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    Clinical Trial Results:
    A Randomized, Double-blind, Placebo-controlled, Phase 3 Study of Nivolumab or Nivolumab plus Cisplatin, in Combination with Radiotherapy in Participants with Cisplatin Ineligible and Cisplatin Eligible Locally Advanced Squamous Cell Carcinoma of the Head and Neck (SCCHN).

    Summary
    EudraCT number
    		 2017-002676-87
    Trial protocol
    		 ES   GB   PL   IT  
    Global end of trial date
    14 Oct 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Oct 2020
    First version publication date
    29 Oct 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CA209-9TM
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussée de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.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
    14 Oct 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Oct 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Following implementation of Revised Protocol 03, only safety assessments were conducted.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Dec 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 9
    Country: Number of subjects enrolled
    Italy: 3
    Country: Number of subjects enrolled
    Japan: 25
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    Korea, Republic of: 8
    Country: Number of subjects enrolled
    Russian Federation: 4
    Country: Number of subjects enrolled
    Spain: 17
    Country: Number of subjects enrolled
    Taiwan: 6
    Country: Number of subjects enrolled
    Turkey: 1
    Country: Number of subjects enrolled
    United States: 36
    Worldwide total number of subjects
    111
    EEA total number of subjects
    31
    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)
    64
    From 65 to 84 years
    45
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 74 Randomized and 73 Treated

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A (Cohort 1)
    Arm description
    		 Nivolumab + Radiotherapy
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravascular use
    Dosage and administration details
    10 mg/mL – 100 mg fill volume, 240 mg IV x 1 dose then 360 mg IV x 3 doses then 480 mg IV x 6 doses

    Investigational medicinal product name
    Radiotherapy
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Radiopharmaceutical precursor, solution
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    IMRT will be given in 35 fractions over 7 weeks beginning at Day 1 Cycle 3 for Cohort 1 or Day 1 Cycle 2 for Cohort 2, 5 fractions per week

    Arm title
    		 Arm B (Cohort 1)
    Arm description
    		 Cetuximab + Radiotherapy
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Radiotherapy
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Radiopharmaceutical precursor, solution
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    IMRT will be given in 35 fractions over 7 weeks beginning at Day 1 Cycle 3 for Cohort 1 or Day 1 Cycle 2 for Cohort 2, 5 fractions per week

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mg/mL - 500 mg fill volume, 400 mg/m2 IV x 1 dose then 250 mg/m2 IV x 7 doses

    Arm title
    		 Arm C (Cohort 2)
    Arm description
    		 Cisplatin + Nivolumab + Radiotherapy
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravascular use
    Dosage and administration details
    10 mg/mL – 100 mg fill volume, 240 mg IV x 1 dose then 360 mg IV x 3 doses then 480 mg IV x 6 doses

    Investigational medicinal product name
    Radiotherapy
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Radiopharmaceutical precursor, solution
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    IMRT will be given in 35 fractions over 7 weeks beginning at Day 1 Cycle 3 for Cohort 1 or Day 1 Cycle 2 for Cohort 2, 5 fractions per week

    Investigational medicinal product name
    Cisplastin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    1 mg/mL – 100 mg fill volume, 100 mg/m2 IV x 3 doses

    Arm title
    		 Arm D (Cohort 2)
    Arm description
    		 Cisplatin + Radiotherapy
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Cisplastin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    1 mg/mL – 100 mg fill volume, 100 mg/m2 IV x 3 doses

    Investigational medicinal product name
    Radiotherapy
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Radiopharmaceutical precursor, solution
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    IMRT will be given in 35 fractions over 7 weeks beginning at Day 1 Cycle 3 for Cohort 1 or Day 1 Cycle 2 for Cohort 2, 5 fractions per week

    Number of subjects in period 1 [1]
    		Arm A (Cohort 1) Arm B (Cohort 1) Arm C (Cohort 2) Arm D (Cohort 2)
    Started
    12
    10
    27
    25
    Completed
    12
    10
    27
    25
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 74 Randomized and 73 Treated
    Period 2
    Period 2 title
    Treatment Period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A (Cohort 1)
    Arm description
    		 Nivolumab + Radiotherapy
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravascular use
    Dosage and administration details
    10 mg/mL – 100 mg fill volume, 240 mg IV x 1 dose then 360 mg IV x 3 doses then 480 mg IV x 6 doses

