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    Clinical Trial Results:
    A Phase II, Randomized, Open-Label, Multi-Center, Global Study of MEDI4736 Monotherapy, Tremelimumab Monotherapy, and MEDI4736 in Combination with Tremelimumab in Patients with Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN)

    Summary
    EudraCT number
    2014-003717-29
    Trial protocol
    HU   BE   DE   GB   CZ   ES   FR  
    Global end of trial date
    06 Jul 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    27 Sep 2020
    First version publication date
    27 Sep 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D4193C00003
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02319044
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AstraZeneca LP
    Sponsor organisation address
    1 MedImmune Way, Gaithersburg, United States, MD 20878
    Public contact
    Jean Fan, MD, Global Clinical Lead, AstraZeneca LP, +1 13013985080, jean.fan@astrazeneca.com
    Scientific contact
    Jean Fan, MD, Global Clinical Lead, AstraZeneca LP, +1 13013985080, jean.fan@astrazeneca.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
    26 Sep 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Jul 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of durvalumab in combination with tremelimumab treatment in terms of objective response rate (ORR)
    Protection of trial subjects
    The study will be performed in accordance with ethical principles that have their origin in the Declaration of Helsinki and are consistent with International Conference on Harmonisation (ICH)/GCP, applicable regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological Samples.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    15 Apr 2015
    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
    United States: 76
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    Belgium: 13
    Country: Number of subjects enrolled
    Canada: 12
    Country: Number of subjects enrolled
    Czech Republic: 2
    Country: Number of subjects enrolled
    France: 78
    Country: Number of subjects enrolled
    Georgia: 4
    Country: Number of subjects enrolled
    Germany: 12
    Country: Number of subjects enrolled
    Hungary: 15
    Country: Number of subjects enrolled
    Israel: 3
    Country: Number of subjects enrolled
    Korea, Republic of: 3
    Country: Number of subjects enrolled
    Malaysia: 2
    Country: Number of subjects enrolled
    Spain: 32
    Country: Number of subjects enrolled
    United Kingdom: 13
    Worldwide total number of subjects
    267
    EEA total number of subjects
    165
    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)
    176
    From 65 to 84 years
    91
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    127 sites in 14 countries enrolled and screened patients. The study was conducted and managed by PRA, a contract research organization.

    Pre-assignment
    Screening details
    Screening took place between Day -28 and Day -1. Informed consent, study procedures and laboratory assessments were undertaken over the course of 1 or more visits.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    MEDI4736 + Tremelimumab Combination
    Arm description
    MEDI4736 (20 mg/kg) + Tremelimumab (1 mg/kg) combination therapy administered via intravenous infusion every 4 weeks for up to 4 months (4 doses), then MEDI4736 (10 mg/kg) as a single agent every 2 weeks to complete 12 months of treatment
    Arm type
    Experimental

    Investigational medicinal product name
    durvalumab
    Investigational medicinal product code
    MEDI4736
    Other name
    imfinzi
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    MEDI4736 (20 mg/kg) therapy administered via intravenous infusion every 4 weeks for up to 4 months (4 doses), then MEDI4736 (10 mg/kg) as a single agent every 2 weeks to complete 12 months of treatment

    Investigational medicinal product name
    Tremelimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Tremelimumab (1 mg/kg) therapy administered via intravenous infusion every 4 weeks for up to 4 months (4 doses)

    Arm title
    MEDI4736
    Arm description
    MEDI4736 (10 mg/kg) monotherapy administered via intravenous infusion every 2 weeks for up to 12 months (up to 26 doses)
    Arm type
    Experimental

    Investigational medicinal product name
    durvalumab
    Investigational medicinal product code
    MEDI4736
    Other name
    imfinzi
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    MEDI4736 (10 mg/kg) monotherapy administered via intravenous infusion every 2 weeks for up to 12 months (up to 26 doses)

    Arm title
    Tremelimumab
    Arm description
    Tremelimumab (10 mg/kg) monotherapy administered via intravenous infusion every 4 weeks for 7 doses, then every 12 weeks for 2 additional doses for up to 12 months (up to 9 doses)
    Arm type
    Experimental

    Investigational medicinal product name
    Tremelimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Tremelimumab (10 mg/kg) monotherapy administered via intravenous infusion every 4 weeks for 7 doses, then every 12 weeks for 2 additional doses for up to 12 months (up to 9 doses)

    Number of subjects in period 1
    MEDI4736 + Tremelimumab Combination MEDI4736 Tremelimumab
    Started
    133
    67
    67
    Completed
    11
    7
    0
    Not completed
    122
    60
    67
         Death, PI/sponsor decision, med history
    -
    1
    4
         Study specific discontinuation criteria
    2
    2
    1
         Adverse event, non-fatal
    17
    2
    8
         Consent withdrawn by subject
    3
    3
    6
         Condition under investigation worsened
    100
    50
    46
         Not treated
    -
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    MEDI4736 + Tremelimumab Combination
    Reporting group description
    MEDI4736 (20 mg/kg) + Tremelimumab (1 mg/kg) combination therapy administered via intravenous infusion every 4 weeks for up to 4 months (4 doses), then MEDI4736 (10 mg/kg) as a single agent every 2 weeks to complete 12 months of treatment

    Reporting group title
    MEDI4736
    Reporting group description
    MEDI4736 (10 mg/kg) monotherapy administered via intravenous infusion every 2 weeks for up to 12 months (up to 26 doses)

