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    Clinical Trial Results:
    A Randomized, Open-Label, Phase 2 Study of Nivolumab in Combination with Ipilimumab or Nivolumab Monotherapy in Participants with Advanced or Metastatic Solid Tumors of High Tumor Mutational Burden (TMB-H) (CheckMate 848: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 848)

    Summary
    EudraCT number
    		 2016-002898-35
    Trial protocol
    		 DE   FR   DK   GB   ES   NL   PL   BE   Outside EU/EEA   IT   RO  
    Global end of trial date
    02 Aug 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Aug 2024
    First version publication date
    16 Aug 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CA209-848
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussée de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    20 Sep 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Aug 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To estimate BICR-assessed objective response rate (ORR) in participants of either tTMB-H or bTMBH treated with nivolumab combined with ipilimumab.
    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 participants were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Oct 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 5
    Country: Number of subjects enrolled
    United States: 6
    Country: Number of subjects enrolled
    Belgium: 12
    Country: Number of subjects enrolled
    Denmark: 4
    Country: Number of subjects enrolled
    France: 23
    Country: Number of subjects enrolled
    Germany: 12
    Country: Number of subjects enrolled
    Italy: 28
    Country: Number of subjects enrolled
    Netherlands: 11
    Country: Number of subjects enrolled
    Poland: 9
    Country: Number of subjects enrolled
    Romania: 31
    Country: Number of subjects enrolled
    Spain: 7
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    Singapore: 8
    Country: Number of subjects enrolled
    Argentina: 27
    Country: Number of subjects enrolled
    Australia: 9
    Country: Number of subjects enrolled
    Chile: 17
    Worldwide total number of subjects
    212
    EEA total number of subjects
    137
    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)
    132
    From 65 to 84 years
    80
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Participants with refractory metastatic or unresectable solid malignant tumors with high Tumor Mutational Burden (TMB-H) who are refractory to standard therapies or have no standard treatment options were included as salvage setting. Those randomized to Nivolumab monotherapy arm could switch to the Nivolumab-Ipilimumab arm upon progression.

    Period 1
    Period 1 title
    Pre-treatment
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A: Nivolumab+Ipilimumab
    Arm description
    		 Nivolumab 240 mg every 2 weeks (Q2W) + Ipilimumab 1 mg/kg every 6 weeks (Q6W) up to 24 months
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1 mg/kg Q6W (every 6 weeks)

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    240 mg Q2W (every 2 weeks)

    Arm title
    		 Arm B: Nivolumab
    Arm description
    		 Nivolumab Monotherapy 480 mg every 4 weeks (Q4W) up to 24 months
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    480 mg Q4W (every 4 weeks)

    Number of subjects in period 1
    		Arm A: Nivolumab+Ipilimumab Arm B: Nivolumab
    Started
    136
    76
    bTMB-H Started
    80 [1]
    45 [2]
    tTMB-H Started
    88 [3]
    47 [4]
    Completed
    135
    76
    Not completed
    1
    0
         Disease Progression
    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: tTMB-H Started
    [2] - 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: tTMB-H Started
    [3] - 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: bTMB-H Started
    [4] - 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: bTMB-H Started
    Period 2
    Period 2 title
    Treatment
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A: Nivolumab+Ipilimumab
    Arm description
    		 Nivolumab 240 mg every 2 weeks (Q2W) + Ipilimumab 1 mg/kg every 6 weeks (Q6W) up to 24 months
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1 mg/kg Q6W (every 6 weeks)

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    240 mg Q2W (every 2 weeks)

    Arm title
    		 Arm B: Nivolumab
    Arm description
    		 Nivolumab Monotherapy 480 mg every 4 weeks (Q4W) up to 24 months
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    480 mg Q4W (every 4 weeks)

    Number of subjects in period 2
    		Arm A: Nivolumab+Ipilimumab Arm B: Nivolumab
    Started
    135
    76
    bTMB-H Started
    83
    47
    tTMB-H Started
    94
    50
    Arm B Rollover
    0
    22
    Completed
    0
    0
    Not completed
    135
    76
         Adverse event, serious fatal
    3
    -
         Consent withdrawn by subject
    1
    1
         Study drug toxicity
    19
    1
         Adverse Event unrelated to Study drug
    4
    3
         Maximum Clinical Benefit
    -
    1
         Participants completed treatment
    27
    11
         Other reasons
    2
    1
         Disease Progression
    76
    57
         Participant request to discontinue study treatment
    3
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A: Nivolumab+Ipilimumab
    Reporting group description
    		 Nivolumab 240 mg every 2 weeks (Q2W) + Ipilimumab 1 mg/kg every 6 weeks (Q6W) up to 24 months

    Reporting group title
    Arm B: Nivolumab
    Reporting group description
    		 Nivolumab Monotherapy 480 mg every 4 weeks (Q4W) up to 24 months

    Reporting group values
    		 Arm A: Nivolumab+Ipilimumab Arm B: Nivolumab Total
    Number of subjects
    		 136 76 212
    Age categorical
    Units:
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 60.0 ( 11.7 ) 57.6 ( 12.1 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 71 44 115
        Male
    		 65 32 97
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 6 3 9
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 1 1 2
        White
    		 124 60 184
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 5 12 17
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 13 5 18
        Not Hispanic or Latino
    		 45 20 65
        Unknown or Not Reported
    		 78 51 129

