjects not meeting the criteria by the cutoff date are censored at the last evaluable tumor assessment date during the first-line treatment. - Used the investigators’ assessment of response to determine the primary endpoint of PFS because the target 80 PFS events based on response assessment by the independent central review group may not be attained at the time of data cut-off of the PFS analysis. - Consolidated the timing the primary and final analyses into a single analysis approximately 24 months after the last subject was randomized.

    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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