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    Clinical Trial Results:
    A Randomized, Multi-center, Double-blinded, Placebo-controlled Phase 3 Study of Nivolumab and Ipilimumab, Nivolumab Monotherapy, or Placebo in Combination with Trans-arterial ChemoEmbolization (TACE) in Patients with Intermediate-stage Hepatocellular Carcinoma (HCC)

    Summary
    EudraCT number
    		 2019-002790-58
    Trial protocol
    		 AT   FR   DE   BE   CZ   IT  
    Global end of trial date
    23 Dec 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Nov 2024
    First version publication date
    21 Nov 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CA209-74W
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04340193
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussee 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
    12 Dec 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Dec 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The purpose of this study is to evaluate the safety and tolerability of nivolumab with and without ipilimumab in combination with Trans-arterial ChemoEmbolization (TACE) to TACE alone in participants with intermediate liver cancer.
    Protection of trial subjects
    Patient Confidentiality, Personal Data Protection and Biomarker Consent
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Sep 2020
    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
    Austria: 1
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Hong Kong: 2
    Country: Number of subjects enrolled
    Japan: 5
    Country: Number of subjects enrolled
    Korea, Republic of: 3
    Country: Number of subjects enrolled
    Russian Federation: 1
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    Taiwan: 4
    Country: Number of subjects enrolled
    United States: 1
    Worldwide total number of subjects
    26
    EEA total number of subjects
    10
    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)
    11
    From 65 to 84 years
    14
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted in Austria, Belgium, France, Germany, Hong Kong, Japan, Republic of Korea, Russian Federation, Spain, Taiwan and United States

    Pre-assignment
    Screening details
    		 Screening procedures occurred within 28 days prior to first dose. Screening begins by establishing the participant’s initial eligibility and signing of the ICF.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 NIVO+IPI+TACE
    Arm description
    		 Participants with intermediate-stage hepatocellular carcinoma (HCC) received Nivolumab (NIVO) 240 milligram (mg) every 2 weeks (Q2W) and ipilimumab (IPI) 1 milligram per kilogram (mg/kg) every 6 weeks (Q6W) as an approximately 30-minute infusion. Participants received first Trans-arterial ChemoEmbolization (TACE) in 7 days after randomization and then TACE as needed, until participant was no longer eligible for further TACE, unacceptable toxicity, withdrawal of consent, or the study ends, whichever occurs first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Opdivo BMS-936558
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    240 milligram (mg) every 2 weeks (Q2W)

    Investigational medicinal product name
    Trans-arterial ChemoEmbolization (TACE)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for emulsion for infusion
    Routes of administration
    Intraarterial use
    Dosage and administration details
    Inject the emulsion of the anticancer agent(s); Embolize the feeding artery with an embolization agent (eg, gelatin sponge); Inject Drug Eluting Beads (DEB).

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1 milligram per kilogram (mg/kg) every 6 weeks (Q6W) as an approximately 30-minute infusion

    Arm title
    		 NIVO+TACE
    Arm description
    		 Participants with intermediate-stage hepatocellular carcinoma (HCC) received Nivolumab 240 milligram (mg) every 2 weeks (Q2W) as an approximately 30-minute infusion. Participants received first Trans-arterial ChemoEmbolization (TACE) in 7 days after randomization and then TACE as needed, until participant was no longer eligible for further TACE, unacceptable toxicity, withdrawal of consent, or the study ends, whichever occurs first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trans-arterial ChemoEmbolization (TACE)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for emulsion for infusion
    Routes of administration
    Intraarterial use
    Dosage and administration details
    Inject the emulsion of the anticancer agent(s); Embolize the feeding artery with an embolization agent (eg, gelatin sponge); Inject Drug Eluting Beads (DEB).

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Opdivo BMS-936558
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    240 milligram (mg) every 2 weeks (Q2W)

    Arm title
    		 TACE
    Arm description
    		 Participants received first Trans-arterial ChemoEmbolization (TACE) in 7 days after randomization and then TACE as needed, until participant was no longer eligible for further TACE, unacceptable toxicity, withdrawal of consent, or the study ends, whichever occurs first.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Trans-arterial ChemoEmbolization (TACE)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for emulsion for infusion
    Routes of administration
    Intraarterial use
    Dosage and administration details
    Inject the emulsion of the anticancer agent(s); Embolize the feeding artery with an embolization agent (eg, gelatin sponge); Inject Drug Eluting Beads (DEB).