    Reporting group title
    Tremelimumab
    Reporting group description
    Tremelimumab (10 mg/kg) monotherapy administered via intravenous infusion every 4 weeks for 7 doses, then every 12 weeks for 2 additional doses for up to 12 months (up to 9 doses)

    Reporting group values
    MEDI4736 + Tremelimumab Combination MEDI4736 Tremelimumab Total
    Number of subjects
    133 67 67 267
    Age Categorical
    Units: Subjects
        Between 18 and 64 years
    88 46 42 176
        >=65 years
    45 21 25 91
    Age Continuous
    Age characteristics have been reported for all study arms. Values of 0 have been reported where no data is available.
    Units: years
        median (full range (min-max))
    62 (26 to 81) 62 (23 to 82) 61 (42 to 77) -
    Sex: Female, Male
    Units: Subjects
        Female
    20 13 14 47
        Male
    113 54 53 220
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 0 0 0
        Asian
    4 3 2 9
        Native Hawaiian or Other Pacific Islander
    0 0 0 0
        Black or African American
    6 3 1 10
        White
    115 58 57 230
        More than one race
    0 0 0 0
        Unknown or Not Reported
    8 3 7 18
    HPV status
    Units: Subjects
        Positive
    39 18 18 75
        Negative
    94 49 49 192
    Use of nicotine (other than cigarettes)
    Units: Subjects
        Yes (has used nicotine)
    1 1 0 2
        No (has not used nicotine)
    132 66 67 265
    Smoking/nicotine status by nicotine user
    Units: Subjects
        Current smoker >10 pack years
    22 7 6 35
        Current smoker <= 10 pack years
    2 0 1 3
        Former smoker >10 pack years
    59 35 34 128
        Former smoker <= 10 pack years
    30 16 12 58
        Never
    20 9 14 43
    WHO/ECOG performance status at study entry
    Units: Subjects
        (0) Normal activity|
    40 22 19 81
        (1) Restricted activity|
    93 45 48 186
    Negative PD-L1 status
    Programmed cell death ligand 1 status identification performed at screening
    Units: Subjects
        PD-L1 negative patients
    133 67 67 267
    Subject analysis sets

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All randomized patients.

    Subject analysis set title
    Evaluable analysis set
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Inclusive of all patients who received at least one dose of study treatment, who had a baseline tumor assessment, and had measurable disease.

    Subject analysis sets values
    Full analysis set Evaluable analysis set
    Number of subjects
    267
    257
    Age Categorical
    Units: Subjects
        Between 18 and 64 years
        >=65 years
    Age Continuous
    Age characteristics have been reported for all study arms. Values of 0 have been reported where no data is available.
    Units: years
        median (full range (min-max))
    61 (23 to 82)
    0 (0 to 0)
    Sex: Female, Male
    Units: Subjects
        Female
        Male
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
        Asian
        Native Hawaiian or Other Pacific Islander
        Black or African American
        White
        More than one race
        Unknown or Not Reported
    HPV status
    Units: Subjects
        Positive
        Negative
    Use of nicotine (other than cigarettes)
    Units: Subjects
        Yes (has used nicotine)
        No (has not used nicotine)
    Smoking/nicotine status by nicotine user
    Units: Subjects
        Current smoker >10 pack years
        Current smoker <= 10 pack years
        Former smoker >10 pack years
        Former smoker <= 10 pack years
        Never
    WHO/ECOG performance status at study entry
    Units: Subjects
        (0) Normal activity|
        (1) Restricted activity|
    Negative PD-L1 status
    Programmed cell death ligand 1 status identification performed at screening
    Units: Subjects
        PD-L1 negative patients

    End points

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    End points reporting groups
    Reporting group title
    MEDI4736 + Tremelimumab Combination
    Reporting group description
    MEDI4736 (20 mg/kg) + Tremelimumab (1 mg/kg) combination therapy administered via intravenous infusion every 4 weeks for up to 4 months (4 doses), then MEDI4736 (10 mg/kg) as a single agent every 2 weeks to complete 12 months of treatment

    Reporting group title
    MEDI4736
    Reporting group description
    MEDI4736 (10 mg/kg) monotherapy administered via intravenous infusion every 2 weeks for up to 12 months (up to 26 doses)

    Reporting group title
    Tremelimumab
    Reporting group description
    Tremelimumab (10 mg/kg) monotherapy administered via intravenous infusion every 4 weeks for 7 doses, then every 12 weeks for 2 additional doses for up to 12 months (up to 9 doses)

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All randomized patients.

    Subject analysis set title
    Evaluable analysis set
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Inclusive of all patients who received at least one dose of study treatment, who had a baseline tumor assessment, and had measurable disease.

    Primary: Objective response rate at 6 months

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    End point title
    Objective response rate at 6 months [1]
    End point description
    Objective response rate, primary analysis, based on BICR assessments according to RECIST v1.1. The number (%) of patients with a response excludes unconfirmed responses.
    End point type
    Primary
    End point timeframe
    After 6 months
    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 additional statistical analysis was planned for this endpoint
    End point values
    MEDI4736 + Tremelimumab Combination MEDI4736 Tremelimumab
    Number of subjects analysed
    130
    65
    63
    Units: % participants
        number (confidence interval 95%)
    7.7 (3.75 to 13.69)
    9.2 (3.46 to 19.02)
    1.6 (0.04 to 8.53)
    No statistical analyses for this end point

