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    Clinical Trial Results:
    PHASE I - II STUDY OF INTRATUMORAL URELUMAB COMBINED WITH NIVOLUMAB IN PATIENTS WITH SOLID TUMORS

    Summary
    EudraCT number
    		 2017-005106-35
    Trial protocol
    		 ES  
    Global end of trial date
    13 Jan 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Jan 2023
    First version publication date
    13 Jan 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    INTRUST
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03792724
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Clínica Universidad de Navarra (CUN)
    Sponsor organisation address
    Avenida Pio XII, 36, Pamplona, Spain, 31008
    Public contact
    UCEC, Clinica Universidad de Navarra, 34 9482554002725, ucicec@unav.es
    Scientific contact
    UCEC, Clinica Universidad de Navarra, 34 9482554002725, ucicec@unav.es
    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
    07 Jul 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Jan 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    - Phase I: to assess the safety and to establish the recommended dose of the combination of intratumoral urelumab administered in combination with systemic nivolumab in patients with advanced solid tumors. Three doses of intratumoral urelumab will be assessed, in combination with systemic nivolumab at standard doses. - Phase II: to detetermine the objective response rate of the recommended schedule determined by RECIST and immune response criteria.
    Protection of trial subjects
    Study treatment had to be discontinued upon confirmed radiological progression or clinical progression.
    Background therapy
    		 Supportive care for disease-related symptoms was offered to all subjects on the trial. Use of limited field palliative radiotherapy was allowed at any time during the study except on days where study drugs were administered, as well as one day before or after treatment administration.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Apr 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 40
    Worldwide total number of subjects
    40
    EEA total number of subjects
    40
    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)
    26
    From 65 to 84 years
    14
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The inclusion of the first patient was on 09/April/2019. The end of recruitment was on 01/February/2021.

    Pre-assignment
    Screening details
    		 Screening period: within 30 days after informed consent, patients were evaluated for study eligibility. Participants were tested to determine if they met all the inclusion criteria and none of the exclusion criteria. 40 patients were enrolled in the study, but 9 of them were screening failures and did not receive the study treatment.

    Pre-assignment period milestones
    Number of subjects started
    		 40
    Number of subjects completed
    		 31

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Physician decision: 9
    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Masking procedures do not apply to this study since it is an open-label clinical trial.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Phase I: Urelumab 1 mg + Nivolumab
    Arm description
    		 Participants received 1 mg intratumoral Urelumab + intravenous Nivolumab. Urelumab: three doses of intratumoral urelumab every 4 weeks (Cycle 1, Cycle 3, Cycle 5). Nivolumab: starting 2 weeks after the first dose of intratumoral urelumab (240 mg for Cycle 2 and at a fixed dose of 480 mg every 4 weeks from Cycle 4 and beyond).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Urelumab
    Investigational medicinal product code
    Other name
    BMS-663513-01
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Solution for injection
    Dosage and administration details
    Participants received three doses of intratumoral urelumab every 4 weeks (Cycle 1, Cycle 3, Cycle 5).

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    BMS-936558-01
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Nivolumab was administered starting 2 weeks after the first dose of intratumoral urelumab as an intravenous infusion at a fixed dose of 240 mg (Cycle 2) and at a fixed dose of 480 mg for Cycle 4 and beyond every 4 weeks. A maximum duration of nivolumab therapy of 18-24 months was suggested.

    Arm title
    		 Phase II: Urelumab 8 mg + Nivolumab
    Arm description
    		 Participants received 8 mg intratumoral Urelumab + intravenous Nivolumab. Urelumab: three doses of intratumoral urelumab every 4 weeks (Cycle 1, Cycle 3, Cycle 5). Nivolumab: starting 2 weeks after the first dose of intratumoral urelumab (240 mg for Cycle 2 and at a fixed dose of 480 mg every 4 weeks from Cycle 4 and beyond).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Urelumab
    Investigational medicinal product code
    Other name
    BMS-663513-01
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Solution for injection
    Dosage and administration details
    Subjects received three doses of intratumoral urelumab 8 mg every 4 weeks (Cycle 1, Cycle 3, Cycle 5).

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    BMS-663513
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Nivolumab was administered starting 2 weeks after the first dose of intratumoral urelumab as an intravenous infusion at a fixed dose of 240 mg for Cycle 2 and at a fixed dose of 480 mg every 4 weeks from Cycle 4 and beyond. A maximum duration of nivolumab therapy of 18-24 months was suggested.

    Number of subjects in period 1 [1]
    		Phase I: Urelumab 1 mg + Nivolumab Phase II: Urelumab 8 mg + Nivolumab
    Started
    3
    28
    Completed
    0
    14
    Not completed
    3
    14
         Patient could not come in 4 weeks
    -
    1
         Consent withdrawn by subject
    -
    1
         Will continue treatment in other hospital
    -
    1
         Death
    -
    6
         Progression
    1
    2
         Cannot travel to the site
    -
    1
         Lost to follow-up
    2
    2
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 40 patients were enrolled in the study, but 9 of them were screening failures and did not receive the study treatment.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase I: Urelumab 1 mg + Nivolumab
    Reporting group description
    		 Participants received 1 mg intratumoral Urelumab + intravenous Nivolumab. Urelumab: three doses of intratumoral urelumab every 4 weeks (Cycle 1, Cycle 3, Cycle 5). Nivolumab: starting 2 weeks after the first dose of intratumoral urelumab (240 mg for Cycle 2 and at a fixed dose of 480 mg every 4 weeks from Cycle 4 and beyond).

    Reporting group title
    Phase II: Urelumab 8 mg + Nivolumab
    Reporting group description
    		 Participants received 8 mg intratumoral Urelumab + intravenous Nivolumab. Urelumab: three doses of intratumoral urelumab every 4 weeks (Cycle 1, Cycle 3, Cycle 5). Nivolumab: starting 2 weeks after the first dose of intratumoral urelumab (240 mg for Cycle 2 and at a fixed dose of 480 mg every 4 weeks from Cycle 4 and beyond).

    Reporting group values
    		 Phase I: Urelumab 1 mg + Nivolumab Phase II: Urelumab 8 mg + Nivolumab Total
    Number of subjects
    		 3 28 31
    Age categorical
    Age was computed considering the difference in years between the date of birth and the date of the signature of the informed consent form.
    Units: Subjects
        Adults (18-64 years)
    		 1 19 20
        From 65-84 years
    		 2 9 11
    Age continuous
    Age was computed considering the difference in years between the date of birth and the date of the signature of the informed consent form.
    Units: years
        arithmetic mean (standard deviation)
    		 65.67 ( 12.86 ) 60.75 ( 10.92 ) -
    Gender categorical
    Units: Subjects
        Female
    		 3 11 14
        Male
    		 0 17 17
    Subject analysis sets

    Subject analysis set title
    Phase II: Cohort A
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Recruited anti PD1/PDL1 naïve patients presenting tumor types sensitive to PD1/PDL1 blockade. These patients had to be naïve to PD1/PDL1 blockade.

    Subject analysis set title
    Phase II: Cohort B
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Included patients with PD1/PDL1 sensitive tumors that have progressed on previous PD1/ PDL1 blockade.

    Subject analysis sets values
    		 Phase II: Cohort A Phase II: Cohort B
    Number of subjects
    20
    8
    Age categorical
    Age was computed considering the difference in years between the date of birth and the date of the signature of the informed consent form.
    Units: Subjects
        Adults (18-64 years)
    15
    4
        From 65-84 years
    5
    4
    Age continuous
    Age was computed considering the difference in years between the date of birth and the date of the signature of the informed consent form.
    Units: years
        arithmetic mean (standard deviation)
    58.95 ( 10.87 )
    65.25 ( 10.31 )
    Gender categorical
    Units: Subjects
        Female
    8
    3
        Male
    12
    5

    End points

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    End points reporting groups
    Reporting group title
    Phase I: Urelumab 1 mg + Nivolumab
    Reporting group description
    		 Participants received 1 mg intratumoral Urelumab + intravenous Nivolumab. Urelumab: three doses of intratumoral urelumab every 4 weeks (Cycle 1, Cycle 3, Cycle 5). Nivolumab: starting 2 weeks after the first dose of intratumoral urelumab (240 mg for Cycle 2 and at a fixed dose of 480 mg every 4 weeks from Cycle 4 and beyond).

    Reporting group title
    Phase II: Urelumab 8 mg + Nivolumab
    Reporting group description
    		 Participants received 8 mg intratumoral Urelumab + intravenous Nivolumab. Urelumab: three doses of intratumoral urelumab every 4 weeks (Cycle 1, Cycle 3, Cycle 5). Nivolumab: starting 2 weeks after the first dose of intratumoral urelumab (240 mg for Cycle 2 and at a fixed dose of 480 mg every 4 weeks from Cycle 4 and beyond).

