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    Clinical Trial Results:
    A Phase II, Multi-Center, Open-Label Study of Tremelimumab Monotherapy in Patients with Advanced Solid Tumors

    Summary
    EudraCT number
    2015-002934-32
    Trial protocol
    NL   BE   PL  
    Global end of trial date
    28 Mar 2023

    Results information
    Results version number
    v1(current)
    This version publication date
    01 Dec 2023
    First version publication date
    01 Dec 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D4884C00001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02527434
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    City House,132 Hills Road, Cambridge, United Kingdom, CB2 1RY
    Public contact
    Global Clinical Lead, AstraZeneca, +1 302 885 1180, ClinicalTrialTransparency@astrazeneca.com
    Scientific contact
    Global Clinical Lead, AstraZeneca, +1 302 885 1180, ClinicalTrialTransparency@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
    31 Dec 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Feb 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Mar 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the efficacy and safety of tremelimumab monotherapy, with subsequent treatment with either durvalumab monotherapy or durvalumab + tremelimumab combination therapy in patients with select advanced solid tumors.
    Protection of trial subjects
    This study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with International Council for Harmonisation/Good Clinical Practice, applicable regulatory requirements and the AstraZeneca policy on Bioethics.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    02 Nov 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 12
    Country: Number of subjects enrolled
    Korea, Republic of: 32
    Country: Number of subjects enrolled
    United States: 11
    Country: Number of subjects enrolled
    Poland: 3
    Country: Number of subjects enrolled
    Netherlands: 6
    Worldwide total number of subjects
    64
    EEA total number of subjects
    21
    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)
    35
    From 65 to 84 years
    28
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 64 patients with select advanced solid tumors were treated in this phase II, open-label, multi-center study from November 2015. Primary data cut off date: 17 February 2018. Final data cut off date: 31 December 2018.

    Pre-assignment
    Screening details
    The patients were split into 3 different analysis cohorts based on their tumor types: urothelial bladder cancer (UBC), triple-negative breast cancer (TNBC) and pancreatic ductal adenocarcinoma (PDAC).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    UBC Cohort
    Arm description
    Patients with UBC entered the initial tremelimumab monotherapy phase and were administered tremelimumab for up to a total of 12 months or until confirmed progressive disease (PD). Eligible patients with confirmed PD on tremelimumab monotherapy or during the follow-up period were given the option for retreatment with tremelimumab monotherapy or to be sequenced to receive MEDI4736 (durvalumab) + tremelimumab combination therapy (also referred to as COMBO) for up to a total of 8 months or to receive durvalumab monotherapy (also referred to as MEDI) for up to a total of 12 months.
    Arm type
    Experimental

    Investigational medicinal product name
    Durvalumab
    Investigational medicinal product code
    MEDI4736
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Retreatment Phase (MEDI): Durvalumab 1.5 g via IV infusion q4w for up to a total of 12 months (13 doses). Retreatment Phase (COMBO): Durvalumab 1.5 g via IV infusion q4w (in combination with tremelimumab 75 mg) for up to 4 doses, followed by durvalumab 1.5 g via IV infusion q4w for up to a total of 8 months (9 additional doses).

    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
    Monotherapy Phase: Tremelimumab 750 milligrams (mg) via intravenous (IV) infusion once every 4 weeks (q4w) for 7 doses (cycles), then every 12 weeks (q12w) for 2 additional cycles for up to a total of 12 months or until confirmed PD. Retreatment Phase (COMBO): Tremelimumab 75 mg via IV infusion q4w for up to 4 doses (in combination with durvalumab 1.5 g).

    Arm title
    TNBC Cohort
    Arm description
    Patients with TNBC entered the initial tremelimumab monotherapy phase and were administered tremelimumab for up to a total of 12 months or until confirmed PD. Eligible patients with confirmed PD on tremelimumab monotherapy or during the follow-up period were given the option for retreatment with tremelimumab monotherapy or to be sequenced to receive durvalumab + tremelimumab combination therapy (also referred to as COMBO) for up to a total of 8 months or to receive durvalumab monotherapy (also referred to as MEDI) for up to a total of 12 months.
    Arm type
    Experimental

    Investigational medicinal product name
    Durvalumab
    Investigational medicinal product code
    MEDI4736
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Retreatment Phase (COMBO): Durvalumab 1.5 g via IV infusion q4w (in combination with tremelimumab 75 mg) for up to 4 doses, followed by durvalumab 1.5 g via IV infusion q4w for up to a total of 8 months (9 additional doses).

    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
    Monotherapy Phase: Tremelimumab 750 mg via IV infusion q4w for 7 doses, then q12w for 2 additional doses for up to a total of 12 months or until confirmed PD. Retreatment Phase (COMBO): Tremelimumab 75 mg via IV infusion q4w for up to 4 doses (in combination with durvalumab 1.5 g).

    Arm title
    PDAC Cohort
    Arm description
    Patients with PDAC entered the initial tremelimumab monotherapy phase and were administered tremelimumab for up to a total of 12 months or until confirmed PD. Eligible patients with confirmed PD on tremelimumab monotherapy or during the follow-up period were given the option for retreatment with tremelimumab monotherapy or to be sequenced to receive durvalumab + tremelimumab combination therapy (also referred to as COMBO) for up to a total of 8 months or to receive durvalumab monotherapy (also referred to as MEDI) for up to a total of 12 months.
    Arm type
    Experimental

    Investigational medicinal product name
    Durvalumab
    Investigational medicinal product code
    MEDI4736
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Retreatment Phase (MEDI): Durvalumab 1.5 g via IV infusion q4w for up to a total of 12 months (13 doses). Retreatment Phase (COMBO): Durvalumab 1.5 g via IV infusion q4w (in combination with tremelimumab 75 mg) for up to 4 doses, followed by durvalumab 1.5 g via IV infusion q4w for up to a total of 8 months (9 additional doses).