    Investigational medicinal product name
    Radiotherapy
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Radiopharmaceutical precursor, solution
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    IMRT will be given in 35 fractions over 7 weeks beginning at Day 1 Cycle 3 for Cohort 1 or Day 1 Cycle 2 for Cohort 2, 5 fractions per week

    Arm title
    		 Arm B (Cohort 1)
    Arm description
    		 Cetuximab + Radiotherapy
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mg/mL - 500 mg fill volume, 400 mg/m2 IV x 1 dose then 250 mg/m2 IV x 7 doses

    Investigational medicinal product name
    Radiotherapy
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Radiopharmaceutical precursor, solution
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    IMRT will be given in 35 fractions over 7 weeks beginning at Day 1 Cycle 3 for Cohort 1 or Day 1 Cycle 2 for Cohort 2, 5 fractions per week

    Arm title
    		 Arm C (Cohort 2)
    Arm description
    		 Cisplatin + Nivolumab + Radiotherapy
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Cisplastin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    1 mg/mL – 100 mg fill volume, 100 mg/m2 IV x 3 doses

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravascular use
    Dosage and administration details
    10 mg/mL – 100 mg fill volume, 240 mg IV x 1 dose then 360 mg IV x 3 doses then 480 mg IV x 6 doses

    Investigational medicinal product name
    Radiotherapy
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Radiopharmaceutical precursor, solution
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    IMRT will be given in 35 fractions over 7 weeks beginning at Day 1 Cycle 3 for Cohort 1 or Day 1 Cycle 2 for Cohort 2, 5 fractions per week

    Arm title
    		 Arm D (Cohort 2)
    Arm description
    		 Cisplatin + Radiotherapy
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Cisplastin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    1 mg/mL – 100 mg fill volume, 100 mg/m2 IV x 3 doses

    Investigational medicinal product name
    Radiotherapy
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Radiopharmaceutical precursor, solution
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    IMRT will be given in 35 fractions over 7 weeks beginning at Day 1 Cycle 3 for Cohort 1 or Day 1 Cycle 2 for Cohort 2, 5 fractions per week

    Number of subjects in period 2 [2]
    		Arm A (Cohort 1) Arm B (Cohort 1) Arm C (Cohort 2) Arm D (Cohort 2)
    Started
    12
    10
    27
    24
    Completed
    0
    0
    0
    0
    Not completed
    12
    10
    27
    24
         Adverse event, serious fatal
    -
    -
    1
    -
         completed
    6
    -
    18
    1
         Adverse event unrelated to Study Drug
    2
    1
    1
    1
         Other Reason
    2
    -
    2
    1
         Study Drug Toxicity
    1
    -
    1
    1
         admin reason by sponsor
    -
    7
    -
    19
         Disease Progression
    -
    2
    -
    1
         participant request to discontinue
    -
    -
    4
    -
         participant withdrew consent
    1
    -
    -
    -
    Notes
    [2] - 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: 74 Randomized and 73 Treated

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A (Cohort 1)
    Reporting group description
    		 Nivolumab + Radiotherapy

    Reporting group title
    Arm B (Cohort 1)
    Reporting group description
    		 Cetuximab + Radiotherapy

    Reporting group title
    Arm C (Cohort 2)
    Reporting group description
    		 Cisplatin + Nivolumab + Radiotherapy

    Reporting group title
    Arm D (Cohort 2)
    Reporting group description
    		 Cisplatin + Radiotherapy

    Reporting group values
    		 Arm A (Cohort 1) Arm B (Cohort 1) Arm C (Cohort 2) Arm D (Cohort 2) Total
    Number of subjects
    		 12 10 27 25 74
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 2 1 24 19 46
        From 65-84 years
    		 8 9 3 6 26
        85 years and over
    		 2 0 0 0 2
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 74.5 ( 8.3 ) 74.7 ( 6.5 ) 59.0 ( 6.6 ) 60.8 ( 7.0 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 2 2 3 2 9
        Male
    		 10 8 24 23 65
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0
        Asian
    		 3 4 6 15 28
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0
        Black or African American
    		 0 0 2 0 2
        White
    		 8 5 16 7 36
        More than one race
    		 0 0 0 0 0
        Unknown or Not Reported
    		 1 1 3 3 8
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 0 0 0 0
        Not Hispanic or Latino
    		 5 4 9 2 20
        Unknown or Not Reported
    		 7 6 18 23 54

