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    Clinical Trial Results:
    A Phase 1/2 Dose Escalation and Cohort Expansion Study of the Safety and Tolerability of Urelumab Administered in Combination with Nivolumab in Advanced /Metastatic Solid Tumors and B Cell Non-Hodgkins Lymphoma

    Summary
    EudraCT number
    		 2014-002241-22
    Trial protocol
    		 ES   DE  
    Global end of trial date
    24 May 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Jun 2020
    First version publication date
    26 Jun 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CA186-107
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussée de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    Bristol-Myers Squibb International Corporation, EU Study Start-Up Unit, Clinical.Trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    24 May 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 May 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective is to determine the Safety and tolerability of Urelumab Administered in Combination with Nivolumab in Advanced /Metastatic Solid Tumors and B Cell Non-Hodgkins Lymphoma
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Oct 2014
    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
    France: 42
    Country: Number of subjects enrolled
    Germany: 20
    Country: Number of subjects enrolled
    Spain: 12
    Country: Number of subjects enrolled
    United States: 154
    Worldwide total number of subjects
    228
    EEA total number of subjects
    74
    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)
    118
    From 65 to 84 years
    107
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 228 Participants were enrolled, 160 entered the treatment period, 68 did not entered , reasons for not entering the treatment period:7 withdrew consent, 54 did not meet study crieteria,1 adverse event, 2 death, 1 sponsor reason,2 other, 1 lost follow up.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 TRT A
    Arm description
    		 URE3 Q4WK+NIV3 Q2WK
    Arm type
    		 Experimental

    Investigational medicinal product name
    Urelumab
    Investigational medicinal product code
    BMS-663513
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    5mg/ml

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    BMS-936558
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    10mg/ml

    Arm title
    		 TRT B
    Arm description
    		 URE8 Q4WK+NIV3 Q2WK
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    BMS-936558
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    10mg/ml

    Investigational medicinal product name
    Urelumab
    Investigational medicinal product code
    BMS-663513
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    5mg/ml

    Arm title
    		 TRT D
    Arm description
    		 URE8 Q4WK+NIV240mg Q2WK
    Arm type
    		 Experimental

    Investigational medicinal product name
    Urelumab
    Investigational medicinal product code
    BMS-663513
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    5mg/ml

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    BMS-936558
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    10mg/ml

    Number of subjects in period 1 [1]
    		TRT A TRT B TRT D
    Started
    6
    4
    150
    Completed
    0
    0
    6
    Not completed
    6
    4
    144
         Adverse event, serious fatal
    -
    -
    1
         Consent withdrawn by subject
    -
    -
    3
         Disease progression
    4
    3
    98
         Study drug toxicity
    1
    -
    10
         Adverse event, non-fatal
    -
    -
    8
         Unspecified
    -
    -
    1
         Subject discontinued study drug
    1
    -
    1
         Completed treatment as per protocol
    -
    1
    22
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 228 Participants were enrolled, 160 entered the treatment period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    TRT A
    Reporting group description
    		 URE3 Q4WK+NIV3 Q2WK

    Reporting group title
    TRT B
    Reporting group description
    		 URE8 Q4WK+NIV3 Q2WK

    Reporting group title
    TRT D
    Reporting group description
    		 URE8 Q4WK+NIV240mg Q2WK

    Reporting group values
    		 TRT A TRT B TRT D Total
    Number of subjects
    		 6 4 150 160
    Age Categorical
    Units: Participants
        <=18 years
    		 0 0 0 0
        Between 18 and 65 years
    		 1 2 67 70
        >=65 years
    		 5 2 83 90
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 64.7 ± 9.40 64.0 ± 8.52 63.8 ± 11.71 -
    Sex: Female, Male
    Units: Participants
        Female
    		 2 2 47 51
        Male
    		 4 2 103 109
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 0 0 1 1
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 0 0 9 9
        White
    		 6 4 136 146
        More than one race
    		 0 0 0 0
        Unknown or Not Reported
    		 0 0 4 4
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 1 1 2
        Not Hispanic or Latino
    		 5 2 107 114
        Unknown or Not Reported
    		 1 1 42 44

    End points

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    End points reporting groups
    Reporting group title
    TRT A
    Reporting group description
    		 URE3 Q4WK+NIV3 Q2WK

    Reporting group title
    TRT B
    Reporting group description
    		 URE8 Q4WK+NIV3 Q2WK

    Reporting group title
    TRT D
    Reporting group description
    		 URE8 Q4WK+NIV240mg Q2WK

    Subject analysis set title
    TRT D - NSCLC pd1/pd-l1 experienced
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    URE8 Q4WK+NIV240mg Q2WK- Non small cell lung cancer pd1/pd-l1 experienced

    Subject analysis set title
    TRT D - NSCLC pd1/pd-l1 naive
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    URE8 Q4WK+NIV240mg Q2WK - Non samll cell lung cancer pd1/pd-l1 naive.