    Subject analysis set title
    Phase II: Cohort A
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Recruited anti PD1/PDL1 naïve patients presenting tumor types sensitive to PD1/PDL1 blockade. These patients had to be naïve to PD1/PDL1 blockade.

    Subject analysis set title
    Phase II: Cohort B
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Included patients with PD1/PDL1 sensitive tumors that have progressed on previous PD1/ PDL1 blockade.

    Primary: Best overall response (BOR)

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    End point title
    		 Best overall response (BOR) [1]
    End point description
    Best overall response: overall, 3.57% of patients had Partial response, 28.57% Stable disease, 42.86% Pogression and 7.14% Stable disease + progression.
    End point type
    Primary
    End point timeframe
    End of treatment
    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: The analyses performed are descriptive and therefore no statistical analysis can be applied.
    End point values
    		 Phase I: Urelumab 1 mg + Nivolumab Phase II: Urelumab 8 mg + Nivolumab
    Number of subjects analysed
    3
    25 [2]
    Units: Number of patients
        Complete response (CR)
    0
    0
        Partial response (PR)
    1
    1
        Stable disease (SD)
    1
    8
        Progression (PD)
    1
    12
        Stable disease + progression
    0
    2
    Notes
    [2] - There are 5 patients without available data
    No statistical analyses for this end point

    Primary: Objective response rate (ORR)

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    End point title
    		 Objective response rate (ORR) [3]
    End point description
    ORR is defined as the proportion of all treated subjects whose best overall response (BOR) is complete response or partial response.
    End point type
    Primary
    End point timeframe
    End of the treatment
    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: The analyses performed are descriptive and therefore no statistical analysis can be applied.
    End point values
    		 Phase I: Urelumab 1 mg + Nivolumab Phase II: Urelumab 8 mg + Nivolumab
    Number of subjects analysed
    3
    28
    Units: Number of patients
    1
    1
    No statistical analyses for this end point

    Primary: Dose Limiting toxicities (DLT)

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    End point title
    		 Dose Limiting toxicities (DLT) [4] [5]
    End point description
    There were two dose levels for intratumoral urelumab: 1 mg and 8 mg. As no DLTs were observed in the intratumoral urelumab 1 mg level, the dose of intratumoral urelumab was escalated to 8 mg. In addition, as no DLT were observed in the intratumoral urelumab 8 mg level recruitment, in the phase II part continued at that dose until the study was completed.
    End point type
    Primary
    End point timeframe
    The observation period for DTL lasted 6 weeks for each dose level (2 doses of intratumoral urelumab + 2 doses of systemic nivolumab, i.e: it ended before the third dose of urelumab).
    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: The analyses performed are descriptive and therefore no statistical analysis can be applied.
    [5] - 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: Dose Limiting Toxicities (DLT) were evaluated only in Phase I. There were no DLT in the present study.
    End point values
    		 Phase I: Urelumab 1 mg + Nivolumab
    Number of subjects analysed
    3
    Units: Dose Limiting Toxicities
    0
    No statistical analyses for this end point

    Secondary: Duration of response (DOR)

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    End point title
    		 Duration of response (DOR)
    End point description
    DOR is defined as time (in weeks) between the date of first radiographic documented objective response and the date of the radiographic disease progression.
    End point type
    Secondary
    End point timeframe
    Between the date of first radiographic documented objective response and the date of the radiographic disease progression.
    End point values
    		 Phase I: Urelumab 1 mg + Nivolumab Phase II: Urelumab 8 mg + Nivolumab
    Number of subjects analysed
    1
    1
    Units: week
        number (not applicable)
    26.20
    59.50
    No statistical analyses for this end point

    Secondary: Progression-free survival (PFS)

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    End point title
    		 Progression-free survival (PFS)
    End point description
    PFS is assessed from the date of inclusion until the date of first sign of disease progression or death due to any cause. Overall, PFS mean was 17.00 and SD was 2.63.
    End point type
    Secondary
    End point timeframe
    PFS is assessed from the date of inclusion until the date of first sign of disease progression or death due to any cause.
    End point values
    		 Phase I: Urelumab 1 mg + Nivolumab Phase II: Urelumab 8 mg + Nivolumab Phase II: Cohort A Phase II: Cohort B
    Number of subjects analysed
    3
    28
    20
    8
    Units: week
        arithmetic mean (standard error)
    21.50 ( 6.72 )
    16.50 ( 2.81 )
    18.60 ( 3.75 )
    11.10 ( 1.93 )
    No statistical analyses for this end point

    Secondary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    Overall survival (OS) was assessed from the date of inclusion until the date of death due to any cause. Overall, OS mean was 53.10 and SD was 9.45.
    End point type
    Secondary
    End point timeframe
    OS was assessed from the date of inclusion until the date of death due to any cause.
    End point values
    		 Phase I: Urelumab 1 mg + Nivolumab Phase II: Urelumab 8 mg + Nivolumab Phase II: Cohort A Phase II: Cohort B
    Number of subjects analysed
    3
    28
    20
    8
    Units: week
        arithmetic mean (standard error)
    81.40 ( 0.00 )
    48.70 ( 10.90 )
    46.80 ( 10.89 )
    71.70 ( 9.14 )
    No statistical analyses for this end point

    Secondary: Summary of safety results (number of events)

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    End point title
    		 Summary of safety results (number of events)
    End point description
    Summary of the safety results related to the count of each type of adverse event for overall patients and by phase and cohort of the study. For Urelumab/Nivolumab related events, AEs whose causal relation is “likely” or “related” were considered. Overall, there were 302 AEs, 28 SAEs, 0 DLT, 7 urelumab related-events, 5 nivolumab-related events and 5 urelumab and nivolumab related events.
    End point type
    Secondary
    End point timeframe
    Adverse events were assessed continuously during the study and for a minimum of 100 days following the last dose of study treatment.
    End point values
    		 Phase I: Urelumab 1 mg + Nivolumab Phase II: Urelumab 8 mg + Nivolumab Phase II: Cohort A Phase II: Cohort B
    Number of subjects analysed
    3
    28
    20
    8
    Units: number of events
        Adverse Events (AEs)
    26
    276
    217
    59
        Serious Adverse Events (SAEs)
    0
    28
    24
    4
        Dose Limiting Toxicities (DLT)
    0
    0
    0
    0
        Urelumab-related events
    0
    7
    2
    5
        Nivolumab-related events
    0
    5
    1
    4
        Urelumab and nivolumab related events
    0
    5
    1
    4
    No statistical analyses for this end point

    Secondary: Summary of safety results (number of patients)

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    End point title
    		 Summary of safety results (number of patients)
    End point description
    Shows the results related to the number of patients within each category. Overall, there were 30 pacients with AEs, 14 with SAEs, 0 with DLT, 4 with urelumab related-events, 3 with nivolumab-related events and 3 with urelumab and nivolumab related events.
    End point type
    Secondary
    End point timeframe
    Adverse events were assessed continuously during the study and for a minimum of 100 days following the last dose of study treatment.
    End point values
    		 Phase I: Urelumab 1 mg + Nivolumab Phase II: Urelumab 8 mg + Nivolumab Phase II: Cohort A Phase II: Cohort B
    Number of subjects analysed
    3
    28
    20
    8
    Units: number of patients
        Adverse Events (AEs)
    3
    28
    20
    7
        Serious Adverse Events (SAEs)
    0
    14
    11
    3
        Dose Limiting Toxicities (DLT)
    0
    0
    0
    0
        Urelumab-related events
    0
    4
    2
    2
        Nivolumab-related events
    0
    3
    1
    2
        Urelumab and nivolumab related events
    0
    3
    1
    2
    No statistical analyses for this end point

    Secondary: Overview of Adverse Events by study phase (number of events within each study phase)

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    End point title
    		 Overview of Adverse Events by study phase (number of events within each study phase)
    End point description
    Summarizes the results of the number of Adverse Events for overall patients and by phase and cohort
    End point type
    Secondary
    End point timeframe
    Adverse events were assessed continuously during the study and for a minimum of 100 days following the last dose of study treatment.
    End point values
    		 Phase I: Urelumab 1 mg + Nivolumab Phase II: Urelumab 8 mg + Nivolumab Phase II: Cohort A Phase II: Cohort B
    Number of subjects analysed
    3
    28
    20
    8
    Units: number of events
        Grade: Mild
    13
    184
    141
    43
        Grade: Moderate
    12
    83
    67
    16
        Grade: Severe
    1
    9
    9
    0
        Grade: Life threatening or disabling
    0
    0
    0
    0
        Grade: Death related to the AE
    0
    0
    0
    0
        Progression: Death
    0
    6
    0
    6
        Progression: Persistence of the AE
    9
    125
    110
    15
        Progression: Recovery with consequences
    5
    15
    14
    1
        Progression: Recovery without consequences
    12
    130
    93
    37
        Action taken: None
    25
    266
    209
    57
        Action taken: Dose reduction of drug
    1
    1
    1
    0
        Action taken: Dose increase of drug
    0
    1
    1
    0
        Action taken: Temporary disruption of drug
    0
    8
    6
    2
        Action taken: Permanent disruption of drug
    0
    0
    0
    0
        Action taken: Study withdrawal
    0
    0
    0
    0
        Relation to Urelumab: Not related
    22
    258
    208
    50
        Relation to Urelumab: Unlikely
    1
    5
    4
    1
        Relation to Urelumab: Possible
    3
    7
    4
    3
        Relation to Urelumab: Likely
    0
    4
    0
    4
        Relation to Urelumab: Related
    0
    2
    1
    1
        Relation to Nivolumab: Not related
    23
    260
    209
    51
        Relation to Nivolumab: Unlikely
    1
    5
    4
    1
        Relation to Nivolumab: Possible
    2
    7
    4
    3
        Relation to Nivolumab: Likely
    0
    4
    0
    4
        Relation to Nivolumab: Related
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Overview of Adverse Events by study phase (number of patients within each group)