    End points

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    End points reporting groups
    Reporting group title
    Arm A (Cohort 1)
    Reporting group description
    		 Nivolumab + Radiotherapy

    Reporting group title
    Arm B (Cohort 1)
    Reporting group description
    		 Cetuximab + Radiotherapy

    Reporting group title
    Arm C (Cohort 2)
    Reporting group description
    		 Cisplatin + Nivolumab + Radiotherapy

    Reporting group title
    Arm D (Cohort 2)
    Reporting group description
    		 Cisplatin + Radiotherapy
    Reporting group title
    Arm A (Cohort 1)
    Reporting group description
    		 Nivolumab + Radiotherapy

    Reporting group title
    Arm B (Cohort 1)
    Reporting group description
    		 Cetuximab + Radiotherapy

    Reporting group title
    Arm C (Cohort 2)
    Reporting group description
    		 Cisplatin + Nivolumab + Radiotherapy

    Reporting group title
    Arm D (Cohort 2)
    Reporting group description
    		 Cisplatin + Radiotherapy

    Primary: Number of Participants with an Adverse Event (AE)

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    End point title
    		 Number of Participants with an Adverse Event (AE) [1]
    End point description
    Number of Participants with an Adverse Event
    End point type
    Primary
    End point timeframe
    30 days
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis performed due to the type of endpoint
    End point values
    		 Arm A (Cohort 1) Arm B (Cohort 1) Arm C (Cohort 2) Arm D (Cohort 2)
    Number of subjects analysed
    12
    10
    27
    24
    Units: participants
    12
    10
    27
    24
    No statistical analyses for this end point

    Primary: Number of Participants with an Serious Adverse Event (SAE)

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    End point title
    		 Number of Participants with an Serious Adverse Event (SAE) [2]
    End point description
    Number of Participants with an Serious Adverse Event (SAE)
    End point type
    Primary
    End point timeframe
    30 days
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis performed due to the type of endpoint
    End point values
    		 Arm A (Cohort 1) Arm B (Cohort 1) Arm C (Cohort 2) Arm D (Cohort 2)
    Number of subjects analysed
    12
    10
    27
    24
    Units: participants
    5
    5
    9
    6
    No statistical analyses for this end point

    Primary: Number of Participants with an Adverse Event Leading to Discontinuation

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    End point title
    		 Number of Participants with an Adverse Event Leading to Discontinuation [3]
    End point description
    Number of Participants with an Adverse Event Leading to Discontinuation
    End point type
    Primary
    End point timeframe
    30 days
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis performed due to the type of endpoint
    End point values
    		 Arm A (Cohort 1) Arm B (Cohort 1) Arm C (Cohort 2) Arm D (Cohort 2)
    Number of subjects analysed
    12
    10
    27
    24
    Units: participants
    2
    3
    8
    4
    No statistical analyses for this end point

    Primary: Number of Participants with an Adverse Event Leading to dose modification

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    End point title
    		 Number of Participants with an Adverse Event Leading to dose modification [4]
    End point description
    Number of Participants with an Adverse Event Leading to dose modification Here '9999' signifies data not available as does modification did not take place
    End point type
    Primary
    End point timeframe
    30 days
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis performed due to the type of endpoint
    End point values
    		 Arm A (Cohort 1) Arm B (Cohort 1) Arm C (Cohort 2) Arm D (Cohort 2)
    Number of subjects analysed
    12
    10
    27
    24
    Units: participants
    9999
    9999
    9999
    9999
    No statistical analyses for this end point