    End points

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    End points reporting groups
    Reporting group title
    Arm A: Nivolumab+Ipilimumab
    Reporting group description
    		 Nivolumab 240 mg every 2 weeks (Q2W) + Ipilimumab 1 mg/kg every 6 weeks (Q6W) up to 24 months

    Reporting group title
    Arm B: Nivolumab
    Reporting group description
    		 Nivolumab Monotherapy 480 mg every 4 weeks (Q4W) up to 24 months
    Reporting group title
    Arm A: Nivolumab+Ipilimumab
    Reporting group description
    		 Nivolumab 240 mg every 2 weeks (Q2W) + Ipilimumab 1 mg/kg every 6 weeks (Q6W) up to 24 months

    Reporting group title
    Arm B: Nivolumab
    Reporting group description
    		 Nivolumab Monotherapy 480 mg every 4 weeks (Q4W) up to 24 months

    Primary: Objective Response Rate (ORR) per Blinded Independent Central Review (BICR) - Arm A

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    End point title
    		 Objective Response Rate (ORR) per Blinded Independent Central Review (BICR) - Arm A [1] [2]
    End point description
    ORR was defined as the percentage of participants with a best overall response of confirmed complete response (CR) or partial response (PR) based on Blinded Independent Central Review (BICR) assessment. RECIST Criteria: CR= Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to < 10 mm. PR= ≥ 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. RANO Criteria: CR= Disappearance of all enhancing measurable and nonmeasurable disease; stable or improved nonenhancing T2/FLAIR lesions; off corticosteroids; and stable or improved clinically PR= ≥ 50% decrease compared with baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions; no progression of nonmeasureable disease; no new lesions; stable or improved nonenhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids compared with baseline scan; and stable or improved clinically.
    End point type
    Primary
    End point timeframe
    From date of randomization up to 42 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: only pre-specified arms reported
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: only pre-specified arms reported
    End point values
    		 Arm A: Nivolumab+Ipilimumab
    Number of subjects analysed
    88
    Units: Precentage of participants
    number (confidence interval 95%)
        Blood TMB-H (bTMB-H)
    22.5 (13.9 to 33.2)
        Tissue TMB-H (tTMB-H)
    38.6 (28.4 to 49.6)
    No statistical analyses for this end point

    Secondary: Objective Response Rate (ORR) per Blinded Independent Central Review (BICR) - Arm B

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    End point title
    		 Objective Response Rate (ORR) per Blinded Independent Central Review (BICR) - Arm B [3]
    End point description
    ORR was defined as the percentage of participants with a best overall response of confirmed complete response (CR) or partial response (PR) based on Blinded Independent Central Review (BICR) assessment. RECIST Criteria: CR= Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to < 10 mm. PR= ≥ 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. RANO Criteria: CR= Disappearance of all enhancing measurable and nonmeasurable disease; stable or improved nonenhancing T2/FLAIR lesions; off corticosteroids; and stable or improved clinically PR= ≥ 50% decrease compared with baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions; no progression of nonmeasureable disease; no new lesions; stable or improved nonenhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids compared with baseline scan; and stable or improved clinically.
    End point type
    Secondary
    End point timeframe
    From date of randomization up to 57 months
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: only pre-specified arms reported
    End point values
    		 Arm B: Nivolumab
    Number of subjects analysed
    47
    Units: Percentage of participants
    number (confidence interval 95%)
        Blood TMB-H (bTMB-H)
    15.6 (6.5 to 29.5)
        Tissue TMB-H (tTMB-H)
    29.8 (17.3 to 44.9)
    No statistical analyses for this end point

    Secondary: Objective Response Rate (ORR) per Investigator

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    End point title
    		 Objective Response Rate (ORR) per Investigator
    End point description
    ORR was defined as the percentage of participants with a best overall response of confirmed complete response (CR) or partial response (PR) based on investigator assessment. Calculated using Clopper-Pearson method. RECIST Criteria: CR= Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to < 10 mm. PR= ≥ 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. RANO Criteria: CR= Disappearance of all enhancing measurable and nonmeasurable disease; stable or improved nonenhancing T2/FLAIR lesions; off corticosteroids; and stable or improved clinically PR= ≥ 50% decrease compared with baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions; no progression of nonmeasureable disease; no new lesions; stable or improved nonenhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids compared with baseline scan; and stable or improved clinically.
    End point type
    Secondary
    End point timeframe
    From date of randomization up to 57 months
    End point values
    		 Arm A: Nivolumab+Ipilimumab Arm B: Nivolumab
    Number of subjects analysed
    88
    47
    Units: Percentage of participants
    number (confidence interval 95%)
        Blood TMB-H (bTMB-H)
    25.0 (16.0 to 35.9)
    13.3 (5.1 to 26.8)
        Tissue TMB-H (tTMB-H)
    44.3 (33.7 to 55.3)
    23.4 (12.3 to 38.0)
    No statistical analyses for this end point