    Number of subjects in period 1
    		NIVO+IPI+TACE NIVO+TACE TACE
    Started
    9
    9
    8
    Completed
    6
    4
    4
    Not completed
    3
    5
    4
         Study drug toxicity
    1
    -
    -
         Adverse event, non-fatal
    1
    1
    -
         Other Reason
    -
    -
    1
         Disease Recurrence
    -
    1
    -
         Disease Progression
    1
    2
    3
         Administrative Reasons by Sponsor
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    NIVO+IPI+TACE
    Reporting group description
    		 Participants with intermediate-stage hepatocellular carcinoma (HCC) received Nivolumab (NIVO) 240 milligram (mg) every 2 weeks (Q2W) and ipilimumab (IPI) 1 milligram per kilogram (mg/kg) every 6 weeks (Q6W) as an approximately 30-minute infusion. Participants received first Trans-arterial ChemoEmbolization (TACE) in 7 days after randomization and then TACE as needed, until participant was no longer eligible for further TACE, unacceptable toxicity, withdrawal of consent, or the study ends, whichever occurs first.

    Reporting group title
    NIVO+TACE
    Reporting group description
    		 Participants with intermediate-stage hepatocellular carcinoma (HCC) received Nivolumab 240 milligram (mg) every 2 weeks (Q2W) as an approximately 30-minute infusion. Participants received first Trans-arterial ChemoEmbolization (TACE) in 7 days after randomization and then TACE as needed, until participant was no longer eligible for further TACE, unacceptable toxicity, withdrawal of consent, or the study ends, whichever occurs first.

    Reporting group title
    TACE
    Reporting group description
    		 Participants received first Trans-arterial ChemoEmbolization (TACE) in 7 days after randomization and then TACE as needed, until participant was no longer eligible for further TACE, unacceptable toxicity, withdrawal of consent, or the study ends, whichever occurs first.

    Reporting group values
    		 NIVO+IPI+TACE NIVO+TACE TACE Total
    Number of subjects
    		 9 9 8 26
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 3 6 2 11
        From 65-84 years
    		 5 3 6 14
        85 years and over
    		 1 0 0 1
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 72.3 ( 10.28 ) 62.7 ( 11.19 ) 70.3 ( 8.89 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 2 1 1 4
        Male
    		 7 8 7 22
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 1 0 1
        Not Hispanic or Latino
    		 0 4 4 8
        Unknown or Not Reported
    		 9 4 4 17
    Race
    Units: Subjects
        White
    		 3 3 2 8
        Black or African American
    		 0 1 0 1
        Asian
    		 0 1 3 4
        Chinese
    		 2 2 1 5
        Japanese
    		 2 1 2 5
        Not Reported
    		 2 1 0 3

    End points

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    End points reporting groups
    Reporting group title
    NIVO+IPI+TACE
    Reporting group description
    		 Participants with intermediate-stage hepatocellular carcinoma (HCC) received Nivolumab (NIVO) 240 milligram (mg) every 2 weeks (Q2W) and ipilimumab (IPI) 1 milligram per kilogram (mg/kg) every 6 weeks (Q6W) as an approximately 30-minute infusion. Participants received first Trans-arterial ChemoEmbolization (TACE) in 7 days after randomization and then TACE as needed, until participant was no longer eligible for further TACE, unacceptable toxicity, withdrawal of consent, or the study ends, whichever occurs first.

    Reporting group title
    NIVO+TACE
    Reporting group description
    		 Participants with intermediate-stage hepatocellular carcinoma (HCC) received Nivolumab 240 milligram (mg) every 2 weeks (Q2W) as an approximately 30-minute infusion. Participants received first Trans-arterial ChemoEmbolization (TACE) in 7 days after randomization and then TACE as needed, until participant was no longer eligible for further TACE, unacceptable toxicity, withdrawal of consent, or the study ends, whichever occurs first.

    Reporting group title
    TACE
    Reporting group description
    		 Participants received first Trans-arterial ChemoEmbolization (TACE) in 7 days after randomization and then TACE as needed, until participant was no longer eligible for further TACE, unacceptable toxicity, withdrawal of consent, or the study ends, whichever occurs first.

