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    Clinical Trial Results:
    A Phase 1/2, Open-Label, Multi-Arm Trial to Investigate the Safety, Tolerability, Pharmacokinetics, Biological, and Clinical Activity of AGEN1884 in Combination with AGEN2034 in Subjects with Metastatic or Locally Advanced Solid Tumors, and Expansion into Select Solid Tumors

    Summary
    EudraCT number
    		 2018-000120-33
    Trial protocol
    		 HU   PL   ES  
    Global end of trial date
    15 Jul 2022

    Results information
    Results version number
    		 v2(current)
    This version publication date
    10 May 2024
    First version publication date
    29 Jul 2023
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    Addition of Phase 1 data.

    Trial information

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    Trial identification
    Sponsor protocol code
    C-550-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03495882
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Agenus, Inc.
    Sponsor organisation address
    3 Forbes Road, Lexington, MA, United States, 02421
    Public contact
    Agenus, Inc. Clinical Trial Information, Agenus, Inc., 1 781-674-4265, clinicaltrialinfo@agenusbio.com
    Scientific contact
    Agenus, Inc. Clinical Trial Information, Agenus, Inc., 1 781-674-4265, clinicaltrialinfo@agenusbio.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    15 Jul 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Jul 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of Phase 1 of this study was to assess safety and tolerability of zalifrelimab (AGEN1884) in combination with balstilimab (AGEN2034) in participants with locally advanced, recurrent and/or metastatic solid tumors. The main objective of Phase 2 was to assess ORR (objective response rate) according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as determined by the Independent Endpoint Review Committee (IERC).
    Protection of trial subjects
    This study was conducted in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Jan 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 7
    Country: Number of subjects enrolled
    Spain: 15
    Country: Number of subjects enrolled
    Hungary: 21
    Country: Number of subjects enrolled
    United States: 19
    Country: Number of subjects enrolled
    Ukraine: 48
    Country: Number of subjects enrolled
    Australia: 40
    Country: Number of subjects enrolled
    Georgia: 11
    Country: Number of subjects enrolled
    Moldova, Republic of: 9
    Country: Number of subjects enrolled
    Brazil: 5
    Worldwide total number of subjects
    175
    EEA total number of subjects
    43
    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)
    155
    From 65 to 84 years
    20
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The trial was conducted at 46 trial centres.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Phase 1 – Dose 1: Zalifrelimab + Balstilimab
    Arm description
    		 Participants received zalifrelimab in combination with balstilimab.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zalifrelimab
    Investigational medicinal product code
    Other name
    AGEN1884
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Zalifrelimab was administered over 30 minutes and following the infusion of balstilimab.

    Investigational medicinal product name
    Balstilimab
    Investigational medicinal product code
    Other name
    AGEN2034, Anti-PD-1
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Balstilimab infusion was administered over 30 minutes.

    Arm title
    		 Phase 1 – Dose 2: Zalifrelimab + Balstilimab
    Arm description
    		 Participants received zalifrelimab in combination with balstilimab.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zalifrelimab
    Investigational medicinal product code
    Other name
    AGEN1884
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Zalifrelimab was administered over 30 minutes and following the infusion of balstilimab.

    Investigational medicinal product name
    Balstilimab
    Investigational medicinal product code
    Other name
    AGEN2034, Anti-PD-1
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Balstilimab infusion was administered over 30 minutes.

    Arm title
    		 Phase 2: Zalifrelimab + Balstilimab
    Arm description
    		 Participants received zalifrelimab in combination with balstilimab.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zalifrelimab
    Investigational medicinal product code
    Other name
    AGEN1884
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Zalifrelimab was administered over 30 minutes and following the infusion of balstilimab.

    Investigational medicinal product name
    Balstilimab
    Investigational medicinal product code
    Other name
    AGEN2034, Anti-PD-1
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Balstilimab infusion was administered over 30 minutes.