    Secondary: Duration of Response (DoR) per Investigator

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    End point title
    		 Duration of Response (DoR) per Investigator
    End point description
    DoR was defined as the time from first confirmed complete or partial response to the date of the first documented tumor progression, or death due to any cause, whichever occurs first. Calculated using KM method. RECIST Criteria: CR= Disappearance of all target lesions. PR= ≥ 30% decrease in the sum of diameters of target lesions. PD= ≥ 20% increase in the sum of diameters of target lesions. RANO Criteria: CR= Disappearance of all enhancing measurable and nonmeasurable disease; stable/improved T2/FLAIR; off corticosteroids; stable/improved clinically PR= ≥ 50% decrease in the sum of diameters of all measurable enhancing lesions; no progression of nonmeasurable disease; no new lesions; stable/improved T2/FLAIR; stable/improved clinically. PD= ≥ 25% increase in sum of diameters of enhancing lesions, on stable/increasing doses of corticosteroids; significant increase in T2/FLAIR; any new lesion; clear clinical deterioration or clear progression of nonmeasurable disease. 99999=NA
    End point type
    Secondary
    End point timeframe
    From date of randomization to date of first documented tumor progression, or date of death, whichever occurs first (Up to 57 months)
    End point values
    		 Arm A: Nivolumab+Ipilimumab Arm B: Nivolumab
    Number of subjects analysed
    39
    11
    Units: Months
    median (confidence interval 95%)
        Blood TMB-H (bTMB-H)
    27.96 (11.20 to 99999)
    99999 (11.24 to 99999)
        Tissue TMB-H (tTMB-H)
    99999 (27.96 to 99999)
    99999 (8.05 to 99999)
    No statistical analyses for this end point

    Secondary: Duration of Response (DoR) per Blinded Independent Central Review (BICR)

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    End point title
    		 Duration of Response (DoR) per Blinded Independent Central Review (BICR)
    End point description
    DoR was defined as the time from first confirmed complete or partial response to the date of the first documented tumor progression, or death due to any cause, whichever occurs first. Calculated using KM method. RECIST Criteria: CR= Disappearance of all target lesions. PR= ≥ 30% decrease in the sum of diameters of target lesions. PD= ≥ 20% increase in the sum of diameters of target lesions. RANO Criteria: CR= Disappearance of all enhancing measurable and nonmeasurable disease; stable/improved T2/FLAIR; off corticosteroids; stable/improved clinically PR= ≥ 50% decrease in the sum of diameters of all measurable enhancing lesions; no progression of nonmeasurable disease; no new lesions; stable/improved T2/FLAIR; stable/improved clinically. PD= ≥ 25% increase in sum of diameters of enhancing lesions, on stable/increasing doses of corticosteroids; significant increase in T2/FLAIR; any new lesion; clear clinical deterioration or clear progression of nonmeasurable disease. 99999=NA
    End point type
    Secondary
    End point timeframe
    From date of randomization to date of first documented tumor progression, or date of death, whichever occurs first (Up to 57 months)
    End point values
    		 Arm A: Nivolumab+Ipilimumab Arm B: Nivolumab
    Number of subjects analysed
    34
    14
    Units: Months
    median (confidence interval 95%)
        Blood TMB-H (bTMB-H)
    99999 (10.15 to 99999)
    99999 (5.52 to 99999)
        Tissue TMB-H (tTMB-H)
    99999 (33.51 to 99999)
    99999 (8.31 to 99999)
    No statistical analyses for this end point

    Secondary: Time to Objective Response (TTR) per Investigator

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    End point title
    		 Time to Objective Response (TTR) per Investigator
    End point description
    TTR is defined as the time from randomization date to the date of the first confirmed response (complete response (CR) or partial response (PR)), based on investigator assessment. RECIST Criteria: CR= Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to < 10 mm. PR= ≥ 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. RANO Criteria: CR= Disappearance of all enhancing measurable and nonmeasurable disease; stable or improved nonenhancing T2/FLAIR lesions; off corticosteroids; and stable or improved clinically PR= ≥ 50% decrease compared with baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions; no progression of nonmeasureable disease; no new lesions; stable or improved nonenhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids compared with baseline scan; and stable or improved clinically.
    End point type
    Secondary
    End point timeframe
    From date of randomization to date of first confirmed response (CR or PR) (Up to 57 months)
    End point values
    		 Arm A: Nivolumab+Ipilimumab Arm B: Nivolumab
    Number of subjects analysed
    39
    11
    Units: Months
    arithmetic mean (standard deviation)
        Blood TMB-H (bTMB-H)
    3.48 ( 1.17 )
    4.08 ( 3.40 )
        Tissue TMB-H (tTMB-H)
    3.56 ( 1.74 )
    3.75 ( 2.50 )
    No statistical analyses for this end point

    Secondary: Time to Objective Response (TTR) per Blinded Independent Central Review (BICR)

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    End point title
    		 Time to Objective Response (TTR) per Blinded Independent Central Review (BICR)
    End point description
    TTR is defined as the time from randomization date to the date of the first confirmed response (complete response (CR) or partial response (PR)), based on Blinded Independent Central Review (BICR) assessment. RECIST Criteria: CR= Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to < 10 mm. PR= ≥ 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. RANO Criteria: CR= Disappearance of all enhancing measurable and nonmeasurable disease; stable or improved nonenhancing T2/FLAIR lesions; off corticosteroids; and stable or improved clinically PR= ≥ 50% decrease compared with baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions; no progression of nonmeasureable disease; no new lesions; stable or improved nonenhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids compared with baseline scan; and stable or improved clinically.
    End point type
    Secondary
    End point timeframe
    From date of randomization to date of first confirmed response (CR or PR) (Up to 57 months)
    End point values
    		 Arm A: Nivolumab+Ipilimumab Arm B: Nivolumab
    Number of subjects analysed
    34
    14
    Units: Months
    arithmetic mean (standard deviation)
        Blood TMB-H (bTMB-H)
    3.59 ( 1.65 )
    4.33 ( 2.93 )
        Tissue TMB-H (tTMB-H)
    4.37 ( 5.10 )
    3.98 ( 2.47 )
    No statistical analyses for this end point