    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
    Monotherapy Phase: Tremelimumab 750 mg via IV infusion q4w for 7 doses, then q12w for 2 additional doses for up to a total of 12 months or until confirmed PD. Retreatment Phase (COMBO): Tremelimumab 75 mg via IV infusion q4w for up to 4 doses (in combination with durvalumab 1.5 g).

    Number of subjects in period 1
    UBC Cohort TNBC Cohort PDAC Cohort
    Started
    32
    12
    20
    Started Retreatment Phase (COMBO)
    7
    5
    4
    Started Retreatment Phase (MEDI)
    4
    0 [1]
    1
    Completed
    4
    1
    0
    Not completed
    28
    11
    20
         Consent withdrawn by subject
    5
    3
    3
         Death
    19
    6
    17
         Reason Not Specified
    1
    -
    -
         Lost to follow-up
    2
    2
    -
         Site closure
    1
    -
    -
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: No patients in this arm received MEDI in the retreatment phase.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    UBC Cohort
    Reporting group description
    Patients with UBC entered the initial tremelimumab monotherapy phase and were administered tremelimumab for up to a total of 12 months or until confirmed progressive disease (PD). Eligible patients with confirmed PD on tremelimumab monotherapy or during the follow-up period were given the option for retreatment with tremelimumab monotherapy or to be sequenced to receive MEDI4736 (durvalumab) + tremelimumab combination therapy (also referred to as COMBO) for up to a total of 8 months or to receive durvalumab monotherapy (also referred to as MEDI) for up to a total of 12 months.

    Reporting group title
    TNBC Cohort
    Reporting group description
    Patients with TNBC entered the initial tremelimumab monotherapy phase and were administered tremelimumab for up to a total of 12 months or until confirmed PD. Eligible patients with confirmed PD on tremelimumab monotherapy or during the follow-up period were given the option for retreatment with tremelimumab monotherapy or to be sequenced to receive durvalumab + tremelimumab combination therapy (also referred to as COMBO) for up to a total of 8 months or to receive durvalumab monotherapy (also referred to as MEDI) for up to a total of 12 months.

    Reporting group title
    PDAC Cohort
    Reporting group description
    Patients with PDAC entered the initial tremelimumab monotherapy phase and were administered tremelimumab for up to a total of 12 months or until confirmed PD. Eligible patients with confirmed PD on tremelimumab monotherapy or during the follow-up period were given the option for retreatment with tremelimumab monotherapy or to be sequenced to receive durvalumab + tremelimumab combination therapy (also referred to as COMBO) for up to a total of 8 months or to receive durvalumab monotherapy (also referred to as MEDI) for up to a total of 12 months.

    Reporting group values
    UBC Cohort TNBC Cohort PDAC Cohort Total
    Number of subjects
    32 12 20 64
    Age Categorical
    Units: Subjects
        <=18 years
    0 0 0 0
        Between 18 and 65 years
    13 8 14 35
        >=65 years
    19 4 6 29
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    64.8 ± 8.81 58.2 ± 13.16 59.4 ± 8.24 -
    Sex: Female, Male
    Units: Subjects
        Female
    6 12 9 27
        Male
    26 0 11 37
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 0 0 0
        Asian
    10 11 11 32
        Native Hawaiian or Other Pacific Islander
    0 0 0 0
        Black or African American
    0 0 1 1
        White
    21 1 8 30
        More than one race
    0 0 0 0
        Unknown or Not Reported
    1 0 0 1
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    1 0 0 1
        Not Hispanic or Latino
    31 12 20 63
        Unknown or Not Reported
    0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    UBC Cohort
    Reporting group description
    Patients with UBC entered the initial tremelimumab monotherapy phase and were administered tremelimumab for up to a total of 12 months or until confirmed progressive disease (PD). Eligible patients with confirmed PD on tremelimumab monotherapy or during the follow-up period were given the option for retreatment with tremelimumab monotherapy or to be sequenced to receive MEDI4736 (durvalumab) + tremelimumab combination therapy (also referred to as COMBO) for up to a total of 8 months or to receive durvalumab monotherapy (also referred to as MEDI) for up to a total of 12 months.

    Reporting group title
    TNBC Cohort
    Reporting group description
    Patients with TNBC entered the initial tremelimumab monotherapy phase and were administered tremelimumab for up to a total of 12 months or until confirmed PD. Eligible patients with confirmed PD on tremelimumab monotherapy or during the follow-up period were given the option for retreatment with tremelimumab monotherapy or to be sequenced to receive durvalumab + tremelimumab combination therapy (also referred to as COMBO) for up to a total of 8 months or to receive durvalumab monotherapy (also referred to as MEDI) for up to a total of 12 months.

    Reporting group title
    PDAC Cohort
    Reporting group description
    Patients with PDAC entered the initial tremelimumab monotherapy phase and were administered tremelimumab for up to a total of 12 months or until confirmed PD. Eligible patients with confirmed PD on tremelimumab monotherapy or during the follow-up period were given the option for retreatment with tremelimumab monotherapy or to be sequenced to receive durvalumab + tremelimumab combination therapy (also referred to as COMBO) for up to a total of 8 months or to receive durvalumab monotherapy (also referred to as MEDI) for up to a total of 12 months.

    Subject analysis set title
    UBC - Tremelimumab Monotherapy
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Patients with UBC were administered tremelimumab via IV infusion at a dose of 750 mg q4w for 7 cycles, then q12w for 2 additional cycles, for up to a total of 12 months or until confirmed PD.

    Subject analysis set title
    TNBC - Tremelimumab Monotherapy
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Patients with TNBC were administered tremelimumab via IV infusion at a dose of 750 mg q4w for 7 cycles, then q12w for 2 additional cycles, for up to a total of 12 months or until confirmed PD.