    Primary: Objective response rate at 12 months

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    End point title
    Objective response rate at 12 months [2]
    End point description
    Objective response rate (per RECIST 1.1 as assessed by blinded independent central review [BICR]) is defined as the number (%) of patients with a confirmed complete response or confirmed partial response and will be based on all treated patients who are PD-L1-positive with measurable disease at baseline per BICR. Response Evaluation Criteria in Solid Tumors [RECIST] 1.1. criteria are: Complete response [CR] = disappearance of all target lesions since baseline; and partial response [PR] = at least a 30% decrease in the sum of the diameters of target lesions. Value of '99999' has been entered where there were no participants enrolled.
    End point type
    Primary
    End point timeframe
    After 12 months
    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 additional statistical analysis was planned for this endpoint
    End point values
    MEDI4736 + Tremelimumab Combination MEDI4736 Tremelimumab
    Number of subjects analysed
    129
    65
    63
    Units: % participants
    number (confidence interval 95%)
        Overall|
    7.8 (3.78 to 13.79)
    9.2 (3.46 to 19.02)
    1.6 (0.04 to 8.53)
        Current smoking/nicotine status - Total|
    13.6 (2.91 to 34.91)
    14.3 (0.36 to 57.87)
    14.3 (0.36 to 57.87)
        Current smoking/nicotine status - >10 pack years|
    15.0 (3.21 to 37.89)
    14.3 (0.36 to 57.87)
    16.7 (0.42 to 64.12)
        Current smoking/nicotine status - ≤10 pack years|
    0 (0.00 to 84.19)
    99999 (99999 to 99999)
    0 (0 to 97.5)
        Former smoking/nicotine status -Total|
    6.8 (2.54 to 14.25)
    8.2 (2.27 to 19.60)
    0 (0 to 8.04)
        Former smoking/nicotine status - >10 pack years|
    5.2 (1.08 to 14.38)
    9.1 (1.92 to 24.33)
    0 (0 to 10.89)
        Former smoking/nicotine status - ≤10 pack years|
    10.0 (2.11 to 26.53)
    6.3 (0.16 to 30.23)
    0 (0 to 26.46)
        Smoking/nicotine status - Never|
    5.3 (0.13 to 26.03)
    11.1 (0.28 to 48.25)
    0 (0 to 26.46)
        HPV status - Positive|
    5.4 (0.66 to 18.19)
    16.7 (3.58 to 41.42)
    0 (0 to 18.53)
        HPV status - Negative|
    8.7 (3.83 to 16.42)
    6.4 (1.34 to 17.54)
    2.2 (0.06 to 11.77)
    No statistical analyses for this end point

    Secondary: Best objective response

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    End point title
    Best objective response
    End point description
    The best response a patient has had during their time in the study.
    End point type
    Secondary
    End point timeframe
    After 12 months
    End point values
    MEDI4736 + Tremelimumab Combination MEDI4736 Tremelimumab Evaluable analysis set
    Number of subjects analysed
    129
    65
    63
    257
    Units: % participants
    number (not applicable)
        Response - Total|
    7.8
    9.2
    1.6
    6.6
        Response - Complete response (CR)|
    0
    0
    0
    0
        Response - Partial response (PR)|
    7.8
    9.2
    1.6
    6.6
        Non-response (NR) - Total|
    92.2
    90.8
    98.4
    93.4
        NR - Stable disease (SD) >=6 months (24 weeks)|
    5.4
    6.2
    0
    4.3
        NR - Unconfirmed complete or partial response (PR)
    1.6
    0
    0
    0.8
        NR - Stable disease|
    3.9
    6.2
    0
    3.5
        NR - Progression|
    64.3
    64.6
    69.8
    65.8
        NR - Progression-RECIST 1.1 progression|
    45.7
    46.2
    54.0
    47.9
        NR - Progression-Death|
    18.6
    18.5
    15.9
    17.9
        NR - Not evaluable-Total|
    22.5
    20.0
    28.6
    23.3
        NR - Not evaluable-SD <6 months (24 weeks)|
    20.2
    16.9
    19.0
    19.1
        NR - Not evaluable-Incomplete post baseline tests
    2.3
    3.1
    9.5
    4.3
    No statistical analyses for this end point

    Secondary: Duration of response - Participants remaining in response

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    End point title
    Duration of response - Participants remaining in response
    End point description
    Participants remaining in response - based on BICR assessments according to RECIST v1.1. An ongoing response was defined as a patient who had documented objective response and was still alive and progression-free at the time of the data cut-off. Value of '99999' has been entered where there were no participants enrolled.
    End point type
    Secondary
    End point timeframe
    After 12 months
    End point values
    MEDI4736 + Tremelimumab Combination MEDI4736 Tremelimumab Evaluable analysis set
    Number of subjects analysed
    10
    6
    1
    17 [3]
    Units: % participants
    number (not applicable)
        Percentage remaining in response-3 months|
    90.0
    100
    100
    94.1
        Percentage remaining in response-6 months|
    70.0
    66.7
    100
    70.6
        Percentage remaining in response-9 months|
    58.3
    66.7
    99999
    64.2
        Percentage remaining in response-12 months|
    46.7
    99999
    99999
    53.5
        Percentage of ongoing response|
    50.0
    66.7
    100
    58.8
    Notes
    [3] - Evaluable analysis set patients with objective response
    No statistical analyses for this end point