    Primary: Number of Participants with Adverse Events

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    End point title
    		 Number of Participants with Adverse Events [1]
    End point description
    An Adverse Event (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. All treated participants.
    End point type
    Primary
    End point timeframe
    From first dose and 30 days after last dose of study therapy (up to approximately 25 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: Statistical comparison was not required as per study design
    End point values
    		 NIVO+IPI+TACE NIVO+TACE TACE
    Number of subjects analysed
    9
    9
    8
    Units: participants
    9
    9
    8
    No statistical analyses for this end point

    Primary: Number of Participants with Serious Adverse Events (SAEs)

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    End point title
    		 Number of Participants with Serious Adverse Events (SAEs) [2]
    End point description
    Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any dose that results in death, Is life-threatening (defined as an event in which the participant was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe) or requires inpatient hospitalization or causes prolongation of existing hospitalization, or results in persistent or significant disability/incapacity or is a congenital anomaly/birth defect or is an important medical event. All treated participants.
    End point type
    Primary
    End point timeframe
    From first dose and 30 days after last dose of study therapy (up to approximately 25 months)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical comparison was not required as per study design
    End point values
    		 NIVO+IPI+TACE NIVO+TACE TACE
    Number of subjects analysed
    9
    9
    8
    Units: participants
    7
    6
    2
    No statistical analyses for this end point

    Primary: Number of Participants who Died

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    End point title
    		 Number of Participants who Died [3]
    End point description
    All treated participants
    End point type
    Primary
    End point timeframe
    From first dose and 100 days after last dose of study therapy (up to approximately 27 months)
    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: Statistical comparison was not required as per study design
    End point values
    		 NIVO+IPI+TACE NIVO+TACE TACE
    Number of subjects analysed
    9
    9
    8
    Units: participants
    2
    2
    0
    No statistical analyses for this end point

    Primary: Number of Participants with Adverse Events Leading to Study Drug discontinuation

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    End point title
    		 Number of Participants with Adverse Events Leading to Study Drug discontinuation [4]
    End point description
    An Adverse Event (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. All treated participants.
    End point type
    Primary
    End point timeframe
    From first dose and 30 days after last dose of study therapy (up to approximately 25 months)
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical comparison was not required as per study design
    End point values
    		 NIVO+IPI+TACE NIVO+TACE TACE
    Number of subjects analysed
    9
    9
    8
    Units: participants
    3
    1
    1
    No statistical analyses for this end point

    Primary: Number of Participants with Worst Grade (Grade 3/4) Laboratory Results

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    End point title
    		 Number of Participants with Worst Grade (Grade 3/4) Laboratory Results [5]
    End point description
    Laboratory results were graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (Grade 3 =Severe, Grade 4 = Life-threatening). All treated participants. Highest grade measured for hemoglobin and albumin was Grade 3.
    End point type
    Primary
    End point timeframe
    From first dose and 30 days after last dose of study therapy (up to approximately 25 months)
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical comparison was not required as per study design
    End point values
    		 NIVO+IPI+TACE NIVO+TACE TACE
    Number of subjects analysed
    9
    9
    8
    Units: participants
        Hemoglobin (Grade 3)
    1
    0
    2
        Platelet count (Grade 3)
    2
    0
    0
        Leukocytes (Grade 3)
    1
    0
    0
        Lymphocytes (Grade 3)
    2
    2
    3
        Lymphocytes (Grade 4)
    1
    0
    0
        Aspartate Aminotransferase (Grade 3)
    2
    0
    0
        Aspartate Aminotransferase (Grade 4)
    1
    0
    0
        Alanine Aminotransferase (Grade 3)
    1
    1
    0
        Alanine Aminotransferase (Grade 4)
    1
    0
    0
        Bilirubin, TOTAL (Grade 4)
    1
    0
    0
        Creatinine, (Grade 3)
    0
    1
    0
        Potassium, (Grade 3)
    1
    1
    0
        Amylase (Grade 3)
    2
    0
    0
        Lipase (Grade 3)
    4
    0
    1
        Albumin, (Grade 3)
    1
    0
    0
        Hypokalemia (Grade 3)
    1
    1
    0
        Platelet Count (Grade 4)
    0
    0
    0
        Leukocytes (Grade 4)
    0
    0
    0
        Absolute Neutrophil Count (Grade 3)
    0
    0
    0
        Absolute Neutrophil Count (Grade 4)
    0
    0
    0
        Alkaline Phosphatase (Grade 3)
    0
    0
    0
        Alkaline Phosphatase (Grade 4)
    0
    0
    0
        Bilirubin, Total (Grade 3)
    0
    0
    0
        Creatinine (Grade 4)
    0
    0
    0
        Sodium (Grade 3)
    0
    0
    0
        Sodium (Grade 4)
    0
    0
    0
        Potassium (Grade 4)
    0
    0
    0
        Calcium (Grade 3)
    0
    0
    0
        Calcium (Grade 4)
    0
    0
    0
        Magnesium (Grade 3)
    0
    0
    0
        Magnesium (Grade 4)
    0
    0
    0
        Glucose (Grade 3)
    0
    0
    0
        Glucose (Grade 4)
    0
    0
    0
        Amylase (Grade 4)
    0
    0
    0
        Lipase (Grade 4)
    0
    0
    0
        Hypernatremia (Grade 3)
    0
    0
    0
        Hypernatremia (Grade 4)
    0
    0
    0
        Hyponatremia (Grade 3)
    0
    0
    0
        Hyponatremia (Grade 4)
    0
    0
    0
        Hyperkalemia (Grade 3)
    0
    0
    0
        Hyperkalemia (Grade 4)
    0
    0
    0
        Hypokalemia (Grade 4)
    0
    0
    0
        Hypercalcemia (Grade 3)
    0
    0
    0
        Hypercalcemia (Grade 4)
    0
    0
    0
        Hypocalcemia (Grade 3)
    0
    0
    0
        Hypocalcemia (Grade 4)
    0
    0
    0
        Hypomagnesemia (Grade 3)
    0
    0
    0
        Hypomagnesemia (Grade 4)
    0
    0
    0
        Hypermagnesemia (Grade 3)
    0
    0
    0
        Hypermagnesemia (Grade 4)
    0
    0
    0
        Hypoglycemia (Grade 3)
    0
    0
    0
        Hypoglycemia (Grade 4)
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of Participants with Laboratory Abnormalities in Specific Thyroid Tests