    Number of subjects in period 1
    		Phase 1 – Dose 1: Zalifrelimab + Balstilimab Phase 1 – Dose 2: Zalifrelimab + Balstilimab Phase 2: Zalifrelimab + Balstilimab
    Started
    10
    10
    155
    Received at Least 1 Dose of Study Drug
    10
    10
    155
    Completed
    2
    0
    36
    Not completed
    8
    10
    119
         Consent withdrawn by subject
    -
    -
    15
         Adverse event, non-fatal
    2
    -
    2
         Death
    -
    -
    88
         Progressive Disease
    6
    10
    2
         Study Terminated by Sponsor
    -
    -
    5
         Lost to follow-up
    -
    -
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Study
    Reporting group description
    		 Safety Analysis Set: all participants who received ≥1 dose of any study treatment.

    Reporting group values
    		 Overall Study Total
    Number of subjects
    		 175 175
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 155 155
        From 65-84 years
    		 20 20
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 170 170
        Male
    		 5 5
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 1 1
        Asian (Chinese)
    		 1 1
        Black or African American
    		 1 1
        White
    		 168 168
        South African
    		 1 1
        Indigenous And Torres Strait Islander
    		 1 1
        Australian Aboriginal
    		 1 1
        Unknown
    		 1 1
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 9 9
        Not Hispanic or Latino
    		 163 163
        Unknown
    		 3 3

    End points

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    End points reporting groups
    Reporting group title
    Phase 1 – Dose 1: Zalifrelimab + Balstilimab
    Reporting group description
    		 Participants received zalifrelimab in combination with balstilimab.

    Reporting group title
    Phase 1 – Dose 2: Zalifrelimab + Balstilimab
    Reporting group description
    		 Participants received zalifrelimab in combination with balstilimab.

    Reporting group title
    Phase 2: Zalifrelimab + Balstilimab
    Reporting group description
    		 Participants received zalifrelimab in combination with balstilimab.

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All participants who received ≥1 dose of any study treatment.

    Subject analysis set title
    Intent-to-treat
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All participants who received ≥1 dose of any study treatment, with measurable disease at baseline (per IERC).

    Subject analysis set title
    Pharmacokinetics (PK) Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All participants who received ≥1 dose of any study drug and who had sufficient evaluable drug concentrations measurements prior to and after treatment.

    Subject analysis set title
    Dose-limiting Toxicity (DLT) Analysis Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All participants who were enrolled for DLT evaluation (excluding participants enrolled to backfill cohorts) and either received all study treatment administrations or stopped treatment due to a DLT during the DLT evaluation period.

    Subject analysis set title
    Receptor Occupancy (RO) Analysis Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All participants who completed ≥ 1 infusion of study drug, with adequate measurements of PD-1 receptor occupancy on circulating T cells.

    Primary: Phase 2: Objective Response Rate (ORR): IERC

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    End point title
    		 Phase 2: Objective Response Rate (ORR): IERC [1] [2]
    End point description
    The ORR was defined as the proportion of participants with a confirmed best overall response (BOR) of partial response (PR) or complete response (CR), as determined by an IERC per RECIST 1.1.
    End point type
    Primary
    End point timeframe
    Up to 2 years
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only percentage of participants is reported for this end point.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This end point applies only to Phase 2 of the study.
    End point values
    		 Phase 2: Zalifrelimab + Balstilimab
    Number of subjects analysed
    145 [3]
    Units: Percentage of participants
        number (confidence interval 95%)
    26.2 (19.7 to 33.9)
    Notes
    [3] - Intent-to-treat
    No statistical analyses for this end point

    Primary: Phase 1: Number of Participants Experiencing DLTs

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    End point title
    		 Phase 1: Number of Participants Experiencing DLTs [4] [5]
    End point description
    The number of participants with an occurrence of a DLT during dose escalation during the first 21 days of treatment in Phase 1 are reported. Any DLT immediately led to permanent withdrawal of zalifrelimab and balstilimab.
    End point type
    Primary
    End point timeframe
    Up to Day 21
    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: Only number of participants is reported for this end point.
    [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: This end point applies only to Phase 1 of the study.
    End point values
    		 Phase 1 – Dose 1: Zalifrelimab + Balstilimab Phase 1 – Dose 2: Zalifrelimab + Balstilimab
    Number of subjects analysed
    10 [6]
    10 [7]
    Units: Participants
    0
    0
    Notes
    [6] - DLT Analysis Set
    [7] - DLT Analysis Set
    No statistical analyses for this end point

    Secondary: Phase 1/2: Maximum Drug Concentration Observed Postdose at Steady-state (Cmax-ss)