    Secondary: Clinical Benefit Rate (CBR) per Investigator

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    End point title
    		 Clinical Benefit Rate (CBR) per Investigator
    End point description
    CBR is defined as the percentage of participants with a best overall response of confirmed complete response (CR) or partial response (PR) or stable disease (SD) based on investigator assessment. RECIST Criteria: CR= Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to < 10 mm PR= ≥ 30% decrease in the sum of diameters of target lesions SD= Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD RANO Criteria: CR= Disappearance of all enhancing disease; stable or improved nonenhancing T2/FLAIR lesions; off corticosteroids; and stable or improved clinically PR= ≥ 50% decrease in the sum of products of perpendicular diameters of all measurable enhancing lesions; no progression of nonmeasureable disease; no new lesions; stable or improved nonenhancing (T2/FLAIR) lesions; stable or improved clinically SD= does not qualify for CR, PR, or progression; stable nonenhancing T2/FLAIR lesions
    End point type
    Secondary
    End point timeframe
    From date of randomization up to 57 months
    End point values
    		 Arm A: Nivolumab+Ipilimumab Arm B: Nivolumab
    Number of subjects analysed
    88
    47
    Units: Percentage of participants
    number (confidence interval 95%)
        Blood TMB-H (bTMB-H)
    42.5 (31.5 to 54.1)
    40.0 (25.7 to 55.7)
        Tissue TMB-H (tTMB-H)
    63.6 (52.7 to 73.6)
    46.8 (32.1 to 61.9)
    No statistical analyses for this end point

    Secondary: Clinical Benefit Rate (CBR) per Blinded Independent Central Review (BICR)

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    End point title
    		 Clinical Benefit Rate (CBR) per Blinded Independent Central Review (BICR)
    End point description
    CBR is defined as the percentage of participants with a best overall response of confirmed complete response (CR) or partial response (PR) or stable disease (SD) per Blinded Independent Central Review (BICR) assessment. RECIST Criteria: CR= Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to < 10 mm PR= ≥ 30% decrease in the sum of diameters of target lesions SD= does not qualify for PR or progressive disease RANO Criteria: CR= Disappearance of all enhancing disease; stable or improved nonenhancing T2/FLAIR lesions; off corticosteroids; and stable or improved clinically PR= ≥ 50% decrease in the sum of products of perpendicular diameters of all measurable enhancing lesions; no progression of nonmeasureable disease; no new lesions; stable or improved nonenhancing (T2/FLAIR) lesions; stable or improved clinically SD= does not qualify for CR, PR, or progression; stable nonenhancing T2/FLAIR lesions
    End point type
    Secondary
    End point timeframe
    From date of randomization up to 57 months
    End point values
    		 Arm A: Nivolumab+Ipilimumab Arm B: Nivolumab
    Number of subjects analysed
    88
    47
    Units: Percentage of participants
    number (confidence interval 95%)
        Blood TMB-H (bTMB-H)
    32.5 (22.4 to 43.9)
    28.9 (16.4 to 44.3)
        Tissue TMB-H (tTMB-H)
    53.4 (42.5 to 64.1)
    38.3 (24.5 to 53.6)
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS) per Investigator

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    End point title
    		 Progression Free Survival (PFS) per Investigator
    End point description
    PFS is defined as the time from randomization date to the date of the first documented tumor progression, determined by investigator assessment, or death due to any cause, whichever occurs first. Calculated using KM method. RECIST Criteria: Progressive Disease (PD)= ≥ 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition, the sum must also demonstrate an absolute increase of ≥ 5 mm. RANO Criteria: PD= ≥ 25% increase in sum of the products of perpendicular diameters of enhancing lesions compared with the smallest tumor measurement obtained either at baseline or best response, on stable or increasing doses of corticosteroids; significant increase in T2/FLAIR nonenhancing lesions on stable or increasing doses of corticosteroids compared with baseline scan or best response after initiation of therapy; any new lesion; clear clinical deterioration or clear progression of nonmeasurable disease.
    End point type
    Secondary
    End point timeframe
    From date of randomization to date of first documented tumor progression, or date of death, whichever occurs first (Up to 57 months)
    End point values
    		 Arm A: Nivolumab+Ipilimumab Arm B: Nivolumab
    Number of subjects analysed
    88
    47
    Units: Months
    median (confidence interval 95%)
        Blood TMB-H (bTMB-H)
    2.99 (2.66 to 4.34)
    3.04 (2.79 to 5.36)
        Tissue TMB-H (tTMB-H)
    8.15 (4.83 to 12.94)
    3.06 (2.79 to 10.91)
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS) per Blinded Independent Central Review (BICR)