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    End point title
    		 Number of Participants with Laboratory Abnormalities in Specific Thyroid Tests [6]
    End point description
    Blood samples were collected for specific thyroid test. All treated participants with at least one on-treatment thyroid stimulating hormone (TSH) measurement.
    End point type
    Primary
    End point timeframe
    From first dose and 30 days after last dose of study therapy (up to approximately 25 months)
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical comparison was not required as per study design
    End point values
    		 NIVO+IPI+TACE NIVO+TACE TACE
    Number of subjects analysed
    9
    9
    8
    Units: participants
        TSH > ULN
    5
    5
    5
        TSH > ULN with TSH <= ULN at baseline
    5
    4
    3
        TSH > ULN with FT3/FT4 test value < LLN
    3
    1
    3
        TSH > ULN with FT3/FT4 test values >= LLN
    5
    4
    4
        TSH > ULN with FT3/FT4 test missing
    0
    2
    1
        TSH < LLN
    3
    1
    0
        TSH < LLN with TSH >= LLN at baseline
    3
    1
    0
        TSH < LLN with FT3/FT4 test value > ULN
    2
    0
    0
        With FT3/FT4 test values <= ULN
    3
    0
    0
        With FT3/FT4 test missing
    0
    1
    0
    No statistical analyses for this end point

    Primary: Number of Participants with Clinical Laboratory Abnormalities in Specific Liver Tests

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    End point title
    		 Number of Participants with Clinical Laboratory Abnormalities in Specific Liver Tests [7]
    End point description
    Blood samples were collected for specific liver tests. All treated participants.
    End point type
    Primary
    End point timeframe
    From first dose and 30 days after last dose of study therapy (up to approximately 25 months)
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical comparison was not required as per study design
    End point values
    		 NIVO+IPI+TACE NIVO+TACE TACE
    Number of subjects analysed
    9
    9
    8
    Units: participants
        ALT or AST > 5 X ULN
    3
    2
    0
        ALT or AST > 10 X ULN
    2
    1
    0
        ALT or AST > 20 X ULN
    1
    0
    0
        Total Bilirubin > 2 X ULN
    3
    2
    1
        ALP > 1.5 X ULN
    5
    5
    5
        ALT/AST > 3 X ULN total Bilirubin > 2 X ULN
    3
    1
    0
        ALT/AST > 3XULN total Bilirubin>2XULN in 30 days
    3
    2
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All-cause mortality was collected from randomization until their study completion (up to approximately 38 months). SAEs and non-SAEs were collected from first dose to 100 days after last dose of study therapy (up to approximately 27 months).
    Adverse event reporting additional description
    All treated participants included all enrolled participants who received at least one dose of any study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    NIVO + IPI + TACE
    Reporting group description
    		 Participants with intermediate-stage hepatocellular carcinoma (HCC) received Nivolumab (NIVO) 240 milligram (mg) every 2 weeks (Q2W) and ipilimumab (IPI) 1 milligram per kilogram (mg/kg) every 6 weeks (Q6W) as an approximately 30-minute infusion. Participants received first Trans-arterial ChemoEmbolization (TACE) in in 7 days after randomization and then TACE as needed, until participant was no longer eligible for further TACE, unacceptable toxicity, withdrawal of consent, or the study ends, whichever occurs first.