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    End point title
    		 Phase 1/2: Maximum Drug Concentration Observed Postdose at Steady-state (Cmax-ss)
    End point description
    Blood samples were collected for serum balstilimab and zalifrelimab concentration analyses. Each cycle was 6 weeks (42 days) long. Results are reported as micrograms/millilitre (ug/mL).
    End point type
    Secondary
    End point timeframe
    Pre-dose, up to 4 hours post-dose (Phase 1: Cycle 2 and Cycle 3; Phase 2: Cycle 4)
    End point values
    		 Phase 1 – Dose 1: Zalifrelimab + Balstilimab Phase 1 – Dose 2: Zalifrelimab + Balstilimab Phase 2: Zalifrelimab + Balstilimab
    Number of subjects analysed
    10 [8]
    10 [9]
    145 [10]
    Units: μg/mL
    geometric mean (geometric coefficient of variation)
        Zalifrelimab
    28.7 ( 26.6 )
    27.3 ( 16.4 )
    16.45 ( 120.2 )
        Balstilimab
    23.1 ( 28.7 )
    71.4 ( 26.5 )
    62.40 ( 26.7 )
    Notes
    [8] - Zalifrelimab PK Set: N=6; Balstilimab PK Set: N=9
    [9] - Zalifrelimab PK Set: N=5; Balstilimab PK Set: N=10
    [10] - Zalifrelimab PK Set: N=42; Balstilimab PK Set: N=7
    No statistical analyses for this end point

    Secondary: Phase 1/2: Area Under the Drug Concentration-time Curve From Day 0 to Day 14 at Steady-state (AUC0-14d-ss)

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    End point title
    		 Phase 1/2: Area Under the Drug Concentration-time Curve From Day 0 to Day 14 at Steady-state (AUC0-14d-ss)
    End point description
    Blood samples were collected for serum balstilimab and zalifrelimab concentration analyses. Each cycle was 6 weeks (42 days) long. Results are reported as day times ug/mL (day*ug/mL).
    End point type
    Secondary
    End point timeframe
    Pre-dose, up to 4 hours post-dose (Phase 1: Cycle 2 and Cycle 3; Phase 2: Cycle 4)
    End point values
    		 Phase 1 – Dose 1: Zalifrelimab + Balstilimab Phase 1 – Dose 2: Zalifrelimab + Balstilimab Phase 2: Zalifrelimab + Balstilimab
    Number of subjects analysed
    10 [11]
    10 [12]
    145 [13]
    Units: day*ug/mL
    geometric mean (geometric coefficient of variation)
        Zalifrelimab
    213 ( 29.4 )
    185 ( 13.2 )
    131.1 ( 119.5 )
        Balstilimab
    74.8 ( 37.4 )
    245 ( 28.9 )
    250.9 ( 119.5 )
    Notes
    [11] - Zalifrelimab PK Set: N=6; Balstilimab PK Set: N=8
    [12] - Zalifrelimab PK Set: N=5; Balstilimab PK Set: N=9
    [13] - Zalifrelimab PK Set: N=41; Balstilimab PK Set: N=6
    No statistical analyses for this end point

    Secondary: Phase 1/2: Number of Participants with Serum Anti-drug Antibodies (ADAs) for Balstilimab and Zalifrelimab

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    End point title
    		 Phase 1/2: Number of Participants with Serum Anti-drug Antibodies (ADAs) for Balstilimab and Zalifrelimab
    End point description
    Blood samples were collected for serum balstilimab and zalifrelimab ADA determination.
    End point type
    Secondary
    End point timeframe
    Pre-dose through Month 27
    End point values
    		 Phase 1 – Dose 1: Zalifrelimab + Balstilimab Phase 1 – Dose 2: Zalifrelimab + Balstilimab Phase 2: Zalifrelimab + Balstilimab
    Number of subjects analysed
    10 [14]
    10 [15]
    155 [16]
    Units: Participant
        Zalifrelimab
    0
    0
    3
        Balstilimab
    0
    0
    6
    Notes
    [14] - Safety Analysis Set
    [15] - Safety Analysis Set
    [16] - Safety Analysis Set
    No statistical analyses for this end point