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    End point title
    		 Progression Free Survival (PFS) per Blinded Independent Central Review (BICR)
    End point description
    PFS is defined as the time from randomization date to the date of the first documented tumor progression, determined by Blinded Independent Central Review (BICR) assessment, or death due to any cause, whichever occurs first. Calculated using KM method. RECIST Criteria: Progressive Disease (PD)= ≥ 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition, the sum must also demonstrate an absolute increase of ≥ 5 mm. RANO Criteria: PD= ≥ 25% increase in sum of the products of perpendicular diameters of enhancing lesions compared with the smallest tumor measurement obtained either at baseline or best response, on stable or increasing doses of corticosteroids; significant increase in T2/FLAIR nonenhancing lesions on stable or increasing doses of corticosteroids compared with baseline scan or best response after initiation of therapy; any new lesion; clear clinical deterioration or clear progression of nonmeasurable disease.
    End point type
    Secondary
    End point timeframe
    From date of randomization to date of first documented tumor progression, or date of death, whichever occurs first (Up to 57 months)
    End point values
    		 Arm A: Nivolumab+Ipilimumab Arm B: Nivolumab
    Number of subjects analysed
    88
    47
    Units: Months
    median (confidence interval 95%)
        Blood TMB-H (bTMB-H)
    2.83 (2.33 to 2.99)
    2.83 (2.60 to 3.25)
        Tissue TMB-H (tTMB-H)
    5.68 (3.19 to 11.60)
    2.83 (2.69 to 5.72)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS is defined as the time between the date of randomization and the date of death due to any cause. Participants who did not have a date of death were censored on the last date for which a participant was known to be alive. Calculated using KM method.
    End point type
    Secondary
    End point timeframe
    From date of randomization to date of death (Up to 57 months)
    End point values
    		 Arm A: Nivolumab+Ipilimumab Arm B: Nivolumab
    Number of subjects analysed
    88
    47
    Units: Months
    median (confidence interval 95%)
        Blood TMB-H (bTMB-H)
    8.07 (5.82 to 10.45)
    11.24 (5.26 to 18.99)
        Tissue TMB-H (tTMB-H)
    16.48 (10.18 to 30.52)
    14.59 (7.69 to 18.23)
    No statistical analyses for this end point

    Secondary: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    Number of participants with any grade adverse events (AEs), serious adverse events (SAEs), drug-related AEs, and drug-related SAEs by Tumor Mutational Burden- High (TMB-H) status using worst grade per national cancer institute (NCI) common terminology criteria for adverse events (CTCAE) v5 criteria. An AE is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment. TMB-H = ≥ 10 mutations per megabase bTMB-H and tTMB-H are not mutually exclusive
    End point type
    Secondary
    End point timeframe
    From first dose to 30 days post last dose (Up to 25 months)
    End point values
    		 Arm A: Nivolumab+Ipilimumab Arm B: Nivolumab
    Number of subjects analysed
    94
    50
    Units: Participants
        Blood TMB-H (bTMB-H) AEs
    82
    46
        Tissue TMB-H (tTMB-H) AEs
    93
    50
        bTMB-H SAEs
    51
    17
        tTMB-H SAEs
    46
    16
        bTMB-H drug-related AEs
    64
    29
        tTMB-H drug-related AEs
    78
    27
        bTMB-H drug-related SAEs
    17
    1
        tTMB-H drug-related SAEs
    16
    2
    No statistical analyses for this end point

    Secondary: Number of Participants with On-Treatment Laboratory Parameters

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    End point title
    		 Number of Participants with On-Treatment Laboratory Parameters
    End point description
    Number of participants with grade 3-4 on-treatment laboratory parameters. Parameters include hematology, chemistry, liver function, and renal function using worst grade per national cancer institute (NCI) common terminology criteria for adverse events (CTCAE) v5 criteria. Grade 3=Severe event Grade 4=Life threatening event TMB-H = ≥ 10 mutations per megabase bTMB-H and tTMB-H are not mutually exclusive
    End point type
    Secondary
    End point timeframe
    From first dose to 30 days post last dose (Up to 25 months)
    End point values
    		 Arm A: Nivolumab+Ipilimumab Arm B: Nivolumab
    Number of subjects analysed
    91
    45
    Units: Participants
        Blood TMB-H (bTMB-H) Hemoglobin grade 3
    6
    3
        Tissue TMB-H (tTMB-H) Hemoglobin grade 3
    8
    7
        Blood TMB-H (bTMB-H) Platelet Count grade 3-4
    1
    0
        Tissue TMB-H (tTMB-H) Platelet Count grade 3-4
    0
    1
        Blood TMB-H (bTMB-H) Leukocytes grade 3- 4
    1
    0
        Tissue TMB-H (tTMB-H) Leukocytes grade 3- 4
    0
    0
        bTMB-H Leukocytes Absolute grade 3- 4
    2
    1
        tTMB-H Leukocytes Absolute grade 3- 4
    5
    3
        bTMB-H Absolute Neutrophil grade 3- 4
    1
    1
        tTMB-H Absolute Neutrophil grade 3- 4
    0
    0
        bTMB-H Alkaline Phosphatase grade 3-4
    2
    1
        tTMB-H Alkaline Phosphatase grade 3-4
    2
    0
        bTMB-H Aspartate Aminotransferase grade 3-4
    2
    3
        tTMB-H Aspartate Aminotransferase grade 3-4
    4
    1
        bTMB-H Alanine Aminotransferase grade 3-4
    5
    2
        tTMB-H Alanine Aminotransferase grade 3-4
    3
    1
        bTMB-H Bilirubin grade 3-4
    3
    2
        tTMB-H Bilirubin grade 3-4
    3
    1
        bTMB-H Creatinine grade 3-4
    3
    1
        tTMB-H Creatinine grade 3-4
    3
    0
        bTMB-H Hypernatremia grade 3-4
    0
    0
        tTMB-H Hypernatremia grade 3-4
    0
    0
        bTMB-H Hyponatremia grade 3-4
    4
    1
        tTMB-H Hyponatremia grade 3-4
    3
    1
        bTMB-H Hyperkalemia grade 3-4
    2
    0
        tTMB-H Hyperkalemia grade 3-4
    2
    0
        bTMB-H Hypokalemia grade 3-4
    4
    0
        tTMB-H Hypokalemia grade 3-4
    3
    1
        bTMB-H Hypercalcemia grade 3-4
    0
    1
        tTMB-H Hypercalcemia grade 3-4
    2
    0
        bTMB-H Hypocalcemia grade 3-4
    2
    0
        tTMB-H Hypocalcemia grade 3-4
    0
    1
        bTMB-H Hyperglycemia grade 3-4
    0
    0
        tTMB-H Hyperglycemia grade 3-4
    0
    0
        bTMB-H Hypoglycemia grade 3-4
    0
    0
        tTMB-H Hypoglycemia grade 3-4
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAEs and NSAEs are assessed from first dose to 100 days post last dose (Up to 27 months). Participants were assessed for deaths (all-cause) from their first dose to study completion (Up to 57 months).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Arm A: Nivolumab+Ipilimumab
    Reporting group description
    		 Nivolumab 240 mg every 2 weeks (Q2W) + Ipilimumab 1 mg/kg every 6 weeks (Q6W) up to 24 months