    Subject analysis set title
    PDAC - Tremelimumab Monotherapy
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Patients with PDAC were administered tremelimumab via IV infusion at a dose of 750 mg q4w for 7 cycles, then q12w for 2 additional cycles, for up to a total of 12 months or until confirmed PD.

    Subject analysis set title
    UBC - COMBO
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Eligible UBC patients with confirmed PD on tremelimumab monotherapy or during the follow-up period were sequenced to receive durvalumab + tremelimumab combination therapy (also referred to as COMBO; durvalumab 1.5 g via IV infusion q4w in combination with tremelimumab 75 mg via IV infusion q4w for up to 4 cycles each, followed by durvalumab 1.5 g via IV infusion q4w) for up to a total of 8 months.

    Subject analysis set title
    TNBC - COMBO
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Eligible TNBC patients with confirmed PD on tremelimumab monotherapy or during the follow-up period were sequenced to receive durvalumab + tremelimumab combination therapy (also referred to as COMBO; durvalumab 1.5 g via IV infusion q4w in combination with tremelimumab 75 mg via IV infusion q4w for up to 4 cycles each, followed by durvalumab 1.5 g via IV infusion q4w) for up to a total of 8 months.

    Subject analysis set title
    PDAC - COMBO
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Eligible PDAC patients with confirmed PD on tremelimumab monotherapy or during the follow-up period were sequenced to receive durvalumab + tremelimumab combination therapy (also referred to as COMBO; durvalumab 1.5 g via IV infusion q4w in combination with tremelimumab 75 mg via IV infusion q4w for up to 4 cycles each, followed by durvalumab 1.5 g via IV infusion q4w) for up to a total of 8 months.

    Subject analysis set title
    UBC- MEDI
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Eligible UBC patients with confirmed PD on tremelimumab monotherapy or during the follow-up period were sequenced to receive durvalumab monotherapy (also referred to as MEDI; 1.5 g via IV infusion q4w) for up to a total of 12 months.

    Subject analysis set title
    PDAC - MEDI
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Eligible PDAC patients with confirmed PD on tremelimumab monotherapy or during the follow-up period were sequenced to receive durvalumab monotherapy (also referred to as MEDI; 1.5 g via IV infusion q4w) for up to a total of 12 months.

    Primary: Percentage of Patients with Confirmed Overall Response during Tremelimumab Monotherapy Phase

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    End point title
    Percentage of Patients with Confirmed Overall Response during Tremelimumab Monotherapy Phase [1]
    End point description
    Objective response rate (ORR) during the initial tremelimumab monotherapy phase was assessed by the site Investigator using Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1) and was defined as the percentage of patients with a confirmed overall response of complete response (CR) or partial response (PR) and was based on all treated patients who had measurable disease at baseline (Day 1). 95% confidence intervals (CIs) were calculated using the Clopper Pearson method. Analysis was performed on the Full Analysis Set (FAS) (all treated patients who received at least 1 dose of tremelimumab monotherapy).
    End point type
    Primary
    End point timeframe
    From baseline to 12 months in the tremelimumab monotherapy phase
    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: In accordance with the protocol, no comparative analyses were performed.
    End point values
    UBC - Tremelimumab Monotherapy TNBC - Tremelimumab Monotherapy PDAC - Tremelimumab Monotherapy
    Number of subjects analysed
    32
    12
    20
    Units: Percentage of Patients
        number (confidence interval 95%)
    18.8 (7.2 to 36.4)
    8.3 (0.2 to 38.5)
    0.0 (0.0 to 16.8)
    No statistical analyses for this end point

    Secondary: Median Duration of Response (DoR) during Tremelimumab Monotherapy Phase

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    End point title
    Median Duration of Response (DoR) during Tremelimumab Monotherapy Phase
    End point description
    DoR during the initial tremelimumab monotherapy phase was assessed by the site Investigator using RECIST 1.1 and was defined as the time from the date of first documented response until the first date of documented progression or death in the absence of disease progression. The time of the initial response was defined as the latest of the dates contributing toward the first visit response of CR or PR. If a patient did not progress following a response, then their DoR was censored at the progression-free survival (PFS) censoring time. Analysis was performed on the FAS (all treated patients who received at least 1 dose of tremelimumab monotherapy). DoR was not defined for those patients who did not have documented response. Median DoR was calculated using the Kaplan-Meier technique.
    End point type
    Secondary
    End point timeframe
    From baseline to 12 months in the tremelimumab monotherapy phase
    End point values
    UBC - Tremelimumab Monotherapy TNBC - Tremelimumab Monotherapy PDAC - Tremelimumab Monotherapy
    Number of subjects analysed
    6 [2]
    1
    0 [3]
    Units: Months
        median (inter-quartile range (Q1-Q3))
    999999.99 (999999.99 to 999999.99)
    12.9 (12.9 to 12.9)
    ( to )
    Notes
    [2] - 999999.99 = data not estimable
    [3] - As no patients had a documented response, no DoR could be calculated.
    No statistical analyses for this end point

    Secondary: Disease Control Rate (DCR) during Tremelimumab Monotherapy Phase

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    End point title
    Disease Control Rate (DCR) during Tremelimumab Monotherapy Phase
    End point description
    DCR during the initial tremelimumab monotherapy phase was defined as the percentage of patients who had a best objective response (BoR) of CR or PR in the first 3 months (PDAC patients) or 4 months (UBC and TNBC patients) and 12 months (all patients), or who had demonstrated stable disease (SD) for a minimum interval of 3, 4 or 12 months following the start of study treatment. DCR was determined programmatically based on RECIST 1.1 using site Investigator data and all data up until the first progression event. 95% CIs were calculated using the Clopper Pearson method. Analysis was performed on the FAS (all treated patients who received at least 1 dose of tremelimumab monotherapy).
    End point type
    Secondary
    End point timeframe
    From baseline to 12 months in the tremelimumab monotherapy phase
    End point values
    UBC - Tremelimumab Monotherapy TNBC - Tremelimumab Monotherapy PDAC - Tremelimumab Monotherapy
    Number of subjects analysed
    32
    12
    20
    Units: Percentage of patients
    number (confidence interval 95%)
        DCR at 3 or 4 months
    25.0 (11.46 to 43.40)
    8.3 (0.21 to 38.48)
    0.0 (0.00 to 16.84)
        DCR at 12 months
    21.9 (9.28 to 39.97)
    8.3 (0.21 to 38.48)
    0.0 (0.00 to 16.84)
    No statistical analyses for this end point