    Secondary: Time to response

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    End point title
    Time to response
    End point description
    Time to response in patients with objective response based on BICR assessments according to RECIST 1.1.
    End point type
    Secondary
    End point timeframe
    After 12 months
    End point values
    MEDI4736 + Tremelimumab Combination MEDI4736 Tremelimumab Evaluable analysis set
    Number of subjects analysed
    10
    6
    1
    17 [4]
    Units: % participants
    number (not applicable)
        Percentage with a response
    100
    100
    100
    100
        Week 8, where response is first observed|
    10.0
    0
    0
    5.9
        Week 9, where response is first observed|
    50.0
    16.7
    100
    41.2
        Week 16, where response is first observed|
    10.0
    16.7
    0
    11.8
        Week 17, where response is first observed|
    10.0
    16.7
    0
    11.8
        Week 20, where response is first observed|
    0
    16.7
    0
    5.9
        Week 24, where response is first observed|
    10.0
    16.7
    0
    11.8
        Week 25, where response is first observed|
    10.0
    16.7
    0
    11.8
    Notes
    [4] - Evaluable analysis set patients with objective response
    No statistical analyses for this end point

    Secondary: Time to onset of response from first dose

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    End point title
    Time to onset of response from first dose
    End point description
    Time to onset of response in patients with objective response based on BICR assessments according to RECIST 1.1.
    End point type
    Secondary
    End point timeframe
    After 12 months
    End point values
    MEDI4736 + Tremelimumab Combination MEDI4736 Tremelimumab Evaluable analysis set
    Number of subjects analysed
    10
    6
    1
    17 [5]
    Units: Months
        median (full range (min-max))
    2.0 (2 to 6)
    4.1 (2 to 6)
    1.8 (1.8 to 2)
    3.5 (2 to 6)
    Notes
    [5] - Evaluable analysis set patients with objective response
    No statistical analyses for this end point

    Secondary: Disease control rate (DCR) at 6 months

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    End point title
    Disease control rate (DCR) at 6 months
    End point description
    DCR at 6 months based on BICR assessments according to RECIST v1.1. DCR at 6 months was evaluated using 2 different approaches to the length of stable disease (SD). -Method 1: Patients who had a best objective response of complete response (CR) or partial response (PR) within 24 weeks or had demonstrated SD for a minimum interval of 24 weeks following randomization. -Method 2: Patients who had a best objective response of CR or PR in the first 24 weeks or who had demonstrated SD for a minimum interval of 16 weeks following randomization.
    End point type
    Secondary
    End point timeframe
    After 6 months
    End point values
    MEDI4736 + Tremelimumab Combination MEDI4736 Tremelimumab Evaluable analysis set
    Number of subjects analysed
    129
    65
    63
    257
    Units: % participants
    number (not applicable)
        METHOD 1: Disease control (DC) at 6 months|
    13.2
    21.5
    1.6
    12.5
        METHOD 1: No DC at 6 months|
    86.8
    78.5
    98.4
    87.5
        METHOD 1: No DC at 6 months-Not evaluable/missing|
    20.2
    20.0
    22.2
    20.6
        METHOD 2: DC at 6 months|
    20.2
    26.2
    9.5
    19.1
        METHOD 2: No DC at 6 months|
    79.8
    73.8
    90.5
    80.9
        METHOD 2: No DC at 6 months-Not evaluable/missing|
    20.2
    20.0
    22.2
    20.6
    No statistical analyses for this end point

    Secondary: DCR at 12 months

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    End point title
    DCR at 12 months
    End point description
    DCR at 12 months based on BICR assessments according to RECIST v1.1. DCR at 6 months was evaluated using 2 different approaches to the length of stable disease (SD). -Method 1: Patients who had a best objective response of complete response (CR) or partial response (PR) within 24 weeks or had demonstrated SD for a minimum interval of 24 weeks following randomization. -Method 2: Patients who had a best objective response of CR or PR in the first 24 weeks or who had demonstrated SD for a minimum interval of 16 weeks following randomization.
    End point type
    Secondary
    End point timeframe
    After 12 months
    End point values
    MEDI4736 + Tremelimumab Combination MEDI4736 Tremelimumab Evaluable analysis set
    Number of subjects analysed
    129
    65
    63
    257
    Units: % participants
    number (not applicable)
        DC at 12 months|
    10.1
    12.3
    1.6
    8.6
        No DC at 12 months|
    89.9
    87.7
    98.4
    91.4
        No DC at 12 months-Not evaluable/missing|
    20.2
    20.0
    22.2
    20.6
    No statistical analyses for this end point

    Secondary: Progression-free survival (PFS) at 6 months

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    End point title
    Progression-free survival (PFS) at 6 months
    End point description
    Progression status at 6 months based on BICR assessments according to RECIST v1.1 at time of PFS analysis. Progression was defined as the time from the data of randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdrew from therapy or received another anti-cancer therapy prior to progression. -Target Lesions, Non Target Lesions and New Lesions are not necessarily mutually exclusive categories. -Progression death refers to death in the absence of RECIST 1.1 progression.
    End point type
    Secondary
    End point timeframe
    After 6 months
    End point values
    MEDI4736 + Tremelimumab Combination MEDI4736 Tremelimumab Full analysis set
    Number of subjects analysed
    133
    67
    67
    267
    Units: % participants
    number (not applicable)
        Progression-Total|
    82.0
    82.1
    88.1
    83.5
        Total-RECIST 1.1 Progression|
    57.9
    59.7
    67.2
    60.7
        RECIST 1.1 progression-Target Lesions|
    43.6
    43.3
    55.2
    46.4
        RECIST 1.1 progression-Non-target lesions|
    21.1
    26.9
    32.8
    25.5
        RECIST 1.1 progression-New lesions|
    26.3
    20.9
    26.9
    25.1
        Progression-Death|
    24.1
    22.4
    20.9
    22.8
        No progression-Total|
    18.0
    17.9
    11.9
    16.5
        No progression-PD free and still being followed|
    14.3
    13.4
    4.5
    11.6
        No progression-Censored on Study Day 1|
    1.5
    0
    0
    0.7
        No progression-Withdrawn consent|
    0.8
    3.0
    1.5
    1.5
        No progression- Censored death|
    1.5
    1.5
    3.0
    1.9
        No progression- Discontinued study|
    0
    0
    3.0
    0.7
    No statistical analyses for this end point