    Subject analysis set title
    TRT D - Melanoma pd1/pd-l1 experienced
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    URE8 Q4WK+NIV240mg Q2WK - Melanoma pd1/pd-l1 experienced

    Subject analysis set title
    TRT A - Melanoma pd1/pd-l1 naive
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    URE3 Q4WK+NIV3 Q2WK - Melanoma pd1/pd-l1 naive

    Subject analysis set title
    TRT B -
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    URE8 Q4WK+NIV3 Q2WK - Melanoma pd1/pd-l1 naive

    Subject analysis set title
    TRT D - Melanoma pd1/pd-l1 naive
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    URE8 Q4WK+NIV240mg Q2WK - Melanoma pd1/pd-l1 naive

    Subject analysis set title
    TRT A - SCCHN
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    URE3 Q4WK+NIV3 Q2WK - Squamous cell carcinoma of head and neck.

    Subject analysis set title
    TRT D - SCCHN
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    URE8 Q4WK+NIV240mg Q2WK - Squamous cell carcinoma of head and neck.

    Subject analysis set title
    TRT A - Other Solid Tumors
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    URE3 Q4WK+NIV3 Q2WK - Other solid tumors

    Subject analysis set title
    TRT B - Other Solid Tumors
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    URE8 Q4WK+NIV3 Q2WK - Other Solid tumors.

    Subject analysis set title
    TRT D - DLBCL
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    URE8 Q4WK+NIV240mg Q2WK - Diffuse Large B-cell lymphoma.

    Subject analysis set title
    TRT D - FL
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    URE8 Q4WK+NIV240mg Q2WK - Follicular Lymphoma.

    Subject analysis set title
    Urelumab ADA
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Urelumab Anti drug antibody

    Subject analysis set title
    Nivolumab ADA
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Nivolumab anti drug antibody

    Primary: The incidence of Adverse events.

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    End point title
    		 The incidence of Adverse events. [1]
    End point description
    End point type
    Primary
    End point timeframe
    From day 1 until 100 days after participant last dose of study drug.
    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: Only summary statistics were planned for this endpoint.
    End point values
    		 TRT A TRT B TRT D
    Number of subjects analysed
    6
    4
    150
    Units: Number of participants
    6
    4
    150
    No statistical analyses for this end point

    Primary: The Incidence of seriuos adverse events.

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    End point title
    		 The Incidence of seriuos adverse events. [2]
    End point description
    End point type
    Primary
    End point timeframe
    From day 1 until 100 days after participant last dose of the study drug.
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only summary statistics were planned for this endpoint.
    End point values
    		 TRT A TRT B TRT D
    Number of subjects analysed
    6
    4
    150
    Units: Number of participants
    3
    3
    86
    No statistical analyses for this end point

    Primary: The incidence of death.

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    End point title
    		 The incidence of death. [3]
    End point description
    End point type
    Primary
    End point timeframe
    From day 1 until 100 days after participant last dose of study drug.
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only summary statistics were planned for this endpoint.
    End point values
    		 TRT A TRT B TRT D
    Number of subjects analysed
    6
    4
    150
    Units: Number of participants
    6
    2
    93
    No statistical analyses for this end point

    Secondary: Best Overall Response (BOR)