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    End point title
    		 Overview of Adverse Events by study phase (number of patients within each group)
    End point description
    Presents the results related to the number of patients
    End point type
    Secondary
    End point timeframe
    Adverse events were assessed continuously during the study and for a minimum of 100 days following the last dose of study treatment.
    End point values
    		 Phase I: Urelumab 1 mg + Nivolumab Phase II: Urelumab 8 mg + Nivolumab Phase II: Cohort A Phase II: Cohort B
    Number of subjects analysed
    3
    28
    Units: number of patients
        Grade: Mild
    3
    26
    19
    7
        Grade: Moderate
    3
    24
    17
    7
        Grade: Severe
    1
    6
    6
    0
        Grade: Life threatening or disabling
    0
    0
    0
    0
        Grade: Death related to the AE
    0
    0
    0
    0
        Grade: not available
    0
    0
    0
    0
        Progression: Death
    0
    1
    0
    1
        Progression: Persistence of the AE
    3
    22
    18
    4
        Progression: Recovery with consequences
    1
    8
    7
    1
        Progression: Recovery without consequences
    3
    24
    18
    6
        Action taken: None
    3
    27
    20
    7
        Action taken: Dose reduction of drug
    1
    1
    1
    0
        Action taken: Dose increased of drug
    0
    1
    1
    0
        Action taken: Temporary disruption of drug
    0
    6
    4
    2
        Action taken: Permanent disruption of drug
    0
    0
    0
    0
        Action taken: study withdrawal
    0
    0
    0
    0
        Relation to Urelumab: Not related
    3
    27
    20
    7
        Relation to Urelumab: Unlikely
    1
    5
    4
    1
        Relation to Urelumab: Possible
    2
    4
    2
    2
        Relation to Urelumab: Likely
    0
    2
    0
    2
        Relation to Urelumab: Related
    0
    2
    1
    1
        Relation to Nivolumab: Not related
    3
    27
    20
    7
        Relation to Nivolumab: Unlikely
    1
    5
    4
    1
        Relation to Nivolumab: Possible
    1
    4
    2
    2
        Relation to Nivolumab: Likely
    0
    2
    0
    2
        Relation to Nivolumab: Related
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Overview of Serious Adverse Events by study phase (number of events within each group).

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    End point title
    		 Overview of Serious Adverse Events by study phase (number of events within each group).
    End point description
    Summarizes the results of the number of Serious Adverse Events for overall patients and by group
    End point type
    Secondary
    End point timeframe
    Adverse events were assessed continuously during the study and for a minimum of 100 days following the last dose of study treatment.
    End point values
    		 Phase I: Urelumab 1 mg + Nivolumab Phase II: Urelumab 8 mg + Nivolumab Phase II: Cohort A Phase II: Cohort B
    Number of subjects analysed
    3
    28
    20
    8
    Units: number of events
        Grade: Mild
    0
    0
    0
    0
        Grade: Moderate
    0
    6
    6
    0
        Grade: Severe
    0
    15
    13
    2
        Grade: Life threatening or disabling
    0
    1
    0
    1
        Grade: Death related to the AE
    0
    6
    5
    1
        Progression: Death
    0
    7
    6
    1
        Prgression: Persistence of the AE
    0
    1
    1
    0
        Progression: Recovery with consequences
    0
    2
    2
    0
        Progression: Recovery without consequences
    0
    18
    15
    3
        Action taken: None
    0
    20
    18
    2
        Action taken: Dose reduction of drug
    0
    0
    0
    0
        Action taken: Dose increase of drug
    0
    0
    0
    0
        Action taken: Temporary disruption of drug
    0
    7
    5
    2
        Action taken: Permanent disruption of drug
    0
    1
    1
    0
        Action taken: Study withdrawal
    0
    0
    0
    0
        Relation to Urelumab: Not related
    0
    23
    21
    2
        Relation to Urelumab: Unlikely
    0
    0
    0
    0
        Relation to Urelumab: Possible
    0
    4
    2
    2
        Relation to Urelumab: Likely
    0
    0
    0
    0
        Relation to Urelumab: Related
    0
    1
    1
    0
        Relation to Nivolumab: Not related
    0
    22
    20
    2
        Relation to Nivolumab: Unlikely
    0
    0
    0
    0
        Relation to Nivolumab: Possible
    0
    5
    3
    2
        Relation to Nivolumab: Likely
    0
    0
    0
    0
        Relation to Nivolumab: Related
    0
    1
    1
    0
    No statistical analyses for this end point

    Secondary: Overview of Serious Adverse Events by study phase (number of patients within each group).

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    End point title
    		 Overview of Serious Adverse Events by study phase (number of patients within each group).
    End point description
    Results related to the number of patients
    End point type
    Secondary
    End point timeframe
    Adverse events were assessed continuously during the study and for a minimum of 100 days following the last dose of study treatment.
    End point values
    		 Phase I: Urelumab 1 mg + Nivolumab Phase II: Urelumab 8 mg + Nivolumab Phase II: Cohort A Phase II: Cohort B
    Number of subjects analysed
    3
    28
    20
    8
    Units: number of patients
        Grade: Mild
    0
    0
    0
    0
        Grade: Moderate
    0
    5
    5
    0
        Grade: Severe
    0
    9
    7
    2
        Grade: Life threatening or disabling
    0
    1
    0
    1
        Grade: Death related to the AE
    0
    6
    5
    1
        Progression: Death
    0
    7
    6
    1
        Progression: Persistence of the AE
    0
    1
    1
    0
        Progression: Recovery with consequences
    0
    2
    2
    0
        Progression: Recovery without consequence
    0
    10
    8
    2
        Action taken: None
    0
    11
    9
    2
        Action taken: Dose reduction of drug
    0
    0
    0
    0
        Action taken: Dose increase of drug
    0
    0
    0
    0
        Action taken: Temporary disruption of drug
    0
    5
    4
    1
        Action taken: Permanent disruption of drug
    0
    1
    1
    0
        Action taken: Study withdrawal
    0
    0
    0
    0
        Relation to Urelumab: Not related
    0
    12
    10
    2
        Relation to Urelumab: Unlikely
    0
    0
    0
    0
        Relation to Urelumab: Possible
    0
    3
    2
    1
        Relation to Urelumab: Likely
    0
    0
    0
    0
        Relation to Urelumab: Related
    0
    1
    1
    0
        Relation to Nivolumab: Not related
    0
    12
    10
    2
        Relation to Nivolumab: Unlikely
    0
    0
    0
    0
        Relation to Nivolumab: Possible
    0
    3
    2
    1
        Relation to Nivolumab: Likely
    0
    0
    0
    0
        Relation to Nivolumab: Related
    0
    1
    1
    0
    No statistical analyses for this end point

    Secondary: Overview of Urelumab-related Adverse Events by study phase (number of events within each group).

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    End point title
    		 Overview of Urelumab-related Adverse Events by study phase (number of events within each group).
    End point description
    Summarizes the results related to the number of Urelumab-related Adverse Events. Important note. Drug-related AEs are considered when relation with Urelumab is likely or related.
    End point type
    Secondary
    End point timeframe
    Adverse events were assessed continuously during the study and for a minimum of 100 days following the last dose of study treatment.
    End point values
    		 Phase I: Urelumab 1 mg + Nivolumab Phase II: Urelumab 8 mg + Nivolumab Phase II: Cohort A Phase II: Cohort B
    Number of subjects analysed
    3
    28
    20
    8
    Units: number of events
        Grade: Mild
    0
    5
    1
    4
        Grade: Moderate
    0
    2
    1
    1
        Grade: Severe
    0
    0
    0
    0
        Grade: Life threatening or disabling
    0
    0
    0
    0
        Grade: Death related to the AE
    0
    0
    0
    0
        Progression: Death
    0
    0
    0
    0
        Progression: Persistence of the AE
    0
    3
    0
    3
        Progression: Recovery with consequences
    0
    1
    1
    0
        Progression: Recovery without consequence
    0
    3
    1
    2
        Action taken: None
    0
    6
    1
    5
        Action taken: Dose reduction of drug
    0
    0
    0
    0
        Action taken: Dose increase of drug
    0
    0
    0
    0
        Action taken: Temporary disruption of drug
    0
    1
    1
    0
        Action taken: Permanent disruption of drug
    0
    0
    0
    0
        Action taken: Study withdrawal
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Overview of Urelumab-related Adverse Events by study phase (number of patients within each group).