    Primary: Number of Participants with select adverse events

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    End point title
    		 Number of Participants with select adverse events [5]
    End point description
    Number of Participants with select adverse events. Select Adverse events include: gastrointestinal, hepatic, hypersensitivity/infusion reaction, pulmonary, renal, or skin.
    End point type
    Primary
    End point timeframe
    30 days
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis performed due to the type of endpoint
    End point values
    		 Arm A (Cohort 1) Arm B (Cohort 1) Arm C (Cohort 2) Arm D (Cohort 2)
    Number of subjects analysed
    12
    10
    27
    24
    Units: participants
        Gastrointestinal
    4
    3
    3
    1
        Hepatic
    1
    2
    2
    3
        Hypersensitivity/Infusion Reaction
    1
    3
    0
    0
        Pulmonary
    0
    0
    0
    0
        Renal
    2
    1
    13
    6
        Skin
    7
    7
    12
    11
    No statistical analyses for this end point

    Primary: Number of Participants with an immune-mediated adverse event (IMAE)

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    End point title
    		 Number of Participants with an immune-mediated adverse event (IMAE) [6]
    End point description
    Number of Participants with an immune-mediated adverse event (IMAE)
    End point type
    Primary
    End point timeframe
    100 days
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis performed due to the type of endpoint
    End point values
    		 Arm A (Cohort 1) Arm B (Cohort 1) Arm C (Cohort 2) Arm D (Cohort 2)
    Number of subjects analysed
    12
    10
    27
    24
    Units: participants
        Non-Endocrine related IMAE
    1
    0
    3
    0
        Endocrine related IMAE
    0
    0
    4
    0
    No statistical analyses for this end point

    Primary: Time to onset and time to resolution of immune-related adverse events

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    End point title
    		 Time to onset and time to resolution of immune-related adverse events [7]
    End point description
    Time to onset and time to resolution of immune-related adverse events
    End point type
    Primary
    End point timeframe
    100 days
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis performed due to the type of endpoint
    End point values
    		 Arm A (Cohort 1) Arm B (Cohort 1) Arm C (Cohort 2) Arm D (Cohort 2)
    Number of subjects analysed
    0 [8]
    0 [9]
    0 [10]
    0 [11]
    Units: Weeks
    arithmetic mean (confidence interval 95%)
        Endocrine IMAE
    ( to )
    ( to )
    ( to )
    ( to )
        Non Endocrine IMAE
    ( to )
    ( to )
    ( to )
    ( to )
    Notes
    [8] - Too few subjects, can risk subject identification
    [9] - Too few subjects, can risk subject identification
    [10] - Too few subjects, can risk subject identification
    [11] - Too few subjects, can risk subject identification
    No statistical analyses for this end point

    Primary: Number of Participants who experienced death

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    End point title
    		 Number of Participants who experienced death [12]
    End point description
    Number of Participants who experienced death
    End point type
    Primary
    End point timeframe
    100 days
    Notes
    [12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis performed due to the type of endpoint
    End point values
    		 Arm A (Cohort 1) Arm B (Cohort 1) Arm C (Cohort 2) Arm D (Cohort 2)
    Number of subjects analysed
    12
    10
    27
    24
    Units: participants
    2
    2
    2
    1
    No statistical analyses for this end point

    Primary: Number of participants with an abnormality in specific thyroid tests

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    End point title
    		 Number of participants with an abnormality in specific thyroid tests [13]
    End point description
    Number of participants with an abnormality in specific thyroid tests
    End point type
    Primary
    End point timeframe
    30 Days
    Notes
    [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis performed due to the type of endpoint
    End point values
    		 Arm A (Cohort 1) Arm B (Cohort 1) Arm C (Cohort 2) Arm D (Cohort 2)
    Number of subjects analysed
    10
    10
    27
    23
    Units: participants
        TSH > ULN
    5
    1
    7
    1
        TSH > ULN WITH TSH <= ULN AT BASELINE
    5
    1
    7
    1
        TSH >ULN WITH ATLEAST ONE FT3/FT4 TEST VALUE <LLN
    4
    0
    4
    0
        TSH >ULN WITH ALL OTHER FT3/FT4 TEST VALUES >= LLN
    0
    0
    2
    1
        TSH > ULN WITH FT3/FT4 TEST MISSING
    1
    1
    1
    0
        TSH < LLN
    4
    3
    16
    13
        TSH <LLN WITH TSH >= LLN AT BASELINE
    3
    3
    13
    13
        TSH <LLN WITH ATLEAST ONE FT3/FT4 TEST VALUE > ULN
    0
    0
    9
    2
        TSH <LLN WITH ALL OTHER FT3/FT4 TEST VALUES <= ULN
    4
    1
    6
    7
        TSH < LLN WITH FT3/FT4 TEST MISSING
    0
    2
    1
    4
    No statistical analyses for this end point