    Reporting group title
    Arm B: Nivolumab+Ipilimumab (Rollover)
    Reporting group description
    		 Nivolumab 240 mg every 2 weeks (Q2W) + Ipilimumab 1 mg/kg every 6 weeks (Q6W)

    Reporting group title
    Arm B: Nivolumab
    Reporting group description
    		 Nivolumab Monotherapy 480 mg every 4 weeks (Q4W) up to 24 months

    Serious adverse events
    		 Arm A: Nivolumab+Ipilimumab Arm B: Nivolumab+Ipilimumab (Rollover) Arm B: Nivolumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    90 / 135 (66.67%)
    11 / 22 (50.00%)
    39 / 76 (51.32%)
         number of deaths (all causes)
    97
    20
    42
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Meningioma
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Basal cell carcinoma
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Malignant neoplasm progression
         subjects affected / exposed
    43 / 135 (31.85%)
    7 / 22 (31.82%)
    25 / 76 (32.89%)
         occurrences causally related to treatment / all
    0 / 44
    0 / 7
    0 / 26
         deaths causally related to treatment / all
    0 / 40
    0 / 7
    0 / 23
    Tumour pain
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Vascular disorders
    Pelvic venous thrombosis
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Jugular vein thrombosis
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 22 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Superior vena cava syndrome
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 22 (0.00%)
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    General disorders and administration site conditions
    Hyperpyrexia
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 22 (0.00%)
    1 / 76 (1.32%)
         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
    2 / 135 (1.48%)
    0 / 22 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    3 / 135 (2.22%)
    0 / 22 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    3 / 135 (2.22%)
    0 / 22 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 22 (4.55%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Sudden death
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    5 / 135 (3.70%)
    1 / 22 (4.55%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    4 / 7
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine fistula
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Female genital tract fistula
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    2 / 135 (1.48%)
    1 / 22 (4.55%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 22 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 22 (0.00%)
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 22 (4.55%)
    0 / 76 (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
    Product issues
    Device occlusion
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    2 / 135 (1.48%)
    0 / 22 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Urine output decreased
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 22 (4.55%)
    0 / 76 (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
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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 injury
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Cardiac disorders
    Myocarditis
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Myocardial infarction
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 22 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 22 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Pericarditis malignant
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Nervous system disorders
    Intracranial pressure increased
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 22 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    2 / 135 (1.48%)
    0 / 22 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Cognitive disorder
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Brain oedema
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Transient ischaemic attack
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Anaemia
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal adhesions
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Abdominal pain
         subjects affected / exposed
    2 / 135 (1.48%)
    0 / 22 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Colitis
         subjects affected / exposed
    4 / 135 (2.96%)
    1 / 22 (4.55%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    3 / 135 (2.22%)
    0 / 22 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestinal stenosis
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Intestinal obstruction
         subjects affected / exposed
    3 / 135 (2.22%)
    0 / 22 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    2 / 135 (1.48%)
    0 / 22 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    4 / 6
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric perforation
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 22 (4.55%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Large intestine perforation
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Vomiting
         subjects affected / exposed
    3 / 135 (2.22%)
    0 / 22 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Small intestinal obstruction
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Rectal haemorrhage
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Pancreatitis chronic
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Pancreatitis
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Nausea
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 22 (4.55%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hypertransaminasaemia
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 22 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 22 (4.55%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Biliary obstruction