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    End point title
    		 Best Overall Response (BOR)
    End point description
    The total number of subjects whose best overall response (BOR) is either a complete response or partial response for solid tumors and complete remission or partial remission for B-cell NHL, divided by the total number of subjects in the population of interest.
    End point type
    Secondary
    End point timeframe
    Every 8 weeks for Cycle 1 through Cycle 6 then every 12 weeks thereafter for approximately 2 years.
    End point values
    		 TRT D - NSCLC pd1/pd-l1 experienced TRT D - NSCLC pd1/pd-l1 naive TRT D - Melanoma pd1/pd-l1 experienced TRT A - Melanoma pd1/pd-l1 naive TRT B - TRT D - Melanoma pd1/pd-l1 naive TRT A - SCCHN TRT D - SCCHN TRT A - Other Solid Tumors TRT B - Other Solid Tumors TRT D - DLBCL TRT D - FL
    Number of subjects analysed
    20
    20
    20
    4
    1
    43
    1
    21
    1
    3
    22
    4
    Units: Number of participants
        Complete response
    0
    0
    0
    0
    1
    6
    0
    1
    0
    0
    0
    0
        Partial response
    1
    1
    2
    1
    0
    15
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Objective response rate (ORR)

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    End point title
    		 Objective response rate (ORR)
    End point description
    Objective response rate (ORR) is defined as the total number of subjects whose BOR is either CR or PR divided by the total number of subjects in the population of interest.
    End point type
    Secondary
    End point timeframe
    Every 8 weeks for Cycle 1 through Cycle 6 then every 12 weeks thereafter for approximately 2 years.
    End point values
    		 TRT D - NSCLC pd1/pd-l1 experienced TRT D - NSCLC pd1/pd-l1 naive TRT D - Melanoma pd1/pd-l1 experienced TRT A - Melanoma pd1/pd-l1 naive TRT B - TRT D - Melanoma pd1/pd-l1 naive TRT A - SCCHN TRT D - SCCHN TRT A - Other Solid Tumors TRT B - Other Solid Tumors TRT D - DLBCL TRT D - FL
    Number of subjects analysed
    20
    20
    20
    4
    1
    43
    1
    21
    1
    3
    22
    4
    Units: Percentage of participants
        number (confidence interval 95%)
    5.0 (0.1 to 24.9)
    5.0 (0.1 to 24.9)
    10.0 (1.2 to 31.7)
    25.0 (0.6 to 80.6)
    100.0 (2.5 to 100.0)
    48.8 (33.3 to 64.5)
    0 (0.0 to 97.5)
    4.8 (0.1 to 23.8)
    0 (0.0 to 97.5)
    0 (0.0 to 70.8)
    0 (0.0 to 16.1)
    0 (0.0 to 60.2)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR)

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    End point title
    		 Duration of Response (DOR)
    End point description
    DOR is defined as the number of days between the date of first response and the subsequent date of objectively documented disease progression based on the criteria (RECIST v1.1) or relapse based on IWG, or death due to any cause, if death occurred within 100 days after last dose, whichever occurs first. Data was not collected due to discontinuation of the study/Due to study termination.
    End point type
    Secondary
    End point timeframe
    Every 8 weeks for Cycle 1 through Cycle 6 then every 12 weeks thereafter for approximately 2 years
    End point values
    		 TRT A TRT B TRT D
    Number of subjects analysed
    6 [4]
    4 [5]
    150 [6]
    Units: Months
    9999
    9999
    9999
    Notes
    [4] - Data was not collected due to discontinuation of the study/Due to study termination
    [5] - Data was not collected due to discontinuation of the study/Due to study termination
    [6] - Data was not collected due to discontinuation of the study/Due to study termination
    No statistical analyses for this end point

    Secondary: Progression-free survival rate (PFSR)

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    End point title
    		 Progression-free survival rate (PFSR)
    End point description
    PFSR is defined as the probability of a subject remaining progression-free and surviving a specific length of time. Data was not collected due to discontinuation of the study/Due to study termination.
    End point type
    Secondary
    End point timeframe
    Every 8 weeks for Cycle 1 through Cycle 6 then every 12 weeks thereafter for approximately 2 years.
    End point values
    		 TRT A TRT B TRT D
    Number of subjects analysed
    6 [7]
    4 [8]
    150 [9]
    Units: Number of participants
    9999
    9999
    9999
    Notes
    [7] - Data was not collected due to discontinuation of the study/Due to study termination
    [8] - Data was not collected due to discontinuation of the study/Due to study termination
    [9] - Data was not collected due to discontinuation of the study/Due to study termination
    No statistical analyses for this end point

    Secondary: Maximum observed serum concentration (Cmax)