    Primary: Number of participants with an abnormality in specific liver tests

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    End point title
    		 Number of participants with an abnormality in specific liver tests [14]
    End point description
    Number of participants with an abnormality in specific liver tests
    End point type
    Primary
    End point timeframe
    30 days
    Notes
    [14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis performed due to the type of endpoint
    End point values
    		 Arm A (Cohort 1) Arm B (Cohort 1) Arm C (Cohort 2) Arm D (Cohort 2)
    Number of subjects analysed
    12
    10
    27
    24
    Units: participants
        ALT OR AST > 3XULN
    2
    0
    0
    0
        ALT OR AST> 5XULN
    1
    0
    0
    0
        ALT OR AST> 10XULN
    0
    0
    0
    0
        ALT OR AST > 20XULN
    0
    0
    0
    0
        TOTAL BILIRUBIN > 2XULN
    0
    0
    0
    0
        ALT/AST ELEV>3XULN;TOTAL BILIRUBIN>2XULN IN 1 DAY
    0
    0
    0
    0
        ALT/AST ELEV>3XULN;TOTAL BILIRUBIN>2XULN IN 30DAYS
    0
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from start of treatment up to 30 days after last treatment dose.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    RT + Nivo
    Reporting group description
    		 Subjects who were ineligible for cisplatin chemotherapy received nivolumab 240 milligrams (mg) single dose on day 1 then 3 dose of 360 mg every 3 weeks followed by 6 dose of 480 mg every 4 weeks intravenously (IV) plus placebo cetuximab 400 milligrams per square meter (mg/m2) single dose and 250 mg/m2 every week for 7 weeks in combination with radiotherapy (RT). The infusion duration of nivolumab was 30 minutes.

    Reporting group title
    RT + Cetu
    Reporting group description
    		 Subjects who were ineligible for cisplatin chemotherapy received placebo nivolumab 240 mg single dose on day 1 then 3 dose of 360 mg every 3 weeks followed by 6 dose of 480 mg every 4 weeks IV in plus cetuximab 400 mg/m2 single dose and 250 mg/m2 every week for 7 weeks in combination with RT. The infusion duration of nivolumab was 30 minutes. The infusion of cetuximab began at least 30 minutes after the completion of the nivolumab infusion.

    Reporting group title
    RT + Cis + Nivo
    Reporting group description
    		 Subjects who were ineligible for cisplatin chemotherapy received nivolumab 240 mg single dose on day 1 then 3 dose of 360 mg every 3 weeks followed by 6 dose of 480 mg every 4 weeks IV in combination with 3 dose of cisplatin 100 mg/m2 and RT. The infusion duration of nivolumab was 30 minutes. The infusion of cisplatin began at least 30 minutes after the completion of the nivolumab infusion.

    Reporting group title
    RT + Cis
    Reporting group description
    		 Subjects who were ineligible for cisplatin chemotherapy received placebo nivolumab 240 mg single dose on day 1 then 3 dose of 360 mg every 3 weeks followed by 6 dose of 480 mg every 4 weeks IV in combination with 3 dose of cisplatin 100 mg/m2 and RT. The infusion duration of nivolumab was 30 minutes. The infusion of cisplatin began at least 30 minutes after the completion of the nivolumab infusion.