    Secondary: Median PFS during Tremelimumab Monotherapy Phase

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    End point title
    Median PFS during Tremelimumab Monotherapy Phase
    End point description
    PFS during the initial tremelimumab monotherapy phase was assessed by the site Investigator using RECIST 1.1 and was defined as the time from the date of enrollment 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 anticancer therapy prior to progression. Progression events that did not occur within 3 months (PDAC patients) or 4 months (UBC/TNBC patients) of the last evaluable assessment (or first dose) were censored. Median PFS was calculated using the Kaplan-Meier technique. Analysis was performed on the FAS (all treated patients who received at least 1 dose of tremelimumab monotherapy).
    End point type
    Secondary
    End point timeframe
    From baseline to 12 months in the tremelimumab monotherapy phase
    End point values
    UBC - Tremelimumab Monotherapy TNBC - Tremelimumab Monotherapy PDAC - Tremelimumab Monotherapy
    Number of subjects analysed
    32 [4]
    12
    20
    Units: Months
        median (inter-quartile range (Q1-Q3))
    2.63 (1.77 to 999999.99)
    3.58 (1.40 to 4.04)
    1.77 (1.38 to 2.92)
    Notes
    [4] - 999999.99 = data not estimable
    No statistical analyses for this end point

    Secondary: Best Objective Response (BoR) during Tremelimumab Monotherapy Phase

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    End point title
    Best Objective Response (BoR) during Tremelimumab Monotherapy Phase
    End point description
    BoR during the initial tremelimumab monotherapy phase was calculated based on the overall visit responses from each RECIST 1.1 assessment and was defined as the best response a patient had during their time in the study (from CR, PR, SD, PD or not evaluable [NE]) obtained among all tumor assessment visits from baseline until end of treatment or determination of PD. The BoR was summarized by percentage of patients for each category (CR, PR, SD, PD, and NE). Analysis was performed on the FAS (all treated patients who received at least 1 dose of tremelimumab monotherapy).
    End point type
    Secondary
    End point timeframe
    From baseline to 12 months in the tremelimumab monotherapy phase
    End point values
    UBC - Tremelimumab Monotherapy TNBC - Tremelimumab Monotherapy PDAC - Tremelimumab Monotherapy
    Number of subjects analysed
    32
    12
    20
    Units: Percentage of Patients
    number (not applicable)
        CR
    6.3
    0.0
    0.0
        PR
    12.5
    8.3
    0.0
        SD
    9.4
    0.0
    0.0
        PD
    68.8
    91.7
    90.0
        NE
    3.1
    0.0
    10.0
    No statistical analyses for this end point

    Secondary: Median Overall Survival (OS) during Tremelimumab Monotherapy Phase

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    End point title
    Median Overall Survival (OS) during Tremelimumab Monotherapy Phase
    End point description
    OS was defined as the time from the date of first dose until death due to any cause. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. OS is presented from start of tremelimumab monotherapy phase and includes the retreatment phase if the patient entered the corresponding treatment phase. Median OS was calculated using the Kaplan-Meier technique. Analysis was performed on the FAS (all treated patients who received at least 1 dose of tremelimumab monotherapy).
    End point type
    Secondary
    End point timeframe
    From baseline to primary data cut-off date
    End point values
    UBC - Tremelimumab Monotherapy TNBC - Tremelimumab Monotherapy PDAC - Tremelimumab Monotherapy
    Number of subjects analysed
    32
    12 [5]
    20
    Units: Months
        median (confidence interval 95%)
    10.32 (5.91 to 24.61)
    12.88 (2.53 to 999999.99)
    3.98 (2.83 to 5.13)
    Notes
    [5] - 999999.99 = data not estimable
    No statistical analyses for this end point

    Secondary: Percentage of Patients with Confirmed Overall Response during Retreatment Phase

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    End point title
    Percentage of Patients with Confirmed Overall Response during Retreatment Phase
    End point description
    ORR was assessed by the site Investigator using RECIST 1.1 and was defined as the percentage of patients with a confirmed overall response of CR or PR and was based on all treated patients who had measurable disease at baseline (Day 1) and who sequenced to durvalumab monotherapy (MEDI treatment phase) or durvalumab + tremelimumab combination therapy (COMBO treatment phase). 95% CIs were calculated using the Clopper Pearson method. Analysis was performed on the MEDI and COMBO analysis sets (all patients who were treated with tremelimumab, received at least 1 dose of durvalumab monotherapy or durvalumab + tremelimumab combination therapy as applicable, and who had a baseline tumor assessment prior to dosing).
    End point type
    Secondary
    End point timeframe
    From baseline to 12 months in retreatment phase
    End point values
    UBC - COMBO TNBC - COMBO PDAC - COMBO UBC- MEDI PDAC - MEDI
    Number of subjects analysed
    7
    5
    4
    4
    1
    Units: Percentage of Patients
        number (confidence interval 95%)
    0.0 (0.0 to 41.0)
    0.0 (0.0 to 52.2)
    0.0 (0.0 to 60.2)
    25.0 (0.6 to 80.6)
    0.0 (0.0 to 97.5)
    No statistical analyses for this end point