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    End point title
    		 Maximum observed serum concentration (Cmax)
    End point description
    Data was not collected due to discontinuation of the study/Due to study termination.
    End point type
    Secondary
    End point timeframe
    Cycles 1, 2, 3, 4, 6, and followup Days up to 100 days.
    End point values
    		 TRT A TRT B TRT D
    Number of subjects analysed
    6 [10]
    4 [11]
    150 [12]
    Units: µg/mL
    9999
    9999
    9999
    Notes
    [10] - Data was not collected due to discontinuation of the study/Due to study termination
    [11] - Data was not collected due to discontinuation of the study/Due to study termination
    [12] - Data was not collected due to discontinuation of the study/Due to study termination
    No statistical analyses for this end point

    Secondary: Time of maximum observed serum concentration (Tmax)

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    End point title
    		 Time of maximum observed serum concentration (Tmax)
    End point description
    Data was not collected due to discontinuation of the study/Due to study termination.
    End point type
    Secondary
    End point timeframe
    Cycles 1, 2, 3, 4, 6, and followup Days up to 100 days.
    End point values
    		 TRT A TRT B TRT D
    Number of subjects analysed
    6 [13]
    4 [14]
    150 [15]
    Units: Hours
    9999
    9999
    9999
    Notes
    [13] - Data was not collected due to discontinuation of the study/Due to study termination
    [14] - Data was not collected due to discontinuation of the study/Due to study termination
    [15] - Data was not collected due to discontinuation of the study/Due to study termination
    No statistical analyses for this end point

    Secondary: Area under the concentration-time curve in one dosing interval (AUCTAU)

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    End point title
    		 Area under the concentration-time curve in one dosing interval (AUCTAU)
    End point description
    Data was not collected due to discontinuation of the study/Due to study termination.
    End point type
    Secondary
    End point timeframe
    Cycles 1, 2, 3, 4, 6, and followup Days up to 100 days
    End point values
    		 TRT A TRT B TRT D
    Number of subjects analysed
    6 [16]
    4 [17]
    150 [18]
    Units: µg.hr/mL
    9999
    9999
    9999
    Notes
    [16] - Data was not collected due to discontinuation of the study/Due to study termination
    [17] - Data was not collected due to discontinuation of the study/Due to study termination
    [18] - Data was not collected due to discontinuation of the study/Due to study termination
    No statistical analyses for this end point

    Secondary: Trough observed plasma concentration(Ctrough)

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    End point title
    		 Trough observed plasma concentration(Ctrough)
    End point description
    Data was not collected due to discontinuation of the study/Due to study termination.
    End point type
    Secondary
    End point timeframe
    Cycles 1, 2, 3, 4, 6, and followup Days up to 100 days.
    End point values
    		 TRT A TRT B TRT D
    Number of subjects analysed
    6 [19]
    4 [20]
    150 [21]
    Units: μg/mL
    9999
    9999
    9999
    Notes
    [19] - Data was not collected due to discontinuation of the study/Due to study termination
    [20] - Data was not collected due to discontinuation of the study/Due to study termination
    [21] - Data was not collected due to discontinuation of the study/Due to study termination
    No statistical analyses for this end point

    Secondary: End of infusion concentration (Ceoinf)

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    End point title
    		 End of infusion concentration (Ceoinf)
    End point description
    Data was not collected due to discontinuation of the study/Due to study termination.
    End point type
    Secondary
    End point timeframe
    Cycles 1, 2, 3, 4, 6, and followup Days up to 100 days.
    End point values
    		 TRT A TRT B TRT D
    Number of subjects analysed
    6 [22]
    4 [23]
    150 [24]
    Units: Number
    9999
    9999
    9999
    Notes
    [22] - Data was not collected due to discontinuation of the study/Due to study termination
    [23] - Data was not collected due to discontinuation of the study/Due to study termination
    [24] - Data was not collected due to discontinuation of the study/Due to study termination
    No statistical analyses for this end point

    Secondary: Area under the plasma concentration-time curve, 0 to time of last quantifiable concentration (AUC(0-T)

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    End point title
    		 Area under the plasma concentration-time curve, 0 to time of last quantifiable concentration (AUC(0-T)
    End point description
    Data was not collected due to discontinuation of the study/Due to study termination.
    End point type
    Secondary
    End point timeframe
    Cycles 1, 2, 3, 4, 6, and followup Days up to 100 days.
    End point values
    		 TRT A TRT B TRT D
    Number of subjects analysed
    6 [25]
    4 [26]
    150 [27]
    Units: µg.hr/mL
    9999
    9999
    9999
    Notes
    [25] - Data was not collected due to discontinuation of the study/Due to study termination
    [26] - Data was not collected due to discontinuation of the study/Due to study termination
    [27] - Data was not collected due to discontinuation of the study/Due to study termination
    No statistical analyses for this end point