    Serious adverse events
    		 RT + Nivo RT + Cetu RT + Cis + Nivo RT + Cis
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 12 (41.67%)
    5 / 10 (50.00%)
    9 / 27 (33.33%)
    6 / 24 (25.00%)
         number of deaths (all causes)
    2
    1
    2
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Oropharyngeal squamous cell carcinoma
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Hypoxia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngeal necrosis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Dysphagia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    2 / 27 (7.41%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacillus bacteraemia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mucosal infection
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 27 (0.00%)
    2 / 24 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 RT + Nivo RT + Cetu RT + Cis + Nivo RT + Cis
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 12 (100.00%)
    10 / 10 (100.00%)
    26 / 27 (96.30%)
    24 / 24 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Pyogenic granuloma
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Tumour haemorrhage
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    2 / 27 (7.41%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0
    2
    1
    Hypotension
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Lymphoedema
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 10 (0.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 10 (0.00%)
    2 / 27 (7.41%)
    2 / 24 (8.33%)
         occurrences all number
    3
    0
    2
    2
    Fatigue
         subjects affected / exposed
    4 / 12 (33.33%)
    5 / 10 (50.00%)
    8 / 27 (29.63%)
    3 / 24 (12.50%)
         occurrences all number
    5
    5
    12
    3
    Gait disturbance
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Malaise
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 27 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    0
    0
    2
    Mucosal inflammation
         subjects affected / exposed
    2 / 12 (16.67%)
    2 / 10 (20.00%)
    7 / 27 (25.93%)
    8 / 24 (33.33%)
         occurrences all number
    2
    4
    7
    8
    Oedema peripheral
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 27 (0.00%)
    3 / 24 (12.50%)
         occurrences all number
    1
    0
    0
    5
    Pain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    2 / 27 (7.41%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Pyrexia
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 10 (10.00%)
    4 / 27 (14.81%)
    1 / 24 (4.17%)
         occurrences all number
    2
    1
    4
    1
    Xerosis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 10 (10.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    4
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 10 (10.00%)
    4 / 27 (14.81%)
    0 / 24 (0.00%)
         occurrences all number
    3
    1
    4
    0
    Dysphonia
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 10 (20.00%)
    2 / 27 (7.41%)
    2 / 24 (8.33%)
         occurrences all number
    0
    2
    2
    2
    Dyspnoea
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    3 / 27 (11.11%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    3
    1
    Haemoptysis
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 10 (0.00%)
    1 / 27 (3.70%)
    1 / 24 (4.17%)
         occurrences all number
    2
    0
    1
    1
    Hiccups
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 10 (10.00%)
    4 / 27 (14.81%)
    7 / 24 (29.17%)
         occurrences all number
    1
    1
    5
    7
    Laryngeal inflammation
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    3 / 12 (25.00%)
    3 / 10 (30.00%)
    8 / 27 (29.63%)
    2 / 24 (8.33%)
         occurrences all number
    3
    3
    8
    2
    Paranasal sinus hyposecretion
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pharyngeal inflammation
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 10 (10.00%)
    1 / 27 (3.70%)
    5 / 24 (20.83%)
         occurrences all number
    2
    1
    1
    5
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Anxiety
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 27 (3.70%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    1
    1
    Delirium
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Depression
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Insomnia
         subjects affected / exposed
    3 / 12 (25.00%)
    1 / 10 (10.00%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    3
    1
    0
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 10 (20.00%)
    2 / 27 (7.41%)
    1 / 24 (4.17%)
         occurrences all number
    1
    2
    2
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 10 (10.00%)
    2 / 27 (7.41%)
    1 / 24 (4.17%)
         occurrences all number
    1
    1
    2
    1
    Blood creatinine increased
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 10 (10.00%)
    8 / 27 (29.63%)
    3 / 24 (12.50%)
         occurrences all number
    2
    1
    10
    3
    Blood electrolytes abnormal
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Blood magnesium decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Blood thyroid stimulating hormone decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    2 / 27 (7.41%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood urea increased
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 27 (3.70%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    1
    1
    Lipase increased
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    4 / 27 (14.81%)
    2 / 24 (8.33%)
         occurrences all number
    0
    0
    5
    2
    Neutrophil count decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    9 / 27 (33.33%)
    8 / 24 (33.33%)
         occurrences all number
    0
    0
    10
    13
    Platelet count decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    3 / 27 (11.11%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0
    5
    1
    Protein total decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Weight decreased