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    End point title
    		 Overview of Urelumab-related Adverse Events by study phase (number of patients within each group).
    End point description
    Counts the number of patients with Urelumab-related Adverse Events. Important note. Drug-related AEs are considered when relation with Urelumab is likely or related.
    End point type
    Secondary
    End point timeframe
    Adverse events were assessed continuously during the study and for a minimum of 100 days following the last dose of study treatment.
    End point values
    		 Phase I: Urelumab 1 mg + Nivolumab Phase II: Urelumab 8 mg + Nivolumab Phase II: Cohort A Phase II: Cohort B
    Number of subjects analysed
    3
    28
    20
    8
    Units: number of patients
        Grade: Mild
    0
    3
    1
    2
        Grade: Moderate
    0
    2
    1
    1
        Grade: Severe
    0
    0
    0
    0
        Grade: Life threatening or disabling
    0
    0
    0
    0
        Grade: Death related to the AE
    0
    0
    0
    0
        Progression: Death
    0
    0
    0
    0
        Progression: Persistence of the AE
    0
    1
    0
    1
        Progression: Recovery with consequences
    0
    1
    1
    0
        Progression: Recovery without consequences
    0
    3
    1
    2
        Action taken: None
    0
    3
    1
    2
        Action taken: Dose reduction of drug
    0
    0
    0
    0
        Action taken: Dose increase of drug
    0
    0
    0
    0
        Action taken: Temporary disruption of drug
    0
    1
    1
    0
        Action taken: Permanent disruption of drug
    0
    0
    0
    0
        Action taken: Study withdrawal
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Overview of Nivolumab-related Adverse Events by study phase (number of events within each group).

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    End point title
    		 Overview of Nivolumab-related Adverse Events by study phase (number of events within each group).
    End point description
    Summarizes the results related to the number of Nivolumab-related Adverse Events Important note. Drug-related AEs are considered when relation with Nivolumab is likely or related.
    End point type
    Secondary
    End point timeframe
    Adverse events were assessed continuously during the study and for a minimum of 100 days following the last dose of study treatment.
    End point values
    		 Phase I: Urelumab 1 mg + Nivolumab Phase II: Urelumab 8 mg + Nivolumab Phase II: Cohort A Phase II: Cohort B
    Number of subjects analysed
    3
    28
    20
    8
    Units: number of events
        Grade: Mild
    0
    3
    0
    3
        Grade: Moderate
    0
    2
    1
    1
        Grade: Severe
    0
    0
    0
    0
        Grade: Life threatening or disabling
    0
    0
    0
    0
        Grade: Death related to the AE
    0
    0
    0
    0
        Progression: Death
    0
    0
    0
    0
        Progression: Persistence of the AE
    0
    3
    0
    3
        Progression: Recovery with consequences
    0
    1
    1
    0
        Progression: Recovery without consequences
    0
    1
    0
    1
        Action taken: None
    0
    4
    0
    4
        Action taken: Dose reduction of drug
    0
    0
    0
    0
        Action taken: Dose increase of drug
    0
    0
    0
    0
        Action taken: Temporary disruption of drug
    0
    1
    1
    0
        Action taken: Permanent disruption of drug
    0
    0
    0
    0
        Action taken: Study withdrawal
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Overview of Nivolumab-related Adverse Events by study phase (number of patients within each group).

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    End point title
    		 Overview of Nivolumab-related Adverse Events by study phase (number of patients within each group).
    End point description
    Number of patients with Nivolumab-related Adverse Events. Important note. Drug-related AEs are considered when relation with Nivolumab is likely or related.
    End point type
    Secondary
    End point timeframe
    Adverse events were assessed continuously during the study and for a minimum of 100 days following the last dose of study treatment.
    End point values
    		 Phase I: Urelumab 1 mg + Nivolumab Phase II: Urelumab 8 mg + Nivolumab Phase II: Cohort A Phase II: Cohort B
    Number of subjects analysed
    3
    28
    20
    8
    Units: number of patients
        Grade: Mild
    0
    2
    0
    2
        Grade: Moderate
    0
    2
    1
    1
        Grade: Severe
    0
    0
    0
    0
        Grade: Life threatening or disabling
    0
    0
    0
    0
        Grade: Death related to the AE
    0
    0
    0
    0
        Progression: Death
    0
    0
    0
    0
        Progression: Persistence of the AE
    0
    1
    0
    1
        Progression: Recovery with consequences
    0
    1
    1
    0
        Progression: Recovery without consequences
    0
    1
    0
    1
        Action taken: None
    0
    2
    0
    2
        Action taken: Dose reduction of drug
    0
    0
    0
    0
        Action taken: Dose increase of drug
    0
    0
    0
    0
        Action taken: Temporary disruption of drug
    0
    1
    1
    0
        Action taken: Permanent disruption of drug
    0
    0
    0
    0
        Action taken: Study withdrawal
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: AEs by System Organ Class (SOC) and Preferred Term (PT) (number of patients)