    Secondary: PFS at 12 months

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    End point title
    PFS at 12 months
    End point description
    Progression status at 12 months based on BICR assessments according to RECIST v1.1 at time of PFS analysis. Progression was defined as the time from the data of randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdrew from therapy or received another anti-cancer therapy prior to progression. -Target Lesions, Non Target Lesions and New Lesions are not necessarily mutually exclusive categories. -Progression death refers to death in the absence of RECIST 1.1 progression.
    End point type
    Secondary
    End point timeframe
    After 12 months
    End point values
    MEDI4736 + Tremelimumab Combination MEDI4736 Tremelimumab Full analysis set
    Number of subjects analysed
    133
    67
    67
    267
    Units: % participants
    number (not applicable)
        Progression-Total|
    88.7
    83.6
    89.6
    87.6
        Total-RECIST 1.1 Progression|
    64.7
    59.7
    68.7
    64.4
        RECIST 1.1 progression-Target Lesions|
    50.4
    47.8
    56.7
    51.3
        RECIST 1.1 progression-Non-target lesions|
    23.3
    28.4
    32.8
    27.0
        RECIST 1.1 progression-New lesions|
    27.1
    23.9
    23.9
    25.5
        Progression-Death|
    24.1
    23.9
    20.9
    23.2
        No progression-Total|
    11.3
    16.4
    10.4
    12.4
        No progression-PD free and still being followed|
    6.8
    11.9
    3.0
    7.1
        No progression-Censored death|
    3.8
    0
    3.0
    2.6
        No progression-Withdrawn consent|
    0.8
    4.5
    1.5
    1.9
        No progression-Discontinued study|
    0
    0
    3.0
    0.7
    No statistical analyses for this end point

    Secondary: Overall survival

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    End point title
    Overall survival
    End point description
    Survival status at time of overall survival analysis. 'Still in survival follow-up' includes patients known to be alive at data cut-off. 'Terminated prior to death' includes patients with unknown survival status or patients who were lost to follow-up.
    End point type
    Secondary
    End point timeframe
    After 12 months
    End point values
    MEDI4736 + Tremelimumab Combination MEDI4736 Tremelimumab Full analysis set
    Number of subjects analysed
    133
    67
    67
    267
    Units: % participants
    number (not applicable)
        Death|
    64.7
    65.7
    76.1
    67.8
        Still in survival follow-up|
    30.1
    28.4
    16.4
    26.2
        Terminated prior to death|
    5.3
    6.0
    7.5
    6.0
        Terminated prior to death-Voluntary discon.|
    5.3
    6.0
    4.5
    5.2
        Terminated prior to death-Other|
    0
    0
    3.0
    0.7
    No statistical analyses for this end point

    Secondary: Quality of life

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    End point title
    Quality of life
    End point description
    Improvement in quality of life was assessed using European Organisation for Research and Treatment of Cancer (EORTC) questionnaires: -The impact of treatment on Health-Related Quality of Life, functioning, and symptoms was evaluated using the EORTC QLQ-C30 v3. -Head and neck cancer-specific symptoms were evaluated using the EORTC QLQ-H&N35. The symptom and QoL/function improvement rate was defined as the number (%) of patients with 2 consecutive assessments at least 14 days apart that showed a clinically meaningful improvement (a decrease from baseline score ≥10 or EORTC QLQ-C30 scales) in that symptom/function from baseline. For QLQ-H&N35A a minimum clinically meaningful change was defined as a change in the score from baseline of >10 for scales/items.
    End point type
    Secondary
    End point timeframe
    After 12 months
    End point values
    MEDI4736 + Tremelimumab Combination MEDI4736 Tremelimumab
    Number of subjects analysed
    133
    67
    67
    Units: % patients
    number (confidence interval 95%)
        EORTC QLQ-C30 Function-Physical|
    12 (6.7 to 20.8)
    13.6 (6.4 to 26.7)
    5.1 (1.4 to 16.9)
        EORTC QLQ-C30 Function-Role|
    16.3 (10.0 to 25.5)
    16.7 (8.3 to 30.6)
    11.8 (4.7 to 26.6)
        EORTC QLQ-C30 Function-Cognitive|
    25 (16.2 to 36.4)
    29.4 (16.8 to 46.2)
    10.7 (3.7 to 27.2)
        EORTC QLQ-C30 Function-Emotional|
    13.5 (7.9 to 22.1)
    13.6 (6.4 to 26.7)
    2.6 (0.5 to 13.2)
        EORTC QLQ-C30 Function-Social|
    18.3 (11.0 to 28.8)
    15.2 (6.7 to 30.9)
    16.1 (7.1 to 32.6)
        EORTC QLQ-C30 Symptom-Fatigue|
    16.8 (10.9 to 25.0)
    17.3 (9.4 to 29.7)
    7.5 (3.0 to 17.9)
        EORTC QLQ-C30 Symptom-Pain|
    22.8 (15.4 to 32.4)
    20.8 (11.7 to 34.3)
    6.7 (2.3 to 17.9)
        EORTC QLQ-C30 Symptom-Nausea/vomiting|
    22.2 (12.5 to 36.3)
    16.7 (4.7 to 44.8)
    17.6 (6.2 to 41.0)
        EORTC QLQ-C30 Global health status/QoL|
    13.4 (8.3 to 20.9)
    7.3 (2.9 to 17.3)
    3.7 (1.0 to 12.5)
        EORTC QLQ-H&N35 Scale-Pain|
    16.7 (9.8 to 26.9)
    19.4 (9.8 to 35.0)
    8.3 (2.9 to 21.8)
        EORTC QLQ-H&N35 Scale-Swallowing|
    16.0 (9.4 to 25.9)
    13.3 (6.3 to 26.2)
    10.3 (4.1 to 23.6)
        EORTC QLQ-H&N35 Scale-Senses|
    17.8 (10.7 to 28.1)
    24.3 (13.4 to 40.1)
    23.1 (12.6 to 38.3)
        EORTC QLQ-H&N35 Scale-Speech|
    20.2 (13.3 to 29.4)
    9.8 (4.3 to 21.0)
    19.6 (10.7 to 33.2)
        EORTC QLQ-H&N35 Scale-Social eating|
    21.3 (13.7 to 31.4)
    20.0 (10.9 to 33.8)
    15.0 (7.1 to 29.1)
        EORTC QLQ-H&N35 Scale-Social contact|
    22.6 (14.0 to 34.4)
    5.9 (1.6 to 19.1)
    13.0 (4.5 to 32.1)
        EORTC QLQ-H&N35 Scale-Sexuality|
    16.2 (9.5 to 26.2)
    9.5 (3.8 to 22.1)
    9.5 (3.8 to 22.1)
    No statistical analyses for this end point