         subjects affected / exposed
    3 / 12 (25.00%)
    2 / 10 (20.00%)
    11 / 27 (40.74%)
    7 / 24 (29.17%)
         occurrences all number
    5
    2
    13
    8
    White blood cell count decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    7 / 27 (25.93%)
    7 / 24 (29.17%)
         occurrences all number
    0
    0
    8
    13
    C-Reactive protein increased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 27 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    0
    0
    2
    Injury, poisoning and procedural complications
    Incision site inflammation
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Infusion related reaction
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 10 (20.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Radiation skin injury
         subjects affected / exposed
    3 / 12 (25.00%)
    5 / 10 (50.00%)
    8 / 27 (29.63%)
    11 / 24 (45.83%)
         occurrences all number
    3
    5
    8
    11
    Recall phenomenon
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Stoma site inflammation
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 10 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    4
    0
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 27 (3.70%)
    3 / 24 (12.50%)
         occurrences all number
    0
    1
    1
    3
    Dysgeusia
         subjects affected / exposed
    2 / 12 (16.67%)
    2 / 10 (20.00%)
    12 / 27 (44.44%)
    6 / 24 (25.00%)
         occurrences all number
    2
    2
    12
    7
    Headache
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 10 (20.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences all number
    1
    2
    1
    0
    Hemiparesis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Neuralgia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    3 / 27 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Taste disorder
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    3 / 27 (11.11%)
    2 / 24 (8.33%)
         occurrences all number
    0
    1
    3
    2
    Tremor
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 12 (33.33%)
    3 / 10 (30.00%)
    12 / 27 (44.44%)
    7 / 24 (29.17%)
         occurrences all number
    4
    3
    14
    7
    Leukocytosis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Leukopenia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    2 / 27 (7.41%)
    4 / 24 (16.67%)
         occurrences all number
    2
    0
    2
    5
    Lymphopenia
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 10 (10.00%)
    2 / 27 (7.41%)
    1 / 24 (4.17%)
         occurrences all number
    1
    1
    2
    1
    Neutropenia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    3 / 27 (11.11%)
    5 / 24 (20.83%)
         occurrences all number
    1
    0
    3
    5
    Thrombocytopenia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Ear and labyrinth disorders
    Deafness
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    2 / 27 (7.41%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Ear pain
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 27 (3.70%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    1
    1
    Tinnitus
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    5 / 27 (18.52%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0
    5
    1
    Eye disorders
    Dry eye
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 10 (20.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Vision blurred
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gastrointestinal disorders
    Cheilitis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Constipation
         subjects affected / exposed
    4 / 12 (33.33%)
    2 / 10 (20.00%)
    13 / 27 (48.15%)
    12 / 24 (50.00%)
         occurrences all number
    7
    3
    14
    13
    Diarrhoea
         subjects affected / exposed
    4 / 12 (33.33%)
    3 / 10 (30.00%)
    2 / 27 (7.41%)
    1 / 24 (4.17%)
         occurrences all number
    5
    3
    3
    1
    Dry mouth
         subjects affected / exposed
    4 / 12 (33.33%)
    3 / 10 (30.00%)
    12 / 27 (44.44%)
    7 / 24 (29.17%)
         occurrences all number
    4
    3
    12
    7
    Dyspepsia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 27 (3.70%)
    2 / 24 (8.33%)
         occurrences all number
    0
    1
    1
    2
    Dysphagia
         subjects affected / exposed
    6 / 12 (50.00%)
    3 / 10 (30.00%)
    11 / 27 (40.74%)
    5 / 24 (20.83%)
         occurrences all number
    6
    3
    12
    5
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 10 (10.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Glossodynia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Lip dry
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nausea
         subjects affected / exposed
    3 / 12 (25.00%)
    1 / 10 (10.00%)
    17 / 27 (62.96%)
    11 / 24 (45.83%)
         occurrences all number
    5
    1
    24
    16
    Odynophagia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    7 / 27 (25.93%)
    5 / 24 (20.83%)
         occurrences all number
    0
    0
    8
    5
    Oesophagitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 27 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    0
    0
    2
    Oral pain
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 10 (20.00%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    2
    0
    1
    Saliva altered
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Stomatitis
         subjects affected / exposed
    4 / 12 (33.33%)
    4 / 10 (40.00%)
    10 / 27 (37.04%)
    7 / 24 (29.17%)
         occurrences all number
    6
    4
    12
    7
    Vomiting
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 10 (10.00%)
    6 / 27 (22.22%)
    7 / 24 (29.17%)
         occurrences all number
    1
    1
    8
    7
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 27 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    0
    0
    2
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    2 / 27 (7.41%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0
    2
    1
    Dermatitis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    8 / 27 (29.63%)