    Reporting group title
    NIVO + TACE
    Reporting group description
    		 Participants with intermediate-stage hepatocellular carcinoma (HCC) received Nivolumab 240 milligram (mg) every 2 weeks (Q2W) as an approximately 30-minute infusion. Participants received first Trans-arterial ChemoEmbolization (TACE) in in 7 days after randomization and then TACE as needed, until participant was no longer eligible for further TACE, unacceptable toxicity, withdrawal of consent, or the study ends, whichever occurs first.

    Reporting group title
    TACE
    Reporting group description
    		 Participants received first Trans-arterial ChemoEmbolization (TACE) in in 7 days after randomization and then TACE as needed, until participant was no longer eligible for further TACE, unacceptable toxicity, withdrawal of consent, or the study ends, whichever occurs first.

    Serious adverse events
    		 NIVO + IPI + TACE NIVO + TACE TACE
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 9 (77.78%)
    6 / 9 (66.67%)
    2 / 8 (25.00%)
         number of deaths (all causes)
    2
    2
    0
         number of deaths resulting from adverse events
    2
    1
    0
    Investigations
    International normalised ratio increased
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (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
    Blood bilirubin increased
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (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
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (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
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (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
    Nervous system disorders
    Encephalopathy
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (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
    Hepatic encephalopathy
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 9 (0.00%)
    0 / 8 (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
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 9 (11.11%)
    3 / 9 (33.33%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (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
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (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
    Diarrhoea
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (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
    Haematemesis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (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
    Pleural effusion
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (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
    Renal and urinary disorders
    Tubulointerstitial nephritis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (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
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (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
    Bursitis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (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
    Infections and infestations
    Klebsiella bacteraemia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic infection
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (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
    Metabolism and nutrition disorders
    Cell death
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (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
    Hyponatraemia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 NIVO + IPI + TACE NIVO + TACE TACE
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 9 (100.00%)
    9 / 9 (100.00%)
    8 / 8 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    0
    0
    2
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Raynaud's phenomenon
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    General disorders and administration site conditions
    Feeling hot
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Fatigue
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Device related thrombosis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Asthenia
         subjects affected / exposed
    2 / 9 (22.22%)
    2 / 9 (22.22%)
    1 / 8 (12.50%)
         occurrences all number
    3
    2
    1
    Pyrexia
         subjects affected / exposed
    2 / 9 (22.22%)
    3 / 9 (33.33%)
    2 / 8 (25.00%)
         occurrences all number
    2
    5
    3
    Oedema peripheral
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    3 / 8 (37.50%)
         occurrences all number
    1
    2
    3
    Mucosal inflammation
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Inflammation
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Immune system disorders
    Contrast media allergy
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 9 (22.22%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    4
    1
    0
    Dyspnoea
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    0
    Hiccups
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Pleural effusion
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Productive cough
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    1 / 8 (12.50%)
         occurrences all number
    1
    1
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 9 (22.22%)
    2 / 9 (22.22%)
    1 / 8 (12.50%)
         occurrences all number
    3
    2
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 9 (22.22%)
    2 / 9 (22.22%)
    0 / 8 (0.00%)
         occurrences all number
    3
    6
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 9 (22.22%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    Blood creatinine increased
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    0
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Gastric pH decreased
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Weight increased
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Weight decreased
         subjects affected / exposed
    2 / 9 (22.22%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    2
    4
    0
    Oxygen saturation decreased
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Lymphocyte count decreased
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Lipase increased
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    4
    0
    0
    Inflammatory marker increased
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Injury, poisoning and procedural complications
    Hepatobiliary procedural complication
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Bone contusion
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Craniofacial fracture
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Fall
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Incision site pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Limb injury
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Post embolisation syndrome
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    2
    0
    2
    Skin injury
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Tooth fracture
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Traumatic haematoma
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Cardiac disorders
    Cardiovascular disorder
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Tachycardia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    0
    Encephalopathy
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Paraesthesia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Neuralgia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Hepatic encephalopathy
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    3