    Secondary: Median DoR during Retreatment Phase

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    End point title
    Median DoR during Retreatment Phase
    End point description
    DoR during the retreatment phase was assessed by the site Investigator using RECIST 1.1 and was defined as the time from the date of first documented response until the first date of documented progression or death in the absence of disease progression. The time of the initial response was defined as the latest of the dates contributing toward the first visit response of CR or PR. If a patient did not progress following a response, then their DoR was censored at the PFS censoring time. Analysis was performed on the MEDI and COMBO analysis sets (all patients who were treated with tremelimumab, received at least 1 dose of durvalumab monotherapy or durvalumab + tremelimumab combination therapy as applicable, and who had a baseline tumor assessment prior to dosing). DoR was not defined for those patients who did not have documented response. Median DoR was calculated using the Kaplan-Meier technique.
    End point type
    Secondary
    End point timeframe
    From baseline to 12 months in retreatment phase
    End point values
    UBC - COMBO TNBC - COMBO PDAC - COMBO UBC- MEDI PDAC - MEDI
    Number of subjects analysed
    0 [6]
    0 [7]
    0 [8]
    1
    0 [9]
    Units: Months
        median (inter-quartile range (Q1-Q3))
    ( to )
    ( to )
    ( to )
    7.3 (7.3 to 7.3)
    ( to )
    Notes
    [6] - As no patients had a documented response, no DoR could be calculated.
    [7] - As no patients had a documented response, no DoR could be calculated.
    [8] - As no patients had a documented response, no DoR could be calculated.
    [9] - As no patients had a documented response, no DoR could be calculated.
    No statistical analyses for this end point

    Secondary: DCR during Retreatment Phase

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    End point title
    DCR during Retreatment Phase
    End point description
    DCR during the retreatment phase was defined as the percentage of patients who had a BoR of CR or PR in the first 3 months (PDAC patients) or 4 months (UBC and TNBC patients) or who had demonstrated SD for a minimum interval of 3 or 4 months following the start of study treatment. DCR was determined programmatically based on RECIST 1.1 using site Investigator data and all data up until the first progression event. 95% CIs were calculated using the Clopper Pearson method. Analysis was performed on the MEDI and COMBO analysis sets (all patients who were treated with tremelimumab, received at least 1 dose of durvalumab monotherapy or durvalumab + tremelimumab combination therapy as applicable, and who had a baseline tumor assessment prior to dosing).
    End point type
    Secondary
    End point timeframe
    From baseline to 4 months in retreatment phase
    End point values
    UBC - COMBO TNBC - COMBO PDAC - COMBO UBC- MEDI PDAC - MEDI
    Number of subjects analysed
    7
    5
    4
    4
    1
    Units: Percentage of Patients
    number (confidence interval 95%)
        Disease control at 3 or 4 months
    28.6 (3.67 to 70.96)
    20.0 (0.51 to 71.64)
    25.0 (0.63 to 80.59)
    25.0 (0.63 to 80.59)
    0.0 (0.00 to 97.50)
    No statistical analyses for this end point

    Secondary: Median PFS during Retreatment Phase

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    End point title
    Median PFS during Retreatment Phase
    End point description
    PFS during the retreatment phase was assessed by the site Investigator using RECIST 1.1 and defined as the time from the date of enrollment 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 anticancer therapy prior to progression. Progression events that did not occur within 3 months (PDAC patients) or 4 months (UBC/TNBC patients) of the last evaluable assessment (or first dose) were censored. Median PFS was calculated using the Kaplan-Meier technique. Analysis was performed on the MEDI and COMBO analysis sets (all patients who were treated with tremelimumab, received at least 1 dose of durvalumab monotherapy or durvalumab + tremelimumab combination therapy as applicable, and who had a baseline tumor assessment prior to dosing).
    End point type
    Secondary
    End point timeframe
    From baseline to 12 months in retreatment phase
    End point values
    UBC - COMBO TNBC - COMBO PDAC - COMBO UBC- MEDI PDAC - MEDI
    Number of subjects analysed
    7
    5 [10]
    4
    4
    1
    Units: Months
        median (inter-quartile range (Q1-Q3))
    2.83 (1.81 to 3.65)
    0.99 (0.92 to 999999.99)
    2.86 (1.87 to 3.52)
    2.86 (1.81 to 6.62)
    1.84 (1.84 to 1.84)
    Notes
    [10] - 999999.99 = data not estimable
    No statistical analyses for this end point

    Secondary: BoR during Retreatment Phase

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    End point title
    BoR during Retreatment Phase
    End point description
    BoR during the retreatment phase was calculated based on the overall visit responses from each RECIST 1.1 assessment and was defined as the best response a patient had during their time in the study (from CR, PR, SD, PD or NE) obtained among all tumor assessment visits from baseline until end of treatment or determination of PD. The BoR was summarized by percentage of patients for each category (CR, PR, SD, PD, and NE). Analysis was performed on the MEDI and COMBO analysis sets (all patients who were treated with tremelimumab, received at least 1 dose of durvalumab monotherapy or durvalumab + tremelimumab combination therapy as applicable, and who had a baseline tumor assessment prior to dosing).
    End point type
    Secondary
    End point timeframe
    From baseline to 12 months in retreatment phase
    End point values
    UBC - COMBO TNBC - COMBO PDAC - COMBO UBC- MEDI PDAC - MEDI
    Number of subjects analysed
    7
    5
    4
    4
    1
    Units: Percentage of Patients
    number (not applicable)
        CR
    0.0
    0.0
    0.0
    0.0
    0.0
        PR
    0.0
    0.0
    0.0
    25.0
    0.0
        SD
    14.3
    20.0
    0.0
    0.0
    0.0
        PD
    71.4
    80.0
    100.0
    75.0
    100.0
        NE
    14.3
    0.0
    0.0
    0.0
    0.0
    No statistical analyses for this end point