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Jaundice
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Pruritus
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Ureteric obstruction
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Tubulointerstitial nephritis
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Obstructive nephropathy
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Acute kidney injury
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hypopituitarism
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Hypophysitis
         subjects affected / exposed
    2 / 135 (1.48%)
    0 / 22 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adrenocorticotropic hormone deficiency
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Adrenocortical insufficiency acute
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 22 (0.00%)
    1 / 76 (1.32%)
         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
    2 / 135 (1.48%)
    0 / 22 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thyroiditis
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Secondary adrenocortical insufficiency
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Musculoskeletal and connective tissue disorders
    Myositis
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Bone pain
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Back pain
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Pain in extremity
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 22 (0.00%)
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Anal abscess
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Abdominal abscess
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Infection
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymph gland infection
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 22 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvic inflammatory disease
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Peritonitis
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Pneumonia
         subjects affected / exposed
    2 / 135 (1.48%)
    0 / 22 (0.00%)
    3 / 76 (3.95%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Prostate infection
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 22 (4.55%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 22 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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 infection
         subjects affected / exposed
    3 / 135 (2.22%)
    1 / 22 (4.55%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    2 / 135 (1.48%)
    2 / 22 (9.09%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (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
    Hyperglycaemia
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    2 / 135 (1.48%)
    0 / 22 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 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
    		 Arm A: Nivolumab+Ipilimumab Arm B: Nivolumab+Ipilimumab (Rollover) Arm B: Nivolumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    121 / 135 (89.63%)
    13 / 22 (59.09%)
    64 / 76 (84.21%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    7 / 135 (5.19%)
    1 / 22 (4.55%)
    0 / 76 (0.00%)
         occurrences all number
    8
    2
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    21 / 135 (15.56%)
    2 / 22 (9.09%)
    10 / 76 (13.16%)
         occurrences all number
    35
    2
    13
    Oedema peripheral
         subjects affected / exposed
    22 / 135 (16.30%)
    0 / 22 (0.00%)
    5 / 76 (6.58%)
         occurrences all number
    32
    0
    6
    Fatigue
         subjects affected / exposed
    41 / 135 (30.37%)
    2 / 22 (9.09%)
    17 / 76 (22.37%)
         occurrences all number
    50
    2
    24
    Asthenia
         subjects affected / exposed
    16 / 135 (11.85%)
    1 / 22 (4.55%)
    10 / 76 (13.16%)
         occurrences all number
    25
    3
    12
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    20 / 135 (14.81%)
    1 / 22 (4.55%)
    5 / 76 (6.58%)
         occurrences all number
    20
    2
    6
    Cough
         subjects affected / exposed
    16 / 135 (11.85%)
    0 / 22 (0.00%)
    6 / 76 (7.89%)
         occurrences all number
    21
    0
    13
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    13 / 135 (9.63%)
    1 / 22 (4.55%)
    4 / 76 (5.26%)
         occurrences all number
    13
    1
    4
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    20 / 135 (14.81%)
    1 / 22 (4.55%)
    12 / 76 (15.79%)
         occurrences all number
    26
    1
    12
    Amylase increased
         subjects affected / exposed
    7 / 135 (5.19%)
    0 / 22 (0.00%)
    4 / 76 (5.26%)
         occurrences all number
    17
    0
    5
    Alanine aminotransferase increased
         subjects affected / exposed
    19 / 135 (14.07%)
    2 / 22 (9.09%)
    8 / 76 (10.53%)
         occurrences all number
    33
    3
    8
    Blood alkaline phosphatase increased
         subjects affected / exposed
    13 / 135 (9.63%)
    1 / 22 (4.55%)
    8 / 76 (10.53%)
         occurrences all number
    24
    1
    10
    Blood bilirubin increased
         subjects affected / exposed
    10 / 135 (7.41%)
    0 / 22 (0.00%)
    7 / 76 (9.21%)
         occurrences all number
    13
    0
    9
    Blood creatinine increased
         subjects affected / exposed
    11 / 135 (8.15%)
    2 / 22 (9.09%)
    7 / 76 (9.21%)
         occurrences all number
    27
    3
    9
    Blood glucose increased
         subjects affected / exposed
    7 / 135 (5.19%)
    0 / 22 (0.00%)
    3 / 76 (3.95%)
         occurrences all number
    10
    0
    7
    Weight decreased
         subjects affected / exposed
    4 / 135 (2.96%)
    0 / 22 (0.00%)
    6 / 76 (7.89%)
         occurrences all number