    Secondary: Occurrence of specific anti-drug antibodies (ADA) to Urelumab and Nivolumab

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    End point title
    		 Occurrence of specific anti-drug antibodies (ADA) to Urelumab and Nivolumab
    End point description
    End point type
    Secondary
    End point timeframe
    Cycles 1, 2, 3, 4, 6, and followup Days up to 100 days.
    End point values
    		 Urelumab ADA Nivolumab ADA
    Number of subjects analysed
    133
    128
    Units: Number of participants
        Baseline ADA positive
    5
    2
        ADA positive
    55
    9
        ADA negative
    78
    119
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are reported from start of treatment up to 30 days after last dose of study treatment.
    Adverse event reporting additional description
    Analysis was performed in All treated subjects defined as all subjects who received at least one dose of any study medication.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    TRT A: URE3 Q4WK+NIV3 Q2WK
    Reporting group description
    		 Subjects were intravenously (IV) administered with 3 milligrams per kilogram of body weight (mg/kg) of Urelumab, once every 4 weeks (Q4WK) along with Nivolumab 3 mg/kg IV, every 2 weeks (Q2WK).

    Reporting group title
    TRT B: URE8 Q4WK+NIV3 Q2WK
    Reporting group description
    		 Subjects were IV administered with 8 mg/kg of Urelumab, Q4WK along with Nivolumab 3 mg/kg IV, Q2WK.

    Reporting group title
    TRT D: URE8 Q4WK+NIV240mg Q2WK
    Reporting group description
    		 Subjects were IV administered with 8 mg/kg of Urelumab, Q4WK along with Nivolumab 240 mg IV, Q2WK.