    Secondary: Median OS during Retreatment Phase

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    End point title
    Median OS during Retreatment Phase
    End point description
    OS during the retreatment phase was defined as the time from the date of first dose until death due to any cause. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Median OS was calculated using the Kaplan-Meier technique. Analysis was performed on the MEDI and COMBO analysis sets (all patients who were treated with tremelimumab, received at least 1 dose of durvalumab monotherapy or durvalumab + tremelimumab combination therapy as applicable, and who had a baseline tumor assessment prior to dosing).
    End point type
    Secondary
    End point timeframe
    From baseline in retreatment phase to primary data cut-off date
    End point values
    UBC - COMBO TNBC - COMBO PDAC - COMBO UBC- MEDI PDAC - MEDI
    Number of subjects analysed
    7 [11]
    5
    4
    4
    1 [12]
    Units: Months
        median (confidence interval 95%)
    11.86 (5.91 to 999999.99)
    33.05 (9.69 to 33.05)
    7.18 (3.98 to 18.76)
    16.53 (7.56 to 32.39)
    4.14 (-999999.99 to 999999.99)
    Notes
    [11] - 999999.99 = data not estimable
    [12] - 999999.99 = data not estimable
    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 Day 1 (i.e. first dose) up until 90 days following the end of treatment in the tremelimumab monotherapy phase and the retreatment phase (up to a total of 15 months per treatment phase).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    TNBC - Tremelimumab Monotherapy
    Reporting group description
    Patients with TNBC were administered tremelimumab via IV infusion at a dose of 750 mg q4w for 7 cycles, then q12w for 2 additional cycles, for up to a total of 12 months or until confirmed PD.

    Reporting group title
    PDAC- Tremelimumab Monotherapy
    Reporting group description
    Patients with PDAC were administered tremelimumab via IV infusion at a dose of 750 mg q4w for 7 cycles, then q12w for 2 additional cycles, for up to a total of 12 months or until confirmed PD.

    Reporting group title
    UBC - COMBO
    Reporting group description
    Eligible UBC patients with confirmed PD on tremelimumab monotherapy or during the follow-up period were sequenced to receive durvalumab + tremelimumab combination therapy (also referred to as COMBO; durvalumab 1.5 g via IV infusion q4w in combination with tremelimumab 75 mg via IV infusion q4w for up to 4 cycles each, followed by durvalumab 1.5 g via IV infusion q4w) for up to a total of 8 months.

    Reporting group title
    UBC- Tremelimumab Monotherapy
    Reporting group description
    Patients with UBC were administered tremelimumab via IV infusion at a dose of 750 mg q4w for 7 cycles, then q12w for 2 additional cycles, for up to a total of 12 months or until confirmed PD.

    Reporting group title
    UBC- MEDI
    Reporting group description
    Eligible UBC patients with confirmed PD on tremelimumab monotherapy or during the follow-up period were sequenced to receive durvalumab monotherapy (also referred to as MEDI; 1.5 g via IV infusion q4w) for up to a total of 12 months.

    Reporting group title
    TNBC - COMBO
    Reporting group description
    Eligible TNBC patients with confirmed PD on tremelimumab monotherapy or during the follow-up period were sequenced to receive durvalumab + tremelimumab combination therapy (also referred to as COMBO; durvalumab 1.5 g via IV infusion q4w in combination with tremelimumab 75 mg via IV infusion q4w for up to 4 cycles each, followed by durvalumab 1.5 g via IV infusion q4w) for up to a total of 8 months.

    Reporting group title
    PDAC - COMBO
    Reporting group description
    Eligible PDAC patients with confirmed PD on tremelimumab monotherapy or during the follow-up period were sequenced to receive durvalumab + tremelimumab combination therapy (also referred to as COMBO; durvalumab 1.5 g via IV infusion q4w in combination with tremelimumab 75 mg via IV infusion q4w for up to 4 cycles each, followed by durvalumab 1.5 g via IV infusion q4w) for up to a total of 8 months.

    Reporting group title
    PDAC - MEDI
    Reporting group description
    Eligible PDAC patients with confirmed PD on tremelimumab monotherapy or during the follow-up period were sequenced to receive durvalumab monotherapy (also referred to as MEDI; 1.5 g via IV infusion q4w) for up to a total of 12 months.