    Secondary: Duration of response

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    End point title
    Duration of response
    End point description
    Duration of objective response in patients with objective response based on BICR assessments according to RECIST v1.1. Duration of response was the time from the first documentation of Complete response/Partial response (which was subsequently confirmed) until the date of progression, death, or the last evaluable RECIST assessment for patients that did not progress. An ongoing response was defined as a patient who had documented objective response and was still alive and progression-free at the time of the data cut-off (per RECIST v1.1 as assessed by BICR).
    End point type
    Secondary
    End point timeframe
    After 12 months
    End point values
    MEDI4736 + Tremelimumab Combination MEDI4736 Tremelimumab Evaluable analysis set
    Number of subjects analysed
    10
    6
    1
    17 [6]
    Units: Participants
        No. progressed or died within 12 months|
    5
    2
    0
    7
        No. progressed or died after 12 months|
    0
    0
    0
    0
    Notes
    [6] - Evaluable analysis set patients with objective response
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs and SAEs were collected from time the informed consent was signed through 90 days after the last dose of the last study treatment or until another therapy was initiated.
    Adverse event reporting additional description
    AEs were either spontaneously reported by the patient or reported in response to open questions, revealed by observation, or were changes from baseline/deterioration in tests and vital signs that met SAE criteria or led to IP discontinuation.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    MEDI4736
    Reporting group description
    MEDI4736 (10 mg/kg) monotherapy administered via intravenous infusion every 2 weeks for up to 12 months (up to 26 doses)

    Reporting group title
    MEDI4736 + Tremelimumab Combination
    Reporting group description
    MEDI4736 (20 mg/kg) + Tremelimumab (1 mg/kg) combination therapy administered via intravenous infusion every 4 weeks for up to 4 months (4 doses), then MEDI4736 (10 mg/kg) as a single agent every 2 weeks to complete 12 months of treatment

    Reporting group title
    Tremelimumab
    Reporting group description
    Tremelimumab (10 mg/kg) monotherapy administered via intravenous infusion every 4 weeks for 7 doses, then every 12 weeks for 2 additional doses for up to 12 months (up to 9 doses)