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    End point title
    		 AEs by System Organ Class (SOC) and Preferred Term (PT) (number of patients) [6]
    End point description
    Non-Serious Adverse Events from phase I of the study considering the SOC code, the PT code of the AE.
    End point type
    Secondary
    End point timeframe
    Adverse events were assessed continuously during the study and for a minimum of 100 days following the last dose of study treatment.
    Notes
    [6] - 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: The endpoint reports statistics for both arms (phase I and phase II), but the adverse effect results reported in the second arm are presented only by cohort.
    End point values
    		 Phase I: Urelumab 1 mg + Nivolumab Phase II: Cohort A Phase II: Cohort B
    Number of subjects analysed
    3
    20
    8
    Units: number of patients
        Blood and lymphatic system disorders: Anaemia
    2
    4
    2
        Blood and lymphatic system disorders: Leukocytosis
    0
    1
    1
        Blood and lymphatic system disorders: Neutrophilia
    0
    1
    2
        Blood and lymphatic SD: Thrombocytopenia
    0
    2
    0
        Cardiac disorders: Atrial flutter
    0
    2
    0
        Cardiac disorders: Pericardial effusion
    0
    1
    0
        Cardiac disorders: Tachycardia
    1
    2
    3
        Congenital/genetic disorders: Keratosis follicular
    0
    1
    0
        Endocrine disorders: Adrenal insufficiency
    0
    2
    1
        Endocrine disorders: Hypothyroidism
    0
    3
    2
        Gastrointestinal disorders: Abnormal faeces
    0
    0
    1
        Gastrointestinal disorders: Abdominal distension
    0
    1
    0
        Gastrointestinal disorders: Abdominal pain
    1
    4
    0
        Gastrointestinal disorders: Abdominal pain upper
    0
    1
    0
        Gastrointestinal disorders: Ascites
    0
    1
    0
        Gastrointestinal disorders: Constipation
    0
    8
    2
        Gastrointestinal disorders: Diarrhoea
    1
    4
    2
        Gastrointestinal disorders: Flatulence
    0
    1
    0
        Gastrointestinal disorders: Gastritis
    0
    1
    0
        Gastrointestinal disorders: Gastrointestinal pain
    1
    2
    0
        Gastrointestinal: Gastrooesophageal reflux disease
    0
    1
    0
        Gastrointestinal disorders: Nausea
    0
    4
    0
        Gastrointestinal disorders: Pancreatitis
    0
    1
    0
        Gastrointestinal disorders: Rectal haemorrhage
    0
    1
    0
        Gastrointestinal disorders: Vomiting
    0
    3
    2
        General disorders: Application site pain
    0
    1
    0
        General disorders: Asthenia
    0
    2
    0
        General disorders: Chest pain
    0
    1
    1
        General disorders: Condition aggravated
    1
    0
    0
        General disorders: Fatigue
    2
    13
    2
        General disorders: Malaise
    0
    1
    0
        General disorders: Mucosal inflammation
    0
    1
    0
        General disorders: Oedema
    1
    1
    1
        General disorders: Pain
    0
    1
    0
        General disorders: Pyrexia
    0
    5
    4
        General disorders: Sense of oppression
    1
    0
    0
        General disorders: Suprapubic pain
    0
    1
    0
        Infections and infestations: Adenoviral infection
    0
    2
    0
        Infections and infestations: Cellulitis
    0
    0
    1
        Infections and infestations: Infection
    0
    1
    0
        Infections and infestations: Nasopharyngitis
    0
    1
    0
        Infections and infestations: Pneumonia
    0
    1
    0
        Infections and infestations: Skin infection
    0
    0
    1
        Injury: Craniocerebral injury
    0
    1
    0
        Injury: Contusion
    0
    0
    1
        Injury: Injury
    0
    1
    0
        Injury: Thermal burn
    0
    1
    0
        Injury: Upper limb fracture
    0
    1
    0
        Investigations: Adjusted calcium increased
    0
    1
    1
        Investigations: ALT increased
    1
    3
    1
        Investigations: Amylase increased
    0
    1
    0
        Investigations: Asp-aminotransferase increased
    1
    3
    2
        Investigations: Bleeding time
    0
    0
    1
        Investigation: Blood alkalinephosphatase increased
    0
    1
    0
        Investigations: Blood bilirubin increased
    0
    0
    1
        Investigations: Blood creatinine increased
    0
    2
    0
        Investigations: Blood glucose increased
    0
    2
    0
        Investigations: Blood LDH increased
    0
    1
    0
        Investigations: Blood magnesium decreased
    0
    2
    0
        Investigations: Blood TSH decreased
    1
    0
    0
        Investigations: Lipase increased
    0
    1
    0
        Investigations: Transaminases increased
    0
    1
    0
        Investigations: Weight decreased
    0
    1
    1
        Metabolism/nutrition disorders: Cachexia
    0
    1
    0
        Metabolism/nutrition disorders: Decreased appetite
    0
    7
    2
        Metabolism/nutrition disorders: Hyponatraemia
    0
    1
    0
        Musculoskeletal disorders: Back pain
    0
    1
    1
        Musculoskeletal disorders: Flank pain
    2
    1
    0
        Musculoskeletal disorders: Groin pain
    0
    0
    2
        Musculoskeletal disorders: joint pain
    0
    1
    0
        Musculoskeletal disorders: (M) chest pain
    0
    1
    0
        Musculoskeletal disorders: Musculoskeletal pain
    0
    2
    0
        Musculoskeletal disorders: Myalgia
    0
    1
    0
        Musculoskeletal disorders: Neck pain
    0
    2
    1
        Musculoskeletal disorders: Pain in extremity
    0
    0
    1
        Musculoskeletal disorders: TMJ syndrome
    1
    0
    0
        Neoplasms: Cancer pain
    0
    1
    0
        Nervous system disorders: Dizziness
    0
    2
    1
        Nervous system disorders: Headache
    0
    1
    0
        Nervous system disorders: Hepatic encephalopathy
    0
    1
    0
        Nervous system disorders: Myoclonus
    0
    1
    0
        Nervous system disorders: Neuralgia
    0
    1
    0
        Nervous system disorders: Paraesthesia
    0
    1
    0
        Nervous system: Peripheral sensory neuropathy
    0
    1
    0
        Nervous system disorders: Seizure
    0
    1
    0
        Nervous system disorders: Somnolence
    0
    2
    0
        Nervous system disorders: Syncope
    0
    2
    0
        Psychiatric disorders: Affect lability
    0
    1
    0
        Psychiatric disorders: Anxiety
    0
    1
    0
        Psychiatric disorders: Confusional state
    0
    0
    1
        Psychiatric disorders: Depressed mood
    0
    1
    0
        Psychiatric disorders: Depression
    0
    5
    0
        Psychiatric disorders: Insomnia
    0
    1
    0
        Psychiatric disorders: Nervousness
    0
    1
    0
        Psychiatric : Persistent depressive disorder
    0
    1
    0
        Renal and urinary disorders: Nocturia
    0
    1
    0
        Renal and urinary disorders: Oliguria
    0
    0
    1
        Renal and urinary disorders: Polaquyuria
    0
    1
    0
        Renal and urinary disorders: Urinary retention
    0
    1
    0
        Reproductive system: Genital dysaesthesia
    0
    1
    0
        Reproductive system: Vaginal haemorrhage
    0
    0
    1
        Respiratory/thoracic disorders: Cough
    0
    2
    0
        Respiratory/thoracic disorders: Dyspnoea
    0
    1
    0
        Respiratory/thoracic disorders: Haemoptysis
    0
    2
    0
        Respiratory/thoracic disorders: Pneumonia
    0
    1
    0
        Respiratory/thoracic disorders: Productive cough
    0
    1
    0
        Respiratory/thoracic disorders: Sputum retention
    0
    2
    0
        Skin disorders: Cold sweat
    0
    0
    1
        Skin disorders: Dermatitis allergic
    0
    1
    0
        Skin disorders: Dermatitis contact
    0
    0
    1
        Skin disorders: Pruritus
    0
    0
    1
        Skin disorders: Psoriasis
    0
    1
    0
        Skin disorders: Skin lesion
    0
    1
    0
        Skin disorders: Wound
    0
    1
    0
        Vascular disorders: Bleeding
    0
    0
    1
        Vascular disorders: Hypertension
    0
    3
    0
        Vascular disorders: Hypotension
    0
    2
    0
        Vascular disorders: Orthostatic hypotension
    1
    0
    0
        Vascular disorders: Superior vena cava syndrome
    1
    0
    0
        Vascular disorders: Thrombosis
    1
    0
    0
    No statistical analyses for this end point

    Secondary: AEs by System Organ Class (SOC) and Preferred Term (PT) (number of events)