    6 / 24 (25.00%)
         occurrences all number
    0
    1
    8
    6
    Dermatitis acneiform
         subjects affected / exposed
    0 / 12 (0.00%)
    4 / 10 (40.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    4
    0
    0
    Dermatitis bullous
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Dry skin
         subjects affected / exposed
    2 / 12 (16.67%)
    2 / 10 (20.00%)
    1 / 27 (3.70%)
    1 / 24 (4.17%)
         occurrences all number
    2
    2
    1
    1
    Erythema
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 10 (10.00%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    2
    1
    0
    1
    Lichen planus
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pruritus
         subjects affected / exposed
    3 / 12 (25.00%)
    0 / 10 (0.00%)
    3 / 27 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    3
    0
    4
    0
    Rash
         subjects affected / exposed
    4 / 12 (33.33%)
    4 / 10 (40.00%)
    3 / 27 (11.11%)
    2 / 24 (8.33%)
         occurrences all number
    5
    4
    3
    2
    Rash papular
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Seborrhoeic dermatitis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Skin exfoliation
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Skin fissures
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 10 (20.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Skin reaction
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    3 / 27 (11.11%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0
    3
    1
    Anuria
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dysuria
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 10 (10.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Urinary hesitation
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    4 / 27 (14.81%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    4
    0
    Hypothyroidism
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    6 / 27 (22.22%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    6
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    3 / 27 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Back pain
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    2 / 27 (7.41%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    3
    0
    Muscle spasms
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Neck pain
         subjects affected / exposed
    4 / 12 (33.33%)
    1 / 10 (10.00%)
    2 / 27 (7.41%)
    1 / 24 (4.17%)
         occurrences all number
    4
    1
    2
    1
    Pain in jaw
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Trismus
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Infections and infestations
    Bacterial infection
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Conjunctivitis
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 10 (10.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Herpes simplex
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Infected dermal cyst
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Mucosal infection
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 10 (10.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    5
    1
    0
    0
    Oral candidiasis
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 10 (10.00%)
    2 / 27 (7.41%)
    3 / 24 (12.50%)
         occurrences all number
    2
    1
    3
    4
    Paronychia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pyoderma
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin infection
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    4 / 12 (33.33%)
    2 / 10 (20.00%)
    9 / 27 (33.33%)
    10 / 24 (41.67%)
         occurrences all number
    4
    2
    11
    11
    Dehydration
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    2 / 27 (7.41%)
    2 / 24 (8.33%)
         occurrences all number
    0
    1
    2
    2
    Diabetes mellitus
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    0
    1
    Hyperkalaemia
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 10 (10.00%)
    4 / 27 (14.81%)
    0 / 24 (0.00%)
         occurrences all number
    2
    1
    4
    0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    0
    1
    Hypocalcaemia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Hypokalaemia
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 10 (10.00%)
    5 / 27 (18.52%)
    3 / 24 (12.50%)
         occurrences all number
    1
    1
    6
    3
    Hypomagnesaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    3 / 10 (30.00%)
    4 / 27 (14.81%)
    4 / 24 (16.67%)
         occurrences all number
    0
    4
    5
    4
    Hyponatraemia
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 10 (0.00%)
    2 / 27 (7.41%)
    2 / 24 (8.33%)
         occurrences all number
    2
    0
    2
    2
    Hypophosphataemia
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 10 (10.00%)
    1 / 27 (3.70%)
    1 / 24 (4.17%)
         occurrences all number
    1
    1
    1
    1
    Malnutrition
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences all number
    0
    2
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Nov 2017
    Update to questionnaire administration updated to align with dosing cycles. Outcome research assessment and endpoints redefined updated to align with analysis planned. TNM Staging clarified for high and intermediate risk definition. Other minor corrections, clarifications
    21 Feb 2018
    Added exclusion of participants with active interstitial lung disease (ILD) / pneumonitis or with a history of ILD / pneumonitis requiring steroids.  Aligned thyroid testing to study visits.  Added guidance for premedications for cetuximab if necessary.
    16 Nov 2018
    Enrollment in the study was closed as of 15-Oct-2018. Revised Protocol 03 covers the changes implemented to the protocol post study enrollment closure: study treatment unblinding, removal of placebo treatment, and removal of analysis of efficacy end-points and efficacy follow-up.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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