    Serious adverse events
    MEDI4736 MEDI4736 + Tremelimumab Combination Tremelimumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    18 / 65 (27.69%)
    59 / 133 (44.36%)
    25 / 65 (38.46%)
         number of deaths (all causes)
    44
    86
    51
         number of deaths resulting from adverse events
    Vascular disorders
    Exsanguination
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Hypotension
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Orthostatic hypotension
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Tumour pain
         subjects affected / exposed
    0 / 65 (0.00%)
    2 / 133 (1.50%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Death
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Face oedema
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 133 (0.75%)
    0 / 65 (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
    Fatigue
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 133 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Pain
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Pyrexia
         subjects affected / exposed
    0 / 65 (0.00%)
    3 / 133 (2.26%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Confusional state
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Delirium
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Depression
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 133 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Foreign body aspiration
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 133 (0.00%)
    0 / 65 (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
    Gastrostomy tube site complication
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 133 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 133 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 133 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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 haemorrhage
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 133 (0.00%)
    0 / 65 (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
    Tracheal obstruction
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 133 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Platelet count decreased
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Weight decreased
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 133 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Bradycardia
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Cardiac failure
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 133 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Sinus tachycardia
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Congenital, familial and genetic disorders
    Tracheo-oesophageal fistula
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 133 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Apnoea
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Bronchial obstruction
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 133 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 133 (0.00%)
    0 / 65 (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
    1 / 65 (1.54%)
    4 / 133 (3.01%)
    2 / 65 (3.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Emphysema
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Haemoptysis
         subjects affected / exposed
    0 / 65 (0.00%)
    2 / 133 (1.50%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 133 (0.75%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Increased bronchial secretion
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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 aspiration
         subjects affected / exposed
    0 / 65 (0.00%)
    3 / 133 (2.26%)
    2 / 65 (3.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 133 (0.75%)
    0 / 65 (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
    Pulmonary embolism
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Respiratory failure
         subjects affected / exposed
    1 / 65 (1.54%)
    2 / 133 (1.50%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tachypnoea
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 65 (0.00%)
    2 / 133 (1.50%)
    0 / 65 (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
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Depressed level of consciousness
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Dizziness
         subjects affected / exposed
    2 / 65 (3.08%)
    0 / 133 (0.00%)
    0 / 65 (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
    Ischaemic stroke
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Neuropathy peripheral
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Presyncope
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Syncope
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 133 (0.75%)
    0 / 65 (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
    Autoimmune colitis
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Colitis
         subjects affected / exposed
    0 / 65 (0.00%)
    2 / 133 (1.50%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 65 (0.00%)
    5 / 133 (3.76%)
    5 / 65 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 8
    3 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 133 (0.75%)
    2 / 65 (3.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Impaired gastric emptying
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Large intestine perforation
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Mouth haemorrhage
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    0 / 65 (0.00%)
    3 / 133 (2.26%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oral cavity fistula
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 133 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumatosis intestinalis
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Rectal haemorrhage
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Small intestinal obstruction
         subjects affected / exposed
    0 / 65 (0.00%)
    2 / 133 (1.50%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 65 (0.00%)
    2 / 133 (1.50%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Autoimmune nephritis
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 133 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Hepatobiliary disorders
    Hepatitis
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Psoriasis
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 133 (0.00%)
    0 / 65 (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
    Rash maculo-papular
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 133 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Back pain
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 133 (0.75%)
    0 / 65 (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
    Fistula
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Muscular weakness
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Pain in jaw
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 133 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Lymphocytic hypophysitis
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 65 (0.00%)
    3 / 133 (2.26%)
    0 / 65 (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
    Dehydration
         subjects affected / exposed
    1 / 65 (1.54%)
    4 / 133 (3.01%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 133 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 65 (1.54%)
    4 / 133 (3.01%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypernatraemia
         subjects affected / exposed
    0 / 65 (0.00%)
    2 / 133 (1.50%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Infections and infestations
    Abdominal infection
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Abscess
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Bacteraemia
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Bronchitis
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Cellulitis
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 133 (0.00%)
    0 / 65 (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
    0 / 65 (0.00%)
    0 / 133 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 133 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Localised infection
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 133 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 65 (1.54%)
    4 / 133 (3.01%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Lymph gland infection
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 133 (0.00%)
    0 / 65 (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
    Mastoiditis
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    1 / 65 (1.54%)