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    End point title
    		 AEs by System Organ Class (SOC) and Preferred Term (PT) (number of events) [7]
    End point description
    Non-Serious Adverse Events from phase I of the study considering the SOC code, the PT code of the AE
    End point type
    Secondary
    End point timeframe
    During trial and 100 follow up
    Notes
    [7] - 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: The endpoint reports statistics for both arms (phase I and phase II), but the adverse effect results reported in the second arm are presented only by cohort.
    End point values
    		 Phase I: Urelumab 1 mg + Nivolumab Phase II: Cohort A Phase II: Cohort B
    Number of subjects analysed
    3
    20
    8
    Units: Number of events
        Blood and lymphatic system disorders: Anaemia
    5
    6
    2
        Blood and lymphatic system disorders: Leukocytosis
    0
    1
    1
        Blood and lymphatic system disorders: Neutrophilia
    0
    1
    2
        Blood and lymphatic SD: Thrombocytopenia
    0
    3
    0
        Cardiac disorders: Atrial flutter
    0
    2
    0
        Cardiac disorders: Pericardial effusion
    0
    1
    0
        Cardiac disorders: Tachycardia
    1
    5
    4
        Congenital/genetic disorders: Keratosis follicular
    0
    1
    0
        Endocrine disorders: Adrenal insufficiency
    0
    4
    1
        Endocrine disorders: Hypothyroidism
    0
    5
    2
        Gastrointestinal disorders: Abnormal faeces
    0
    0
    1
        Gastrointestinal disorders: Abdominal distension
    0
    1
    0
        Gastrointestinal disorders: Abdominal pain
    1
    6
    0
        Gastrointestinal disorders: Abdominal pain upper
    0
    1
    0
        Gastrointestinal disorders: Ascites
    0
    1
    0
        Gastrointestinal disorders: Constipation
    0
    13
    2
        Gastrointestinal disorders: Diarrhoea
    1
    6
    3
        Gastrointestinal disorders: Flatulence
    0
    1
    0
        Gastrointestinal disorders: Gastritis
    0
    2
    0
        Gastrointestinal disorders: Gastrointestinal pain
    1
    2
    0
        Gastrointestinal: Gastrooesophageal reflux disease
    0
    1
    0
        Gastrointestinal disorders: Nausea
    0
    5
    0
        Gastrointestinal disorders: Pancreatitis
    0
    2
    0
        Gastrointestinal disorders: Rectal haemorrhage
    0
    1
    0
        Gastrointestinal disorders: Vomiting
    0
    7
    3
        General disorders: Application site pain
    0
    1
    0
        General disorders: Asthenia
    0
    2
    0
        General disorders: Chest pain
    0
    1
    2
        General disorders: Condition aggravated
    1
    0
    0
        General disorders: Fatigue
    5
    16
    2
        General disorders: Malaise
    0
    1
    0
        General disorders: Mucosal inflammation
    0
    1
    0
        General disorders: Oedema
    1
    1
    1
        General disorders: Pain
    0
    1
    0
        General disorders: Pyrexia
    0
    6
    7
        General disorders: Sense of oppression
    1
    0
    0
        General disorders: Suprapubic pain
    0
    1
    0
        Infections and infestations: Adenoviral infection
    0
    2
    0
        Infections and infestations: Cellulitis
    0
    0
    1
        Infections and infestations: Infection
    0
    2
    0
        Infections and infestations: Nasopharyngitis
    0
    1
    0
        Infections and infestations: Pneumonia
    0
    2
    0
        Infections and infestations: Skin infection
    0
    0
    1
        Injury: Craniocerebral injury
    0
    1
    0
        Injury: Contusion
    0
    0
    1
        Injury: Injury
    0
    1
    0
        Injury: Thermal burn
    0
    1
    0
        Injury: Upper limb fracture
    0
    1
    0
        Investigations: Adjusted calcium increased
    0
    1
    1
        Investigations: ALT increased
    1
    3
    1
        Investigations: Amylase increased
    0
    1
    0
        Investigations: Asp-aminotransferase increased
    1
    5
    2
        Investigations: Bleeding time
    0
    0
    1
        Investigation: Blood alkalinephosphatase increased
    0
    2
    0
        Investigations: Blood bilirubin increased
    0
    0
    1
        Investigations: Blood creatinine increased
    0
    2
    0
        Investigations: Blood glucose increased
    0
    2
    0
        Investigations: Blood LDH increased
    0
    1
    0
        Investigations: Blood magnesium decreased
    0
    2
    0
        Investigations: Blood TSH decreased
    1
    0
    0
        Investigations: Lipase increased
    0
    1
    0
        Investigations: Transaminases increased
    0
    1
    0
        Investigations: Weight decreased
    0
    1
    1
        Metabolism/nutrition disorders: Cachexia
    0
    1
    0
        Metabolism/nutrition disorders: Decreased appetite
    0
    8
    2
        Metabolism/nutrition disorders: Hyponatraemia
    0
    1
    0
        Musculoskeletal disorders: Back pain
    0
    2
    1
        Musculoskeletal disorders: Flank pain
    2
    1
    0
        Musculoskeletal disorders: Groin pain
    0
    0
    3
        Musculoskeletal disorders: joint pain
    0
    1
    0
        Musculoskeletal disorders: (M) chest pain
    0
    1
    0
        Musculoskeletal disorders: Musculoskeletal pain
    0
    2
    0
        Musculoskeletal disorders: Myalgia
    0
    1
    0
        Musculoskeletal disorders: Neck pain
    0
    2
    1
        Musculoskeletal disorders: Pain in extremity
    0
    0
    1
        Musculoskeletal disorders: TMJ syndrome
    1
    0
    0
        Neoplasms: Cancer pain
    0
    1
    0
        Nervous system disorders: Dizziness
    0
    2
    1
        Nervous system disorders: Headache
    0
    1
    0
        Nervous system disorders: Hepatic encephalopathy
    0
    1
    0
        Nervous system disorders: Myoclonus
    0
    1
    0
        Nervous system disorders: Neuralgia
    0
    1
    0
        Nervous system disorders: Paraesthesia
    0
    1
    0
        Nervous system: Peripheral sensory neuropathy
    0
    1
    0
        Nervous system disorders: Seizure
    0
    1
    0
        Nervous system disorders: Somnolence
    0
    2
    0
        Nervous system disorders: Syncope
    0
    2
    0
        Psychiatric disorders: Affect lability
    0
    1
    0
        Psychiatric disorders: Anxiety
    0
    1
    0
        Psychiatric disorders: Confusional state
    0
    0
    1
        Psychiatric disorders: Depressed mood
    0
    1
    0
        Psychiatric disorders: Depression
    0
    6
    0
        Psychiatric disorders: Insomnia
    0
    1
    0
        Psychiatric disorders: Nervousness
    0
    1
    0
        Psychiatric : Persistent depressive disorder
    0
    1
    0
        Renal and urinary disorders: Nocturia
    0
    1
    0
        Renal and urinary disorders: Oliguria
    0
    0
    1
        Renal and urinary disorders: Polaquyuria
    0
    1
    0
        Renal and urinary disorders: Urinary retention
    0
    1
    0
        Reproductive system: Genital dysaesthesia
    0
    1
    0
        Reproductive system: Vaginal haemorrhage
    0
    0
    1
        Respiratory/thoracic disorders: Cough
    0
    2
    0
        Respiratory/thoracic disorders: Dyspnoea
    0
    1
    0
        Respiratory/thoracic disorders: Haemoptysis
    0
    4
    0
        Respiratory/thoracic disorders: Pneumonia
    0
    1
    0
        Respiratory/thoracic disorders: Productive cough
    0
    1
    0
        Respiratory/thoracic disorders: Sputum retention
    0
    3
    0
        Skin disorders: Cold sweat
    0
    0
    1
        Skin disorders: Dermatitis allergic
    0
    1
    0
        Skin disorders: Dermatitis contact
    0
    0
    1
        Skin disorders: Pruritus
    0
    0
    1
        Skin disorders: Psoriasis
    0
    1
    0
        Skin disorders: Skin lesion
    0
    1
    0
        Skin disorders: Wound
    0
    1
    0
        Vascular disorders: Bleeding
    0
    0
    1
        Vascular disorders: Hypertension
    0
    7
    0
        Vascular disorders: Hypotension
    0
    2
    0
        Vascular disorders: Orthostatic hypotension
    1
    0
    0
        Vascular disorders: Superior vena cava syndrome
    1
    0
    0
        Vascular disorders: Thrombosis
    1
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Urelumab-related AES by study phase and cohort (Number of patients)

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    End point title
    		 Number of Urelumab-related AES by study phase and cohort (Number of patients)
    End point description
    List of AEs likely or related to Urelumab
    End point type
    Secondary
    End point timeframe
    Adverse events were assessed continuously during the study and for a minimum of 100 days following the last dose of study treatment.
    End point values
    		 Phase I: Urelumab 1 mg + Nivolumab Phase II: Urelumab 8 mg + Nivolumab Phase II: Cohort A Phase II: Cohort B
    Number of subjects analysed
    3
    28
    20
    8
    Units: number of patients
        Gastrointestinal disorders: Nausea
    0
    1
    1
    0
        Gastrointestinal disorders: Diarrhoea
    0
    1
    0
    1
        General disorders: Pyrexia
    0
    1
    0
    1
        Investigations: ALT increased
    0
    1
    0
    1
        Investigations: Asp-aminotransferase increased
    0
    1
    0
    1
        Investigations: Blood bilirubin increased
    0
    1
    0
    1
    No statistical analyses for this end point

    Secondary: Number of Urelumab-related AES by study phase and cohort (number of AEs)

    		 Close Top of page
    End point title
    		 Number of Urelumab-related AES by study phase and cohort (number of AEs)
    End point description
    List of AEs likely or related to Urelumab
    End point type
    Secondary
    End point timeframe
    Adverse events were assessed continuously during the study and for a minimum of 100 days following the last dose of study treatment.
    End point values
    		 Phase I: Urelumab 1 mg + Nivolumab Phase II: Urelumab 8 mg + Nivolumab Phase II: Cohort A Phase II: Cohort B
    Number of subjects analysed
    3
    28
    20
    8
    Units: Number of AEs
        Gastrointestinal disorders: Nausea
    0
    1
    1
    0
        Gastrointestinal disorders: Diarrhoea
    0
    1
    0
    1
        General disorders: Pyrexia
    0
    1
    0
    1
        Investigations: ALT increased
    0
    1
    0
    1
        Investigations: Asp-aminotransferase increased
    0
    1
    0
    1
        Investigations: Blood bilirubin increased
    0
    1
    0
    1
    No statistical analyses for this end point

    Secondary: Number of Nivolumab-related AES by study phase and cohort (number of patients)

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    End point title
    		 Number of Nivolumab-related AES by study phase and cohort (number of patients)
    End point description
    List of AEs by phase of the study likely or related to Nivolumab
    End point type
    Secondary
    End point timeframe
    Adverse events were assessed continuously during the study and for a minimum of 100 days following the last dose of study treatment.
    End point values
    		 Phase I: Urelumab 1 mg + Nivolumab Phase II: Urelumab 8 mg + Nivolumab Phase II: Cohort A Phase II: Cohort B
    Number of subjects analysed
    3
    28
    20
    8
    Units: Number of patients
        General disorders: Pyrexia
    0
    1
    0
    1
        Investigations: ALT increased
    0
    1
    0
    1
        Investigations: asp-aminotransferase increased
    0
    1
    0
    1
        Investigations: Blood bilirubin increased
    0
    1
    0
    1
    No statistical analyses for this end point

    Secondary: Number of Nivolumab-related AES by study phase and cohort (Number of AEs)

    		 Close Top of page
    End point title
    		 Number of Nivolumab-related AES by study phase and cohort (Number of AEs)
    End point description
    List of AEs by phase of the study likely or related to Nivolumab
    End point type
    Secondary
    End point timeframe
    Adverse events were assessed continuously during the study and for a minimum of 100 days following the last dose of study treatment.
    End point values
    		 Phase I: Urelumab 1 mg + Nivolumab Phase II: Urelumab 8 mg + Nivolumab Phase II: Cohort A Phase II: Cohort B
    Number of subjects analysed
    3
    28
    20
    8
    Units: Number of AEs
        General disorders: Pyrexia
    0
    1
    0
    1
        Investigations: ALT increased
    0
    1
    0
    1
        Investigations: asp-aminotransferase increased
    0
    1
    0
    1
        Investigations: Blood bilirubin increased
    0
    1
    0
    1
    No statistical analyses for this end point