    Serious adverse events
    		 TRT A: URE3 Q4WK+NIV3 Q2WK TRT B: URE8 Q4WK+NIV3 Q2WK TRT D: URE8 Q4WK+NIV240mg Q2WK
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 6 (50.00%)
    3 / 4 (75.00%)
    90 / 150 (60.00%)
         number of deaths (all causes)
    1
    1
    50
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Abdominal neoplasm
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    2 / 150 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 4 (25.00%)
    45 / 150 (30.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 48
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 42
    Metastases to central nervous system
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to lymph nodes
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    3 / 150 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    3 / 150 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Embolism
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Extremity necrosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    3 / 150 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperthermia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypothermia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    4 / 150 (2.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvic mass
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    5 / 150 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Immune system disorders
    Contrast media reaction
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemophagocytic lymphohistiocytosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    2 / 150 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydrothorax
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    2 / 150 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Obstructive airways disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pharyngeal haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    2 / 150 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    Pleural effusion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    4 / 150 (2.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pneumonia aspiration
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    3 / 150 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    3 / 150 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Persistent depressive disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    2 / 150 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    2 / 150 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gamma-Glutamyltransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tracheal obstruction
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    2 / 150 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Central nervous system lesion
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral haematoma
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Dizziness
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Monoplegia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paraparesis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    3 / 150 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    3 / 150 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    3 / 150 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    3 / 150 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Abdominal pain upper
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    2 / 150 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulum intestinal haemorrhagic
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    3 / 150 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bile duct stenosis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Diabetes insipidus
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypogonadism
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypophysitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adrenal insufficiency
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    7 / 150 (4.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pneumonia haemophilus
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    3 / 150 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 TRT A: URE3 Q4WK+NIV3 Q2WK TRT B: URE8 Q4WK+NIV3 Q2WK TRT D: URE8 Q4WK+NIV240mg Q2WK
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 6 (100.00%)
    4 / 4 (100.00%)
    147 / 150 (98.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences all number
    1
    0
    1
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences all number
    1
    0
    1
    Vascular disorders
    Hot flush
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences all number
    1
    0
    1
    Hypertension
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 4 (0.00%)
    4 / 150 (2.67%)
         occurrences all number
    2
    0
    4
    Hypotension
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    7 / 150 (4.67%)
         occurrences all number
    2
    0
    8
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 4 (25.00%)
    16 / 150 (10.67%)
         occurrences all number
    1
    1
    17
    Chills
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    14 / 150 (9.33%)
         occurrences all number
    0
    0
    14
    Fatigue
         subjects affected / exposed
    4 / 6 (66.67%)
    2 / 4 (50.00%)
    62 / 150 (41.33%)
         occurrences all number
    5
    2
    73
    Gait disturbance
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences all number
    1
    0
    1
    Oedema peripheral
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    26 / 150 (17.33%)
         occurrences all number
    1
    0
    31
    Performance status decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    1 / 150 (0.67%)
         occurrences all number
    0
    1
    1
    Pyrexia
         subjects affected / exposed
    4 / 6 (66.67%)
    1 / 4 (25.00%)
    30 / 150 (20.00%)
         occurrences all number
    4
    1
    40
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 4 (0.00%)
    34 / 150 (22.67%)
         occurrences all number
    2
    0
    37
    Dyspnoea
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 4 (0.00%)
    26 / 150 (17.33%)
         occurrences all number
    2
    0
    32
    Nasal congestion
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    6 / 150 (4.00%)
         occurrences all number
    1
    0
    6
    Rhinitis allergic
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences all number
    1
    0
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    11 / 150 (7.33%)
         occurrences all number
    0
    0
    12
    Depression
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    3 / 150 (2.00%)
         occurrences all number
    1
    0
    3
    Insomnia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    11 / 150 (7.33%)
         occurrences all number
    0
    0
    11
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 4 (0.00%)
    26 / 150 (17.33%)
         occurrences all number
    3
    0
    40
    Amylase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    14 / 150 (9.33%)
         occurrences all number
    0
    0
    16
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    26 / 150 (17.33%)
         occurrences all number
    0
    1
    39
    Blood alkaline phosphatase increased
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 4 (25.00%)
    20 / 150 (13.33%)
         occurrences all number
    2
    1
    25
    Blood creatinine increased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    10 / 150 (6.67%)
         occurrences all number
    2
    0
    12
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    5 / 150 (3.33%)
         occurrences all number
    0
    3
    6
    Blood uric acid decreased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences all number
    1
    0
    1
    Lipase increased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    18 / 150 (12.00%)
         occurrences all number
    2
    0
    30
    Lymphocyte count decreased
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 4 (0.00%)
    12 / 150 (8.00%)
         occurrences all number
    3
    0
    15
    Neutrophil count decreased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    11 / 150 (7.33%)
         occurrences all number
    1
    0
    17
    Platelet count decreased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    13 / 150 (8.67%)
         occurrences all number
    2
    0
    17
    Weight decreased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    18 / 150 (12.00%)
         occurrences all number
    1
    0
    18
    Gamma-Glutamyltransferase increased
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 4 (25.00%)
    18 / 150 (12.00%)
         occurrences all number
    2
    1
    22
    Thyroxine free decreased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 150 (0.00%)
         occurrences all number
    1
    0
    0
    Tri-Iodothyronine decreased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences all number
    1
    0
    1
    White blood cell count decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    8 / 150 (5.33%)
         occurrences all number
    0
    0
    13
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 4 (25.00%)
    9 / 150 (6.00%)
         occurrences all number
    2
    1
    11
    Infusion related reaction
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    2 / 150 (1.33%)
         occurrences all number
    0
    2
    3
    Skin abrasion
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    1 / 150 (0.67%)
         occurrences all number
    0
    1
    1
    Sunburn
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    1 / 150 (0.67%)
         occurrences all number
    0
    1
    2
    Nervous system disorders
    Balance disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    1 / 150 (0.67%)
         occurrences all number
    0
    1
    1
    Carotid artery occlusion
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 150 (0.00%)
         occurrences all number
    0
    1
    0
    Cognitive disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    1 / 150 (0.67%)