    Serious adverse events
    TNBC - Tremelimumab Monotherapy PDAC- Tremelimumab Monotherapy UBC - COMBO UBC- Tremelimumab Monotherapy UBC- MEDI TNBC - COMBO PDAC - COMBO PDAC - MEDI
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 12 (33.33%)
    11 / 20 (55.00%)
    3 / 7 (42.86%)
    18 / 32 (56.25%)
    1 / 4 (25.00%)
    2 / 5 (40.00%)
    3 / 4 (75.00%)
    0 / 1 (0.00%)
         number of deaths (all causes)
    4
    12
    4
    13
    4
    2
    4
    1
         number of deaths resulting from adverse events
    1
    1
    0
    0
    0
    0
    0
    0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    1 / 32 (3.13%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    1 / 7 (14.29%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Euthanasia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 20 (5.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    1 / 32 (3.13%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    1 / 32 (3.13%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 20 (5.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    1 / 7 (14.29%)
    1 / 32 (3.13%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    1 / 32 (3.13%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 20 (5.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuritis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 20 (5.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 20 (5.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Autoimmune colitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    2 / 32 (6.25%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 20 (5.00%)
    0 / 7 (0.00%)
    3 / 32 (9.38%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    3 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 12 (0.00%)
    3 / 20 (15.00%)
    0 / 7 (0.00%)
    4 / 32 (12.50%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    0 / 0
    2 / 4
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea haemorrhagic
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal obstruction
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 20 (5.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    1 / 32 (3.13%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Impaired gastric emptying
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    1 / 32 (3.13%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    1 / 32 (3.13%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 20 (5.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bile duct obstruction
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 20 (5.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    1 / 32 (3.13%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    2 / 32 (6.25%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    1 / 7 (14.29%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    1 / 32 (3.13%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hypophysitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    1 / 32 (3.13%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    1 / 32 (3.13%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 20 (5.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Kidney infection
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    1 / 32 (3.13%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis aseptic
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    1 / 32 (3.13%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    1 / 32 (3.13%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    1 / 32 (3.13%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    1 / 32 (3.13%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 20 (5.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    TNBC - Tremelimumab Monotherapy PDAC- Tremelimumab Monotherapy UBC - COMBO UBC- Tremelimumab Monotherapy UBC- MEDI TNBC - COMBO PDAC - COMBO PDAC - MEDI
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 12 (83.33%)
    19 / 20 (95.00%)
    7 / 7 (100.00%)
    30 / 32 (93.75%)
    4 / 4 (100.00%)
    5 / 5 (100.00%)
    4 / 4 (100.00%)
    1 / 1 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    1 / 32 (3.13%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    Vascular disorders
    Hot flush
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Embolism
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    1 / 7 (14.29%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    0
    Hypertension
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    2 / 32 (6.25%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    0
    Lymphoedema
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Hypotension
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    1 / 7 (14.29%)
    2 / 32 (6.25%)
    0 / 4 (0.00%)
    2 / 5 (40.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    2
    0
    2
    0
    0
    Vascular fragility
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 20 (5.00%)
    1 / 7 (14.29%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    2 / 4 (50.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    2
    1
    Face oedema
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Fatigue
         subjects affected / exposed
    1 / 12 (8.33%)
    6 / 20 (30.00%)
    2 / 7 (28.57%)
    15 / 32 (46.88%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    6
    2
    20
    1
    0
    0
    0
    Influenza like illness
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    0
    Malaise
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    2 / 32 (6.25%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 20 (10.00%)
    0 / 7 (0.00%)
    4 / 32 (12.50%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    4
    0
    0
    0
    0
    Oedema
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    2 / 32 (6.25%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    1
    1
    0
    Pyrexia
         subjects affected / exposed
    2 / 12 (16.67%)
    2 / 20 (10.00%)
    2 / 7 (28.57%)
    4 / 32 (12.50%)
    1 / 4 (25.00%)
    1 / 5 (20.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    2
    3
    4
    1
    5
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Dysphonia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    1 / 32 (3.13%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    0
    0
    0
    Cough
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 20 (5.00%)
    0 / 7 (0.00%)
    8 / 32 (25.00%)
    0 / 4 (0.00%)
    2 / 5 (40.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    9
    0
    2
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    3 / 12 (25.00%)
    1 / 20 (5.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    2
    0
    0
    0
    3
    0
    0
    Laryngospasm
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Laryngeal inflammation
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Productive cough
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    3 / 5 (60.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    3
    0
    0
    Dyspnoea
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    4 / 32 (12.50%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    5
    0
    0
    0
    0
    Pulmonary embolism
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 20 (5.00%)
    1 / 7 (14.29%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    0
    0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    2 / 32 (6.25%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    0
    Delirium
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Depressed mood
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 20 (5.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    0
    Insomnia
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 20 (0.00%)
    1 / 7 (14.29%)
    3 / 32 (9.38%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    1
    3
    0
    1
    0
    0
    Depression
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 20 (10.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    0
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 12 (0.00%)
    3 / 20 (15.00%)
    0 / 7 (0.00%)
    1 / 32 (3.13%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    3
    0
    1
    0
    0
    0
    0
    Amylase increased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    2 / 32 (6.25%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    4
    0
    1
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 20 (5.00%)
    0 / 7 (0.00%)
    1 / 32 (3.13%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    1
    1
    0
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 20 (10.00%)
    0 / 7 (0.00%)
    1 / 32 (3.13%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    1
    0
    0
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 20 (10.00%)
    0 / 7 (0.00%)
    1 / 32 (3.13%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    3
    0
    1
    0
    0
    0
    0
    Lipase increased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    3 / 32 (9.38%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    4
    0
    0
    0
    0
    Weight decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 20 (10.00%)
    0 / 7 (0.00%)
    4 / 32 (12.50%)
    0 / 4 (0.00%)
    2 / 5 (40.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    4
    0
    2
    0
    0
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    1 / 7 (14.29%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Radiation skin injury
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 20 (0.00%)
    1 / 7 (14.29%)
    3 / 32 (9.38%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    1
    3
    0
    2
    0
    0
    Facial paralysis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Dizziness
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    1 / 32 (3.13%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    1
    Brain oedema
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    0
    Presyncope
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    1 / 7 (14.29%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    1 / 7 (14.29%)
    1 / 32 (3.13%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    1