    Secondary: SAES by study phase and cohort (number of patients)

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    End point title
    		 SAES by study phase and cohort (number of patients)
    End point description
    There were no SAEs in phase I of the study. List of SAEs from phase II by cohort
    End point type
    Secondary
    End point timeframe
    Adverse events were assessed continuously during the study and for a minimum of 100 days following the last dose of study treatment.
    End point values
    		 Phase I: Urelumab 1 mg + Nivolumab Phase II: Urelumab 8 mg + Nivolumab Phase II: Cohort A Phase II: Cohort B
    Number of subjects analysed
    3
    28
    20
    8
    Units: number of patients
        Blood and lymphatic SD: Thrombocytopenia
    0
    1
    0
    1
        Cardiac disorders: Pericardial effusion
    0
    1
    1
    0
        Gastrointestinal disorders: Abdominal infection
    0
    1
    1
    0
        Gastrointestinal disorders: Constipation
    0
    1
    1
    0
        General disorders: Condition aggravated
    0
    1
    1
    0
        General disorders: Disease progression
    0
    4
    3
    1
        General disorders: Pain
    0
    1
    1
    0
        General disorders: Pyrexia
    0
    1
    1
    0
        Infections and infestations: Infection
    0
    2
    2
    0
        Infections and infestations: Pneumonia
    0
    4
    4
    0
        Injury: Biliary anastomosis complication
    0
    1
    1
    0
        Injury: Tracheal obstruction
    0
    1
    1
    0
        Investigations: Transaminases increased
    0
    2
    1
    1
        Nervous system disorders: Clumsiness
    0
    1
    1
    0
        Renal and urinary disorders: Renal failure
    0
    1
    1
    0
        Renal and urinary disorders: Acute kidney injury
    0
    1
    0
    1
        Respiratory, thoracic disorders: Laryngeal oedema
    0
    1
    1
    0
        Skin disorders: Rash maculo-papular
    0
    1
    1
    0
    No statistical analyses for this end point

    Secondary: SAES by study phase and cohort (number of SAEs)

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    End point title
    		 SAES by study phase and cohort (number of SAEs)
    End point description
    There were no SAEs in phase I of the study. List of SAEs from phase II by cohort
    End point type
    Secondary
    End point timeframe
    Adverse events were assessed continuously during the study and for a minimum of 100 days following the last dose of study treatment.
    End point values
    		 Phase I: Urelumab 1 mg + Nivolumab Phase II: Urelumab 8 mg + Nivolumab Phase II: Cohort A Phase II: Cohort B
    Number of subjects analysed
    3
    28
    20
    8
    Units: Number of SAEs
        Blood and lymphatic SD: Thrombocytopenia
    0
    1
    0
    1
        Cardiac disorders: Pericardial effusion
    0
    1
    1
    0
        Gastrointestinal disorders: Abdominal infection
    0
    1
    1
    0
        Gastrointestinal disorders: Constipation
    0
    1
    1
    0
        General disorders: Condition aggravated
    0
    1
    1
    0
        General disorders: Disease progression
    0
    4
    3
    1
        General disorders: Pain
    0
    1
    1
    0
        General disorders: Pyrexia
    0
    1
    1
    0
        Infections and infestations: Infection
    0
    2
    2
    0
        Infections and infestations: Pneumonia
    0
    3
    3
    0
        Injury: Biliary anastomosis complication
    0
    1
    1
    0
        Injury: Tracheal obstruction
    0
    1
    1
    0
        Investigations: Transaminases increased
    0
    2
    1
    1
        Nervous system disorders: Clumsiness
    0
    1
    1
    0
        Renal and urinary disorders: Renal failure
    0
    1
    1
    0
        Renal and urinary disorders: Acute kidney injury
    0
    1
    0
    1
        Respiratory, thoracic disorders: Laryngeal oedema
    0
    1
    1
    0
        Skin disorders: Rash maculo-papular
    0
    1
    1
    0
    No statistical analyses for this end point

    Secondary: Urelumab-related SAEs from Phase II by cohort (number of patients)

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    End point title
    		 Urelumab-related SAEs from Phase II by cohort (number of patients)
    End point description
    There were no SAEs in phase I of the study. List of SAEs from phase II by cohort that were likely or related to Urelumab.
    End point type
    Secondary
    End point timeframe
    Adverse events were assessed continuously during the study and for a minimum of 100 days following the last dose of study treatment.
    End point values
    		 Phase I: Urelumab 1 mg + Nivolumab Phase II: Urelumab 8 mg + Nivolumab Phase II: Cohort A Phase II: Cohort B
    Number of subjects analysed
    3
    28
    20
    8
    Units: number of patients
        Investigations: Transaminases increased
    0
    1
    1
    0
    No statistical analyses for this end point

    Secondary: Urelumab-related SAEs from Phase II by cohort (number of SAEs)

    		 Close Top of page
    End point title
    		 Urelumab-related SAEs from Phase II by cohort (number of SAEs)
    End point description
    There were no SAEs in phase I of the study. List of SAEs from phase II by cohort that were likely or related to Urelumab.
    End point type
    Secondary
    End point timeframe
    Adverse events were assessed continuously during the study and for a minimum of 100 days following the last dose of study treatment.
    End point values
    		 Phase I: Urelumab 1 mg + Nivolumab Phase II: Urelumab 8 mg + Nivolumab Phase II: Cohort A Phase II: Cohort B
    Number of subjects analysed
    3
    28
    20
    8
    Units: Number of SAEs
        Investigations: Transaminases increased
    0
    1
    1
    0
    No statistical analyses for this end point

    Secondary: Nivolumab-related SAEs from Phase II by cohort (number of patients)

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    End point title
    		 Nivolumab-related SAEs from Phase II by cohort (number of patients)
    End point description
    SAEs from phase II by cohort that were likely or related to Nivolumab
    End point type
    Secondary
    End point timeframe
    Adverse events were assessed continuously during the study and for a minimum of 100 days following the last dose of study treatment.
    End point values
    		 Phase I: Urelumab 1 mg + Nivolumab Phase II: Urelumab 8 mg + Nivolumab Phase II: Cohort A Phase II: Cohort B
    Number of subjects analysed
    3
    28
    20
    8
    Units: number of patients
        Investigations: Transaminases increased
    0
    1
    1
    0
    No statistical analyses for this end point

    Secondary: Nivolumab-related SAEs from Phase II by cohort (number of SAEs)

    		 Close Top of page
    End point title
    		 Nivolumab-related SAEs from Phase II by cohort (number of SAEs)
    End point description
    SAEs from phase II by cohort that were likely or related to Nivolumab
    End point type
    Secondary
    End point timeframe
    Adverse events were assessed continuously during the study and for a minimum of 100 days following the last dose of study treatment.
    End point values
    		 Phase I: Urelumab 1 mg + Nivolumab Phase II: Urelumab 8 mg + Nivolumab Phase II: Cohort A Phase II: Cohort B
    Number of subjects analysed
    3
    28
    20
    8
    Units: Number of SAEs
        Investigations: Transaminases increased
    0
    1
    1
    0
    No statistical analyses for this end point

    Secondary: AES leading to a temporary or permanent discontinuation of study therapy by organ class (SOC) and Preferred Term (PT) (number of patients)

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    End point title
    		 AES leading to a temporary or permanent discontinuation of study therapy by organ class (SOC) and Preferred Term (PT) (number of patients)
    End point description
    List of Adverse Events that lead to a temporary or permanent discontinuation of the study therapy by study phase and cohort.
    End point type
    Secondary
    End point timeframe
    During the clinical trial
    End point values
    		 Phase I: Urelumab 1 mg + Nivolumab Phase II: Urelumab 8 mg + Nivolumab Phase II: Cohort A Phase II: Cohort B
    Number of subjects analysed
    3
    28
    20
    8
    Units: number of patients
        Blood and lymphatic SD: Thrombocytopenia
    0
    2
    1
    1
        General disorders: Disease progression
    0
    1
    1
    0
        General disorders: Oedema
    0
    1
    1
    0
        General disorders: Pyrexia
    0
    1
    1
    0
        Infections and infestations: Infection
    0
    1
    1
    0
        Infections and infestations: Pneumonia
    0
    2
    2
    0
        Infections and infestations: Cellulitis
    0
    1
    0
    1
        Injury: Biliary anastomosis complication
    0
    1
    1
    0
        Injury: Craniocerebral injury
    0
    1
    1
    0
        Injury: Tracheal obstruction
    0
    1
    1
    0
        Investigations: Bleeding time
    0
    1
    0
    1
        Investigations: Transaminases increased
    0
    2
    1
    1
        Respiratory, thoracic disorders: Pneumonia
    0
    1
    1
    0
    No statistical analyses for this end point