         occurrences all number
    0
    1
    1
    Dizziness
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    13 / 150 (8.67%)
         occurrences all number
    1
    0
    17
    Headache
         subjects affected / exposed
    4 / 6 (66.67%)
    0 / 4 (0.00%)
    23 / 150 (15.33%)
         occurrences all number
    5
    0
    28
    Peripheral motor neuropathy
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 150 (0.00%)
         occurrences all number
    1
    0
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    3 / 150 (2.00%)
         occurrences all number
    2
    0
    3
    Restless legs syndrome
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    1 / 150 (0.67%)
         occurrences all number
    0
    1
    1
    Sciatica
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 150 (0.00%)
         occurrences all number
    0
    1
    0
    Sinus headache
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences all number
    1
    0
    1
    Dysgeusia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    3 / 150 (2.00%)
         occurrences all number
    1
    0
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 6 (50.00%)
    2 / 4 (50.00%)
    51 / 150 (34.00%)
         occurrences all number
    6
    2
    63
    Eye disorders
    Dry eye
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    5 / 150 (3.33%)
         occurrences all number
    0
    1
    5
    Lacrimation increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    2 / 150 (1.33%)
         occurrences all number
    0
    1
    2
    Vision blurred
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 4 (0.00%)
    2 / 150 (1.33%)
         occurrences all number
    2
    0
    3
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 150 (0.00%)
         occurrences all number
    0
    1
    0
    Abdominal distension
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    6 / 150 (4.00%)
         occurrences all number
    1
    0
    6
    Abdominal pain
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 4 (25.00%)
    19 / 150 (12.67%)
         occurrences all number
    2
    1
    20
    Abdominal pain upper
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    6 / 150 (4.00%)
         occurrences all number
    1
    0
    7
    Anal incontinence
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences all number
    1
    0
    1
    Ascites
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 150 (0.00%)
         occurrences all number
    0
    1
    0
    Constipation
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    33 / 150 (22.00%)
         occurrences all number
    1
    0
    37
    Dental caries
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 150 (0.00%)
         occurrences all number
    0
    1
    0
    Diarrhoea
         subjects affected / exposed
    5 / 6 (83.33%)
    0 / 4 (0.00%)
    32 / 150 (21.33%)
         occurrences all number
    9
    0
    45
    Dry mouth
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    8 / 150 (5.33%)
         occurrences all number
    1
    0
    8
    Dysphagia
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 4 (25.00%)
    6 / 150 (4.00%)
         occurrences all number
    2
    1
    6
    Gastritis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences all number
    1
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    3 / 150 (2.00%)
         occurrences all number
    0
    1
    3
    Lip swelling
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 150 (0.00%)
         occurrences all number
    0
    1
    0
    Melaena
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 150 (0.00%)
         occurrences all number
    1
    0
    0
    Nausea
         subjects affected / exposed
    3 / 6 (50.00%)
    0 / 4 (0.00%)
    37 / 150 (24.67%)
         occurrences all number
    4
    0
    49
    Vomiting
         subjects affected / exposed
    3 / 6 (50.00%)
    0 / 4 (0.00%)
    27 / 150 (18.00%)
         occurrences all number
    4
    0
    37
    Hepatobiliary disorders
    Hepatic haemorrhage
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 150 (0.00%)
         occurrences all number
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Actinic keratosis
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 4 (25.00%)
    5 / 150 (3.33%)
         occurrences all number
    1
    3
    5
    Drug eruption
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    2 / 150 (1.33%)
         occurrences all number
    1
    0
    3
    Dry skin
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    13 / 150 (8.67%)
         occurrences all number
    0
    0
    13
    Hyperkeratosis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 150 (0.00%)
         occurrences all number
    1
    0
    0
    Lichen planus
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 150 (0.00%)
         occurrences all number
    1
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 4 (50.00%)
    22 / 150 (14.67%)
         occurrences all number
    0
    2
    25
    Rash
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    17 / 150 (11.33%)
         occurrences all number
    0
    2
    24
    Rash macular
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    2 / 150 (1.33%)
         occurrences all number
    1
    0
    2
    Rash maculo-papular
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 4 (50.00%)
    9 / 150 (6.00%)
         occurrences all number
    0
    3
    11
    Rash papular
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 150 (0.00%)
         occurrences all number
    0
    1
    0
    Rash pruritic
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    2 / 150 (1.33%)
         occurrences all number
    1
    0
    3
    Skin ulcer
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences all number
    1
    0
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    3 / 150 (2.00%)
         occurrences all number
    1
    0
    3
    Pollakiuria
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    6 / 150 (4.00%)
         occurrences all number
    1
    0
    6
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    2 / 150 (1.33%)
         occurrences all number
    1
    0
    2
    Hypothyroidism
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    17 / 150 (11.33%)
         occurrences all number
    0
    1
    17
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 4 (50.00%)
    18 / 150 (12.00%)
         occurrences all number
    0
    4
    27
    Back pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    24 / 150 (16.00%)
         occurrences all number
    0
    0
    25
    Flank pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences all number
    1
    0
    1
    Joint range of motion decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    1 / 150 (0.67%)
         occurrences all number
    0
    1
    1
    Muscular weakness
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 4 (25.00%)
    5 / 150 (3.33%)
         occurrences all number
    3
    1
    6
    Musculoskeletal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    11 / 150 (7.33%)
         occurrences all number
    0
    0
    11
    Myalgia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    15 / 150 (10.00%)
         occurrences all number
    0
    1
    16
    Neck pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    6 / 150 (4.00%)
         occurrences all number
    0
    1
    6
    Pain in extremity
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    15 / 150 (10.00%)
         occurrences all number
    0
    0
    17
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 150 (0.00%)
         occurrences all number
    1
    0
    0
    Gingivitis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences all number
    1
    0
    1
    Localised infection
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 150 (0.00%)
         occurrences all number
    1
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    6 / 150 (4.00%)
         occurrences all number
    0
    1
    8
    Pneumonia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    4 / 150 (2.67%)
         occurrences all number
    1
    0
    4
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    12 / 150 (8.00%)
         occurrences all number
    1
    0
    14
    Urinary tract infection
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    12 / 150 (8.00%)
         occurrences all number
    1
    0
    16
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 4 (25.00%)
    24 / 150 (16.00%)
         occurrences all number
    3
    1
    26
    Dehydration
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    4 / 150 (2.67%)
         occurrences all number
    1
    0
    6
    Hypercalcaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    8 / 150 (5.33%)
         occurrences all number
    0
    0
    8
    Hyperglycaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    15 / 150 (10.00%)
         occurrences all number
    0
    0
    22
    Hyperkalaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    11 / 150 (7.33%)
         occurrences all number
    3
    0
    23
    Hypermagnesaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    1 / 150 (0.67%)
         occurrences all number
    1
    0
    1
    Hyperuricaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    2 / 150 (1.33%)
         occurrences all number
    2
    0
    3
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    12 / 150 (8.00%)
         occurrences all number
    0
    0
    13
    Hypokalaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    9 / 150 (6.00%)
         occurrences all number
    0
    1
    11
    Hypomagnesaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    6 / 150 (4.00%)
         occurrences all number
    1
    0
    6
    Hyponatraemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    14 / 150 (9.33%)
         occurrences all number
    0
    0
    18
    Hypophosphataemia
         subjects affected / exposed
    3 / 6 (50.00%)
    0 / 4 (0.00%)
    16 / 150 (10.67%)
         occurrences all number
    3
    0
    23