    Secondary: Phase 2: ORR: Investigator

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    End point title
    		 Phase 2: ORR: Investigator [17]
    End point description
    The ORR was defined as the proportion of participants with a confirmed BOR of PR or CR, as determined by the investigator per RECIST 1.1.
    End point type
    Secondary
    End point timeframe
    Up to 2 years
    Notes
    [17] - 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: This end point applies only to Phase 2 of the study.
    End point values
    		 Phase 2: Zalifrelimab + Balstilimab
    Number of subjects analysed
    145 [18]
    Units: Percentage of participants
        number (confidence interval 95%)
    23.4 (17.3 to 31.0)
    Notes
    [18] - Intent-to-treat
    No statistical analyses for this end point

    Secondary: Phase 2: Duration of Response (DOR)

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    End point title
    		 Phase 2: Duration of Response (DOR) [19]
    End point description
    DOR was defined as time from first observation of response to first observation of documented disease progression (or death within 12 weeks after last tumor assessment), as determined by an IERC and investigator, per RECIST 1.1. Participants without an event at the analysis cutoff date were censored on date of last tumor assessment.
    End point type
    Secondary
    End point timeframe
    Up to 3 years
    Notes
    [19] - 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: This end point applies only to Phase 2 of the study.
    End point values
    		 Phase 2: Zalifrelimab + Balstilimab
    Number of subjects analysed
    145 [20]
    Units: month
    number (confidence interval 95%)
        IERC
    9.7 (5.6 to 9999)
        Investigator
    8.5 (6.9 to 18.1)
    Notes
    [20] - IERC Intent-to-treat: N=38; 9999=Not available; Investigator Intent-to-treat: N=34
    No statistical analyses for this end point

    Secondary: Phase 2: Disease Control Rate (DCR)

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    End point title
    		 Phase 2: Disease Control Rate (DCR) [21]
    End point description
    DCR was defined as proportion of participants with CR, PR, or stable disease (SD) without progressive disease (PD) within 81 days of study start, or durable SD following PD, as determined by the investigator per RECIST 1.1.
    End point type
    Secondary
    End point timeframe
    Up to 3 years
    Notes
    [21] - 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: This end point applies only to Phase 2 of the study.
    End point values
    		 Phase 2: Zalifrelimab + Balstilimab
    Number of subjects analysed
    145 [22]
    Units: Percentage of participants
        number (confidence interval 95%)
    58.6 (50.5 to 66.3)
    Notes
    [22] - Intent-to-treat
    No statistical analyses for this end point

    Secondary: Phase 2: Time to Response (TTR)

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    End point title
    		 Phase 2: Time to Response (TTR) [23]
    End point description
    TTR was defined as the time interval between the date of treatment initiation and the earliest date of first documented confirmed complete response or partial response based on independent radiologic review, as determined by an IERC and investigator, per RECIST 1.1.
    End point type
    Secondary
    End point timeframe
    Up to 2 years
    Notes
    [23] - 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: This end point applies only to Phase 2 of the study.
    End point values
    		 Phase 2: Zalifrelimab + Balstilimab
    Number of subjects analysed
    145 [24]
    Units: day
        median (confidence interval 95%)
    79.5 (66.5 to 123.5)
    Notes
    [24] - Intent-to-treat: N=38
    No statistical analyses for this end point

    Secondary: Phase 2: Progression-free Survival (PFS)

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    End point title
    		 Phase 2: Progression-free Survival (PFS) [25]
    End point description
    PFS was defined as the interval from the date of first dose of investigational agent until the earliest date of PD, as determined by IERC and investigator assessment of objective radiographic disease assessments per RECIST 1.1, or death due to any cause if occurring sooner than progression.
    End point type
    Secondary
    End point timeframe
    Up to 2 years
    Notes
    [25] - 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: This end point applies only to Phase 2 of the study.
    End point values
    		 Phase 2: Zalifrelimab + Balstilimab
    Number of subjects analysed
    145 [26]
    Units: month
    median (confidence interval 95%)
        IERC
    2.7 (1.5 to 3.7)
        Investigator
    3.0 (2.7 to 5.4)
    Notes
    [26] - IERC Intent-to-treat: N=110; Investigator Intent-to-treat: N=118
    No statistical analyses for this end point

    Secondary: Phase 2: Overall Survival (OS)