    Secondary: AES leading to a temporary or permanent discontinuation of study therapy by organ class (SOC) and Preferred Term (PT) (number of AEs)

    		 Close Top of page
    End point title
    		 AES leading to a temporary or permanent discontinuation of study therapy by organ class (SOC) and Preferred Term (PT) (number of AEs)
    End point description
    List of Adverse Events that lead to a temporary or permanent discontinuation of the study therapy by study phase and cohort.
    End point type
    Secondary
    End point timeframe
    During the clinical trial
    End point values
    		 Phase I: Urelumab 1 mg + Nivolumab Phase II: Urelumab 8 mg + Nivolumab Phase II: Cohort A Phase II: Cohort B
    Number of subjects analysed
    3
    28
    20
    8
    Units: Number of AEs
        Blood and lymphatic SD: Thrombocytopenia
    0
    2
    1
    1
        General disorders: Disease progression
    0
    1
    1
    0
        General disorders: Oedema
    0
    1
    1
    0
        General disorders: Pyrexia
    0
    1
    1
    0
        Infections and infestations: Infection
    0
    1
    1
    0
        Infections and infestations: Pneumonia
    0
    2
    2
    0
        Infections and infestations: Cellulitis
    0
    1
    0
    1
        Injury: Biliary anastomosis complication
    0
    1
    1
    0
        Injury: Craniocerebral injury
    0
    1
    1
    0
        Injury: Tracheal obstruction
    0
    1
    1
    0
        Investigations: Bleeding time
    0
    1
    0
    1
        Investigations: Transaminases increased
    0
    2
    1
    1
        Respiratory, thoracic disorders: Pneumonia
    0
    1
    1
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Regarding safety assessments, adverse events were assessed continuously during the study and for a minimum of 100 days following the last dose of study treatment.
    Adverse event reporting additional description
    Evaluated according to the National Cancer Institute (NCI) Common Terminology Criter.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Phase I
    Reporting group description
    		 Urelumab 1 mg (Cycle 1, Cycle 3) + Nivolumab 240mg (Cycle 2), 480 mg (Cycle 4)

    Reporting group title
    Phase II Cohort A
    Reporting group description
    		 Cohort A recruited anti PD1/PDL1 naïve patients presenting tumor types sensitive to PD1/PDL1 blockade.

    Reporting group title
    Phase II: Cohort B
    Reporting group description
    		 cohort B included patients with tumors that have progressed on previous PD1/ PDL1 blockade

    Serious adverse events
    		 Phase I Phase II Cohort A Phase II: Cohort B
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 3 (0.00%)
    11 / 20 (55.00%)
    3 / 8 (37.50%)
         number of deaths (all causes)
    0
    7
    1
         number of deaths resulting from adverse events
    0
    5
    1
    Investigations
    Transaminases increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Biliary anastomosis complication
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    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
    Tracheal obtruction
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    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
    Cardiac disorders
    Pericardial effusion
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    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
    Nervous system disorders
    Clumsiness
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    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
    General disorders and administration site conditions
    Condition aggravated
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    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
    Disease progression
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 20 (15.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
    Pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    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
    Pyrexia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    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
    Pneumonia
         subjects affected / exposed
    0 / 3 (0.00%)
    4 / 20 (20.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 20 (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
    Gastrointestinal disorders
    Abdominal infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    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
    Constipation
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    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
    Respiratory, thoracic and mediastinal disorders
    Laryngeal oedema
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    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
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    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
    Acute kidney injury
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 20 (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
    Renal failure
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    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
    Infection
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 20 (10.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Phase I Phase II Cohort A Phase II: Cohort B
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    20 / 20 (100.00%)
    7 / 8 (87.50%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Vascular disorders
    Orthostatic hypotension
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Superior vena cava syndrome
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Thrombosis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Hypertension
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 20 (15.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    7
    0
    Hypotension
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 20 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    Bleeding
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 20 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Condition aggravated
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Fatigue
         subjects affected / exposed
    2 / 3 (66.67%)
    13 / 20 (65.00%)
    2 / 8 (25.00%)
         occurrences all number
    5
    16
    2
    Oedema
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 20 (5.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    1
    1
    Sense of oppression
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Application site pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Asthenia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 20 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    Chest pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    2
    Malaise
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Mucosal inflammation
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Pyrexia
         subjects affected / exposed
    0 / 3 (0.00%)
    5 / 20 (25.00%)
    4 / 8 (50.00%)
         occurrences all number
    0
    6
    7
    Suprapubic pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Reproductive system and breast disorders
    Genital dysaesthesia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 20 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 20 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    Dyspnoea
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Haemoptysis
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 20 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    4
    0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Productive cough
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Sputum retention
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 20 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    3
    0
    Psychiatric disorders
    Affect lability
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Anxiety
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Depressed mood
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Depression
         subjects affected / exposed
    0 / 3 (0.00%)
    5 / 20 (25.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    6
    0
    Insomnia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Nervousness
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Persistent depressive disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Confusional state
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 20 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Investigations
    ALT increased
         subjects affected / exposed
    1 / 3 (33.33%)
    3 / 20 (15.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    3
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 3 (33.33%)
    3 / 20 (15.00%)
    2 / 8 (25.00%)
         occurrences all number
    1
    5
    2
    Blood thyroid stimulating hormone decreased
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Adjusted calcium decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    1
    Amylase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 20 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    Blood glucose increased
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 20 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Blood magnesium decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 20 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    Lipase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Transaminases increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Weight decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    1
    Bleeding time
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 20 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Blood bilirubin increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 20 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Injury, poisoning and procedural complications
    Craniocerebral injury
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Injury
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Thermal burn
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Upper limb fracture
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Contusion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 20 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Congenital, familial and genetic disorders
    Keratosis follicular
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 20 (10.00%)
    3 / 8 (37.50%)
         occurrences all number
    1
    5
    4
    Artrial flutter
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 20 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    Pericardial effusion
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 20 (10.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    2
    1
    Headache
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Hepatic encephalopathy
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Myoclonus
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Neuralgia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Paraesthesia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Seizure
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Somnolence
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 20 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    Syncope
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 20 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 3 (66.67%)
    4 / 20 (20.00%)
    2 / 8 (25.00%)
         occurrences all number
    5
    6
    2
    Leukocytosis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    1
    Neutrophilia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    2 / 8 (25.00%)
         occurrences all number
    0
    1
    2
    Thrombocytopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 20 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    3
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 3 (33.33%)
    4 / 20 (20.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    6
    0
    Diarrhoea
         subjects affected / exposed
    1 / 3 (33.33%)
    4 / 20 (20.00%)
    2 / 8 (25.00%)
         occurrences all number
    1
    6
    3
    Gastrointestinal pain
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 20 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    2
    0
    Abdominal distension
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Ascites
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Constipation
         subjects affected / exposed
    0 / 3 (0.00%)
    8 / 20 (40.00%)
    2 / 8 (25.00%)
         occurrences all number
    0
    13
    2
    Flatulence
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Gastritis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Nausea
         subjects affected / exposed
    0 / 3 (0.00%)
    4 / 20 (20.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    5
    0
    Pancreatitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Vomiting
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 20 (15.00%)
    2 / 8 (25.00%)
         occurrences all number
    0
    7
    3
    Abnormal faeces
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 20 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Psoriasis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Skin lesion
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Wound
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Cold sweat
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 20 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Dermatitis contact
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 20 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Pruritus
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 20 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Renal and urinary disorders
    Nocturia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Polaquyuria
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Urinary retention
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Oliguria
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 20 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 20 (10.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    4
    1
    Hypothyroidism
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 20 (15.00%)
    2 / 8 (25.00%)
         occurrences all number
    0
    5
    2
    Musculoskeletal and connective tissue disorders
    Flank pain
         subjects affected / exposed
    2 / 3 (66.67%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    1
    0
    Temporomandibular joint syndrome
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Back pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    2
    1
    Joint pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 20 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    Myalgia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Neck pain
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 20 (10.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    2
    1
    Groin pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 20 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    0
    0
    3
    Pain in extremity
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 20 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Infections and infestations
    Adenoviral upper respiratory infection
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 20 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    Infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Pneumonia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    Cellulitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 20 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Skin infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 20 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Decreased appetite
         subjects affected / exposed
    0 / 3 (0.00%)
    7 / 20 (35.00%)
    2 / 8 (25.00%)
         occurrences all number
    0
    8
    2
    Hyponatraemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Nov 2018
    Versión 2.0 Changes in the inclusion criteria Changes in the criteria for permanent treatment discontinuation due to toxicity

    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.
    Among the limitations of the study, the small sample size of this type of phase I/II study is the main one. The inferential analyses could not be done because available sample size was too small, especially in Phase I.
    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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