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 9 (22.22%)
    2 / 8 (25.00%)
         occurrences all number
    0
    4
    2
    Thrombocytopenia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Neutropenia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Leukopenia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    3
    Abdominal pain
         subjects affected / exposed
    2 / 9 (22.22%)
    3 / 9 (33.33%)
    2 / 8 (25.00%)
         occurrences all number
    3
    6
    5
    Abdominal pain upper
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    2
    0
    1
    Abdominal pain lower
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Anal haemorrhage
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    0
    Ascites
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    1 / 8 (12.50%)
         occurrences all number
    1
    1
    2
    Chronic gastritis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Colitis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Faeces discoloured
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Dental caries
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Dyspepsia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    2 / 8 (25.00%)
         occurrences all number
    0
    1
    5
    Diarrhoea
         subjects affected / exposed
    3 / 9 (33.33%)
    2 / 9 (22.22%)
    3 / 8 (37.50%)
         occurrences all number
    3
    2
    5
    Constipation
         subjects affected / exposed
    2 / 9 (22.22%)
    2 / 9 (22.22%)
    4 / 8 (50.00%)
         occurrences all number
    3
    2
    4
    Gastric ulcer
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    0
    0
    2
    Gastritis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Vomiting
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Varices oesophageal
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Toothache
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Stomatitis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Portal hypertensive gastropathy
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Nausea
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 9 (22.22%)
    2 / 8 (25.00%)
         occurrences all number
    3
    3
    5
    Melaena
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Gastrointestinal angiodysplasia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Hepatobiliary disorders
    Hypertransaminasaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Cholecystitis acute
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Psoriasis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Dermatitis contact
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Eczema
         subjects affected / exposed
    2 / 9 (22.22%)
    1 / 9 (11.11%)
    1 / 8 (12.50%)
         occurrences all number
    2
    1
    1
    Erythema
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    0
    Onychoclasis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Photosensitivity reaction
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Pruritus
         subjects affected / exposed
    3 / 9 (33.33%)
    4 / 9 (44.44%)
    2 / 8 (25.00%)
         occurrences all number
    3
    4
    2
    Skin hypopigmentation
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Rash maculo-papular
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Rash macular
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Rash
         subjects affected / exposed
    2 / 9 (22.22%)
    1 / 9 (11.11%)
    3 / 8 (37.50%)
         occurrences all number
    2
    1
    3
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Haematuria
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    0
    Hypertonic bladder
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Tubulointerstitial nephritis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Endocrine disorders
    Thyroiditis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Hypothyroidism
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Hyperthyroidism
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Adrenal insufficiency
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Psoriatic arthropathy
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Myalgia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Flank pain
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Bursitis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Back pain
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    1 / 8 (12.50%)
         occurrences all number
    0
    2
    1
    Arthritis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Arthralgia
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    2 / 8 (25.00%)
         occurrences all number
    1
    2
    2
    Infections and infestations
    Bacteriuria
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Anal abscess
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Abdominal infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Cystitis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    COVID-19
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Dermo-hypodermitis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Genital herpes
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    Enteritis infectious
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    1
    Pharyngitis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Pneumonia
         subjects affected / exposed
    2 / 9 (22.22%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    2
    1
    0
    Respiratory tract infection
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Rhinitis
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    0
    Urinary tract infection
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    3
    0
    0
    Vulvovaginal mycotic infection
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Influenza
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Herpes simplex
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Helicobacter infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Pneumonia aspiration
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Metabolism and nutrition disorders
    Fluid retention
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Decreased appetite
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    3 / 8 (37.50%)
         occurrences all number
    2
    1
    4
    Hyperammonaemia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Hyperkalaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 9 (22.22%)
    2 / 8 (25.00%)
         occurrences all number
    2
    7
    3
    Hypocalcaemia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    2
    Hypoglycaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    2
    Hypokalaemia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Diabetes mellitus
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Vitamin D deficiency
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Dec 2021
    Details of closure of the study with provision for participants currently on treatment or in the follow-up period to continue in the study as per the current protocol, study unblinding, Removal of placebo infusions for participants in Arms B and C, only safety assessment will be conducted, removal of on-study imaging assessments, align dose modification criteria and immuno-oncology agent management algorithms, Add the collection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-related AEs and SAEs.

    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.
    Study was terminated due to slow accrual.
    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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