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 20 (10.00%)
    2 / 7 (28.57%)
    7 / 32 (21.88%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    3
    2
    9
    0
    1
    1
    0
    Febrile neutropenia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Ear and labyrinth disorders
    Ear discomfort
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Vertigo
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Eye disorders
    Eyelid oedema
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    2 / 32 (6.25%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    2
    0
    1
    0
    0
    Abdominal distension
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 20 (10.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    0
    0
    0
    Abdominal pain
         subjects affected / exposed
    2 / 12 (16.67%)
    6 / 20 (30.00%)
    1 / 7 (14.29%)
    4 / 32 (12.50%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    6
    1
    4
    0
    0
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    2 / 12 (16.67%)
    2 / 20 (10.00%)
    0 / 7 (0.00%)
    1 / 32 (3.13%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    2
    0
    1
    0
    0
    0
    0
    Anal inflammation
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Ascites
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 20 (5.00%)
    0 / 7 (0.00%)
    1 / 32 (3.13%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    1
    0
    0
    0
    0
    Colitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    4 / 32 (12.50%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    4
    0
    0
    0
    0
    Constipation
         subjects affected / exposed
    5 / 12 (41.67%)
    3 / 20 (15.00%)
    0 / 7 (0.00%)
    9 / 32 (28.13%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    5
    3
    0
    9
    0
    1
    1
    0
    Diarrhoea
         subjects affected / exposed
    2 / 12 (16.67%)
    4 / 20 (20.00%)
    1 / 7 (14.29%)
    8 / 32 (25.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    7
    1
    9
    0
    2
    1
    0
    Diarrhoea haemorrhagic
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Dyspepsia
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 20 (5.00%)
    0 / 7 (0.00%)
    3 / 32 (9.38%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    4
    0
    1
    0
    0
    Gastritis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    1 / 32 (3.13%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    0
    Haematochezia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    1 / 7 (14.29%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    1 / 12 (8.33%)
    4 / 20 (20.00%)
    1 / 7 (14.29%)
    11 / 32 (34.38%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    4
    1
    13
    0
    1
    1
    0
    Stomatitis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    0
    Vomiting
         subjects affected / exposed
    2 / 12 (16.67%)
    2 / 20 (10.00%)
    0 / 7 (0.00%)
    4 / 32 (12.50%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    1 / 4 (25.00%)
    1 / 1 (100.00%)
         occurrences all number
    2
    2
    0
    5
    0
    1
    3
    1
    Skin and subcutaneous tissue disorders
    Dermal cyst
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Blister
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    1 / 7 (14.29%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Dry skin
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 20 (5.00%)
    0 / 7 (0.00%)
    5 / 32 (15.63%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    5
    0
    0
    0
    0
    Pain of skin
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Nail discolouration
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Papule
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Pruritus
         subjects affected / exposed
    5 / 12 (41.67%)
    7 / 20 (35.00%)
    1 / 7 (14.29%)
    8 / 32 (25.00%)
    0 / 4 (0.00%)
    2 / 5 (40.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    5
    7
    1
    9
    0
    2
    1
    0
    Rash
         subjects affected / exposed
    2 / 12 (16.67%)
    5 / 20 (25.00%)
    1 / 7 (14.29%)
    2 / 32 (6.25%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    6
    1
    3
    0
    1
    1
    0
    Pruritus generalised
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    2 / 32 (6.25%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    0
    Rash maculo-papular
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    2 / 32 (6.25%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    0
    0
    0
    Renal and urinary disorders
    Bladder spasm
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    1 / 7 (14.29%)
    1 / 32 (3.13%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    0
    Acute kidney injury
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    2 / 32 (6.25%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    1
    0
    0
    Dysuria
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    1 / 32 (3.13%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    1
    0
    0
    Haematuria
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    3 / 32 (9.38%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    0
    0
    0
    Urinary tract pain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    1 / 7 (14.29%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    2 / 32 (6.25%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    0
    Hypothyroidism
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    3 / 32 (9.38%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    1
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    1 / 7 (14.29%)
    1 / 32 (3.13%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    0
    Back pain
         subjects affected / exposed
    0 / 12 (0.00%)
    3 / 20 (15.00%)
    0 / 7 (0.00%)
    4 / 32 (12.50%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    3
    0
    5
    1
    0
    0
    0
    Muscular weakness
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 20 (5.00%)
    0 / 7 (0.00%)
    3 / 32 (9.38%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    3
    0
    0
    0
    0
    Myalgia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    2 / 32 (6.25%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    1
    0
    0
    Spinal pain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Infections and infestations
    Catheter site infection
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Oral infection
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    2 / 32 (6.25%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    0
    Paronychia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Pneumonia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    2 / 32 (6.25%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    0
    Rhinitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Wound infection
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Urinary tract infection
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 20 (0.00%)
    1 / 7 (14.29%)
    4 / 32 (12.50%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    1
    4
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 12 (16.67%)
    5 / 20 (25.00%)
    1 / 7 (14.29%)
    7 / 32 (21.88%)
    0 / 4 (0.00%)
    4 / 5 (80.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    5
    1
    9
    0
    4
    1
    0
    Dehydration
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    4 / 32 (12.50%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    4
    0
    0
    0
    0
    Hypercalcaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 20 (5.00%)
    0 / 7 (0.00%)
    6 / 32 (18.75%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    6
    1
    0
    0
    0
    Hyperkalaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    1 / 32 (3.13%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    Hypernatraemia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    1 / 7 (14.29%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Hyperuricaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 20 (5.00%)
    1 / 7 (14.29%)
    2 / 32 (6.25%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    1
    2
    0
    0
    1
    0
    Hypocalcaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 20 (5.00%)
    0 / 7 (0.00%)
    2 / 32 (6.25%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    3
    0
    0
    0
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 20 (5.00%)
    0 / 7 (0.00%)
    5 / 32 (15.63%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    7
    0
    0
    3
    0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    3 / 32 (9.38%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    4
    0
    0
    0
    0
    Hyponatraemia
         subjects affected / exposed
    2 / 12 (16.67%)
    3 / 20 (15.00%)
    0 / 7 (0.00%)
    1 / 32 (3.13%)
    0 / 4 (0.00%)
    2 / 5 (40.00%)
    2 / 4 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    3
    0
    1
    0
    2
    2
    0
    Hypophosphataemia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 20 (0.00%)
    0 / 7 (0.00%)
    0 / 32 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 May 2016
    • Inclusion criteria revised to permit evaluation of durvalumab in a broader UBC patient population. • Exclusion criteria revised to exclude patients who had participated in prior durvalumab /tremelimumab studies and permit inclusion of patients with brain metastases or spinal cord compression. • Timeline of major surgical procedure (as defined by the Investigator) prior to the first dose of investigational product was changed from 21 days to 28 days.
    25 Jan 2018
    • Data cut-off (DCO) date for the primary analysis was updated to reflect the latest status of clinical study progression. • Information in protocol revised based on updated DCO.
    13 Sep 2018
    • Final DCO of OS and safety after primary analysis updated. • Information in protocol revised based on final DCO. • To update patient management and treatment options after final DCO.

    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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