    4
    0
    7
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    6 / 135 (4.44%)
    0 / 22 (0.00%)
    4 / 76 (5.26%)
         occurrences all number
    6
    0
    6
    Nervous system disorders
    Neuropathy peripheral
         subjects affected / exposed
    2 / 135 (1.48%)
    0 / 22 (0.00%)
    4 / 76 (5.26%)
         occurrences all number
    2
    0
    7
    Headache
         subjects affected / exposed
    11 / 135 (8.15%)
    2 / 22 (9.09%)
    4 / 76 (5.26%)
         occurrences all number
    16
    2
    8
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    32 / 135 (23.70%)
    3 / 22 (13.64%)
    16 / 76 (21.05%)
         occurrences all number
    62
    3
    19
    Thrombocytopenia
         subjects affected / exposed
    6 / 135 (4.44%)
    0 / 22 (0.00%)
    5 / 76 (6.58%)
         occurrences all number
    7
    0
    8
    Gastrointestinal disorders
    Dry mouth
         subjects affected / exposed
    6 / 135 (4.44%)
    0 / 22 (0.00%)
    6 / 76 (7.89%)
         occurrences all number
    6
    0
    9
    Diarrhoea
         subjects affected / exposed
    50 / 135 (37.04%)
    3 / 22 (13.64%)
    14 / 76 (18.42%)
         occurrences all number
    84
    12
    40
    Constipation
         subjects affected / exposed
    23 / 135 (17.04%)
    1 / 22 (4.55%)
    10 / 76 (13.16%)
         occurrences all number
    28
    1
    11
    Abdominal pain upper
         subjects affected / exposed
    7 / 135 (5.19%)
    2 / 22 (9.09%)
    4 / 76 (5.26%)
         occurrences all number
    10
    3
    4
    Abdominal pain
         subjects affected / exposed
    23 / 135 (17.04%)
    1 / 22 (4.55%)
    6 / 76 (7.89%)
         occurrences all number
    24
    1
    7
    Nausea
         subjects affected / exposed
    19 / 135 (14.07%)
    4 / 22 (18.18%)
    15 / 76 (19.74%)
         occurrences all number
    26
    4
    19
    Colitis
         subjects affected / exposed
    1 / 135 (0.74%)
    2 / 22 (9.09%)
    0 / 76 (0.00%)
         occurrences all number
    1
    2
    0
    Vomiting
         subjects affected / exposed
    19 / 135 (14.07%)
    3 / 22 (13.64%)
    7 / 76 (9.21%)
         occurrences all number
    31
    3
    12
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    25 / 135 (18.52%)
    1 / 22 (4.55%)
    7 / 76 (9.21%)
         occurrences all number
    30
    1
    14
    Pruritus
         subjects affected / exposed
    36 / 135 (26.67%)
    8 / 22 (36.36%)
    15 / 76 (19.74%)
         occurrences all number
    65
    10
    25
    Dry skin
         subjects affected / exposed
    6 / 135 (4.44%)
    2 / 22 (9.09%)
    2 / 76 (2.63%)
         occurrences all number
    8
    2
    2
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    18 / 135 (13.33%)
    0 / 22 (0.00%)
    11 / 76 (14.47%)
         occurrences all number
    20
    0
    11
    Hyperthyroidism
         subjects affected / exposed
    15 / 135 (11.11%)
    1 / 22 (4.55%)
    3 / 76 (3.95%)
         occurrences all number
    15
    1
    3
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    7 / 135 (5.19%)
    0 / 22 (0.00%)
    2 / 76 (2.63%)
         occurrences all number
    9
    0
    2
    Neck pain
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 22 (0.00%)
    4 / 76 (5.26%)
         occurrences all number
    1
    0
    5
    Arthralgia
         subjects affected / exposed
    22 / 135 (16.30%)
    0 / 22 (0.00%)
    7 / 76 (9.21%)
         occurrences all number
    29
    0
    10
    Back pain
         subjects affected / exposed
    18 / 135 (13.33%)
    1 / 22 (4.55%)
    5 / 76 (6.58%)
         occurrences all number
    18
    1
    7
    Myalgia
         subjects affected / exposed
    11 / 135 (8.15%)
    1 / 22 (4.55%)
    8 / 76 (10.53%)
         occurrences all number
    11
    1
    10
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    12 / 135 (8.89%)
    4 / 22 (18.18%)
    2 / 76 (2.63%)
         occurrences all number
    17
    6
    2
    Pharyngitis
         subjects affected / exposed
    1 / 135 (0.74%)
    2 / 22 (9.09%)
    0 / 76 (0.00%)
         occurrences all number
    1
    2
    0
    COVID-19
         subjects affected / exposed
    10 / 135 (7.41%)
    1 / 22 (4.55%)
    2 / 76 (2.63%)
         occurrences all number
    10
    1
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    28 / 135 (20.74%)
    2 / 22 (9.09%)
    6 / 76 (7.89%)
         occurrences all number
    30
    2
    6
    Hyperglycaemia
         subjects affected / exposed
    8 / 135 (5.93%)
    1 / 22 (4.55%)
    3 / 76 (3.95%)
         occurrences all number
    8
    2
    4
    Hypoalbuminaemia
         subjects affected / exposed
    7 / 135 (5.19%)
    1 / 22 (4.55%)
    3 / 76 (3.95%)
         occurrences all number
    10
    1
    3
    Hypocalcaemia
         subjects affected / exposed
    8 / 135 (5.93%)
    0 / 22 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    11
    0
    1
    Hypokalaemia
         subjects affected / exposed
    12 / 135 (8.89%)
    1 / 22 (4.55%)
    1 / 76 (1.32%)
         occurrences all number
    15
    1
    1
    Hyponatraemia
         subjects affected / exposed
    11 / 135 (8.15%)
    1 / 22 (4.55%)
    3 / 76 (3.95%)
         occurrences all number
    11
    1
    3
    Hypophosphataemia
         subjects affected / exposed
    5 / 135 (3.70%)
    2 / 22 (9.09%)
    1 / 76 (1.32%)
         occurrences all number
    7
    2
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Dec 2018
    Study design update
    14 Aug 2019
    pre-screening and enrollment requirements update
    04 May 2021
    Statisical analysis population clarification

    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
    For support, Contact us.
    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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