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Mar 2015
    To implement changes to inclusion/exclusion criteria, clarify requirements and assessments for treatment beyond disease progression and criteria for allowing treatment to resume after a dose delay due to toxicity, add time and events schedules for subjects eligible for retreatment, and clarify PK sampling and biomarker assessments.
    29 Jun 2015
    To implement a change in duration to combination therapy and use of flat dosing for subjects enrolled following approval of Revised Protocol 02
    30 Aug 2015
    Discontinue enrollment into Cohorts A, B, C, D. Implement an update to exclusion Criteria.
    22 Dec 2015
    To expand the study population for cohort expansion to include subjects with follicular lymphoma and to further differentiate subjects with nonsmall-cell lung cancer into two separate groups (those with no prior anti PD-1/anti-PD-L1 therapy and those who have relapsed or are refractory to prior anti-PD-1/anti-PD-L1.
    09 May 2016
    To clarify application to new cohort of subjects with NSCLC and melanoma who have relapsed or are refractory to prior anti-PD-1/anti-PD-L1) therapy and exception for NSCLC and MEL subjects enrolling in the expansion cohorts where prior anti-PD-1 or anti-PD-L1 therapies are specifically required. To include a cohort of NSCLC and melanoma subjects who have relapsed or are refractory to prior anti-PD-1/anti-PD-L1 therapy.
    22 Mar 2017
    In order to further explore an emerging efficacy signal, additional patients with previously untreated metastatic melanoma (ie, no prior systemic anticancer therapy for unresectable or metastatic melanoma) subjects with PD-L1 negative tumors (<1%) will be enrolled under this amendment.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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