    9 / 133 (6.77%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 10
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 133 (0.00%)
    2 / 65 (3.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Respiratory tract infection
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 133 (0.00%)
    0 / 65 (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
    Sepsis
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 133 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Septic rash
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 133 (0.00%)
    0 / 65 (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
    Superinfection
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 133 (0.75%)
    0 / 65 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    MEDI4736 MEDI4736 + Tremelimumab Combination Tremelimumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    52 / 65 (80.00%)
    110 / 133 (82.71%)
    59 / 65 (90.77%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    6 / 65 (9.23%)
    8 / 133 (6.02%)
    1 / 65 (1.54%)
         occurrences all number
    7
    11
    1
    Hypotension
         subjects affected / exposed
    0 / 65 (0.00%)
    7 / 133 (5.26%)
    5 / 65 (7.69%)
         occurrences all number
    0
    7
    5
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    10 / 65 (15.38%)
    21 / 133 (15.79%)
    8 / 65 (12.31%)
         occurrences all number
    12
    24
    11
    Fatigue
         subjects affected / exposed
    19 / 65 (29.23%)
    25 / 133 (18.80%)
    12 / 65 (18.46%)
         occurrences all number
    23
    29
    12
    Mucosal inflammation
         subjects affected / exposed
    4 / 65 (6.15%)
    1 / 133 (0.75%)
    1 / 65 (1.54%)
         occurrences all number
    4
    1
    2
    Oedema peripheral
         subjects affected / exposed
    2 / 65 (3.08%)
    7 / 133 (5.26%)
    2 / 65 (3.08%)
         occurrences all number
    3
    7
    2
    Pain
         subjects affected / exposed
    0 / 65 (0.00%)
    5 / 133 (3.76%)
    8 / 65 (12.31%)
         occurrences all number
    0
    5
    8
    Pyrexia
         subjects affected / exposed
    5 / 65 (7.69%)
    16 / 133 (12.03%)
    12 / 65 (18.46%)
         occurrences all number
    5
    19
    16
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    3 / 65 (4.62%)
    1 / 133 (0.75%)
    4 / 65 (6.15%)
         occurrences all number
    3
    1
    4
    Insomnia
         subjects affected / exposed
    3 / 65 (4.62%)
    9 / 133 (6.77%)
    2 / 65 (3.08%)
         occurrences all number
    3
    9
    3
    Investigations
    Weight decreased
         subjects affected / exposed
    5 / 65 (7.69%)
    18 / 133 (13.53%)
    8 / 65 (12.31%)
         occurrences all number
    5
    18
    9
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 65 (0.00%)
    5 / 133 (3.76%)
    4 / 65 (6.15%)
         occurrences all number
    0
    5
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    11 / 65 (16.92%)
    20 / 133 (15.04%)
    11 / 65 (16.92%)
         occurrences all number
    14
    20
    12
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 65 (12.31%)
    14 / 133 (10.53%)
    7 / 65 (10.77%)
         occurrences all number
    8
    14
    8
    Dyspnoea
         subjects affected / exposed
    10 / 65 (15.38%)
    14 / 133 (10.53%)
    12 / 65 (18.46%)
         occurrences all number
    10
    16
    12
    Productive cough
         subjects affected / exposed
    6 / 65 (9.23%)
    4 / 133 (3.01%)
    5 / 65 (7.69%)
         occurrences all number
    6
    5
    6
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 65 (4.62%)
    4 / 133 (3.01%)
    5 / 65 (7.69%)
         occurrences all number
    3
    5
    6
    Headache
         subjects affected / exposed
    6 / 65 (9.23%)
    6 / 133 (4.51%)
    7 / 65 (10.77%)
         occurrences all number
    7
    7
    7
    Paraesthesia
         subjects affected / exposed
    5 / 65 (7.69%)
    3 / 133 (2.26%)
    1 / 65 (1.54%)
         occurrences all number
    5
    3
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    2 / 65 (3.08%)
    3 / 133 (2.26%)
    4 / 65 (6.15%)
         occurrences all number
    2
    3
    4
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    9 / 65 (13.85%)
    18 / 133 (13.53%)
    8 / 65 (12.31%)
         occurrences all number
    9
    19
    8
    Dysphagia
         subjects affected / exposed
    8 / 65 (12.31%)
    14 / 133 (10.53%)
    6 / 65 (9.23%)
         occurrences all number
    9
    15
    7
    Diarrhoea
         subjects affected / exposed
    12 / 65 (18.46%)
    27 / 133 (20.30%)
    14 / 65 (21.54%)
         occurrences all number
    14
    42
    19
    Nausea
         subjects affected / exposed
    7 / 65 (10.77%)
    18 / 133 (13.53%)
    18 / 65 (27.69%)
         occurrences all number
    8
    24
    22
    Vomiting
         subjects affected / exposed
    4 / 65 (6.15%)
    9 / 133 (6.77%)
    9 / 65 (13.85%)
         occurrences all number
    4
    13
    11
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    5 / 65 (7.69%)
    5 / 133 (3.76%)
    1 / 65 (1.54%)
         occurrences all number
    5
    6
    1
    Pruritus
         subjects affected / exposed
    6 / 65 (9.23%)
    14 / 133 (10.53%)
    4 / 65 (6.15%)
         occurrences all number
    6
    15
    4
    Rash
         subjects affected / exposed
    3 / 65 (4.62%)
    10 / 133 (7.52%)
    5 / 65 (7.69%)
         occurrences all number
    3
    11
    6
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 65 (1.54%)
    13 / 133 (9.77%)
    3 / 65 (4.62%)
         occurrences all number
    1
    13
    3
    Back pain
         subjects affected / exposed
    5 / 65 (7.69%)
    9 / 133 (6.77%)
    1 / 65 (1.54%)
         occurrences all number
    5
    10
    1
    Musculoskeletal pain
         subjects affected / exposed
    1 / 65 (1.54%)
    4 / 133 (3.01%)
    5 / 65 (7.69%)
         occurrences all number
    1
    4
    6
    Neck pain
         subjects affected / exposed
    4 / 65 (6.15%)
    4 / 133 (3.01%)
    6 / 65 (9.23%)
         occurrences all number
    4
    8
    8
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    9 / 65 (13.85%)
    15 / 133 (11.28%)
    6 / 65 (9.23%)
         occurrences all number
    9
    15
    6
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    10 / 65 (15.38%)
    25 / 133 (18.80%)
    10 / 65 (15.38%)
         occurrences all number
    11
    27
    11
    Dehydration
         subjects affected / exposed
    0 / 65 (0.00%)
    6 / 133 (4.51%)
    6 / 65 (9.23%)
         occurrences all number
    0
    10
    6
    Hypercalcaemia
         subjects affected / exposed
    6 / 65 (9.23%)
    7 / 133 (5.26%)
    3 / 65 (4.62%)
         occurrences all number
    7
    8
    3
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 65 (1.54%)
    2 / 133 (1.50%)
    4 / 65 (6.15%)
         occurrences all number
    1
    3
    4
    Hyperkalaemia
         subjects affected / exposed
    4 / 65 (6.15%)
    2 / 133 (1.50%)
    2 / 65 (3.08%)
         occurrences all number
    4
    2
    2
    Hypokalaemia
         subjects affected / exposed
    3 / 65 (4.62%)
    7 / 133 (5.26%)
    5 / 65 (7.69%)
         occurrences all number
    3
    10
    5
    Hypomagnesaemia
         subjects affected / exposed
    5 / 65 (7.69%)
    5 / 133 (3.76%)
    5 / 65 (7.69%)
         occurrences all number
    5
    6
    5
    Hyponatraemia
         subjects affected / exposed
    4 / 65 (6.15%)
    10 / 133 (7.52%)
    5 / 65 (7.69%)
         occurrences all number
    6
    10
    5

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Feb 2015
    Implement changes in dose and regimen of study medication. Implement the change of primary and secondary objectives relating to efficacy.
    06 Aug 2015
    To clarify related tumor biopsy collection procedures. To update the timing of follow-up contact for patients for completed or discontinued participants. To update the toxicity management guidelines with the most recent approved version of the table.
    09 Mar 2016
    Addition of secondary endpoints related to the assessment of the efficacy of durvalumab in combination with tremelimumab treatment. Removal of secondary endpoints to be assessed according to irRECIST. Exclusion criteria were updated to aid clarity. The tables of assessment were modified to include additional thyroid hormone assessment. Subgroup analysis was limited to smoking status and human papillomavirus status.

    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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/30383184
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