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    End point title
    		 Phase 2: Overall Survival (OS) [27]
    End point description
    OS was defined as the interval from the date of first dose of investigational agent until the date of death.
    End point type
    Secondary
    End point timeframe
    Up to 2 years
    Notes
    [27] - 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: This end point applies only to Phase 2 of the study.
    End point values
    		 Phase 2: Zalifrelimab + Balstilimab
    Number of subjects analysed
    145 [28]
    Units: month
        median (confidence interval 95%)
    13.0 (9.7 to 18.5)
    Notes
    [28] - Intent-to-treat
    No statistical analyses for this end point

    Secondary: Phase 1: RO of Balstilimab on Circulating T Cells

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    End point title
    		 Phase 1: RO of Balstilimab on Circulating T Cells [29]
    End point description
    A validated flow cytometry-based assay was used to evaluate programmed cell death protein 1 (PD-1) RO on circulating T cells as an indication of target engagement of balstilimab. Blood samples were collected for the assay. Results are reported as a percentage of available drug receptors occupied (%RO) by balstilimab; the higher the percentage, the greater the engagement of balstilimab with the target receptor. Initial testing revealed technical limitations of the sample isolation procedure prior to the PD-1 RO assessment, causing the PD-1 RO assay to inaccurately reflect the actual PD-1 RO status in response to balstilimab/zalifrelimab combination treatment. As a result, further sample collection and subsequent testing was not conducted. Only initial test results are reported.
    End point type
    Secondary
    End point timeframe
    Day 8 through Day 50
    Notes
    [29] - 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: This end point applies only to Phase 1 of the study.
    End point values
    		 Phase 1 – Dose 1: Zalifrelimab + Balstilimab
    Number of subjects analysed
    3 [30]
    Units: Percent
        number (not applicable)
    30.9
    Notes
    [30] - RO Analysis Set
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    36 months
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Phase 2: Zalifrelimab + Balstilimab
    Reporting group description
    		 Participants received zalifrelimab in combination with balstilimab.

    Reporting group title
    Phase 1 – Dose 1: Zalifrelimab + Balstilimab
    Reporting group description
    		 Participants received zalifrelimab in combination with balstilimab.

    Reporting group title
    Phase 1 – Dose 2: Zalifrelimab + Balstilimab
    Reporting group description
    		 Participants received zalifrelimab in combination with balstilimab.

    Serious adverse events
    		 Phase 2: Zalifrelimab + Balstilimab Phase 1 – Dose 1: Zalifrelimab + Balstilimab Phase 1 – Dose 2: Zalifrelimab + Balstilimab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    68 / 155 (43.87%)
    6 / 10 (60.00%)
    2 / 10 (20.00%)
         number of deaths (all causes)
    88
    1
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour haemorrhage
         subjects affected / exposed
    2 / 155 (1.29%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to the respiratory system
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour associated fever
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 10 (10.00%)
    0 / 10 (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
    Vascular disorders
    Shock haemorrhagic
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 10 (10.00%)
    0 / 10 (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
    Surgical and medical procedures
    Nephrostomy
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 155 (1.29%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Cervix haemorrhage uterine
         subjects affected / exposed [1]
    1 / 155 (0.65%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Female genital tract fistula
         subjects affected / exposed [2]
    1 / 155 (0.65%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vaginal discharge
         subjects affected / exposed [3]
    1 / 155 (0.65%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed [4]
    1 / 155 (0.65%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    3 / 155 (1.94%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Bronchial obstruction
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device occlusion
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Immune-mediated myocarditis
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Thrombotic cerebral infarction
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Neurological decompensation
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 10 (10.00%)
    0 / 10 (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
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 155 (3.87%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 155 (1.94%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated enterocolitis
         subjects affected / exposed
    3 / 155 (1.94%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    2 / 155 (1.29%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal distension
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colonic fistula
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestinal haemorrhage
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 155 (0.00%)
    2 / 10 (20.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenitis
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 10 (10.00%)
    0 / 10 (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
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated hepatitis
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 155 (1.29%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ureteric obstruction
         subjects affected / exposed
    2 / 155 (1.29%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postrenal failure
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated nephritis
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia of malignancy
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypophysitis
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypopituitarism
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated hypothyroidism
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 155 (1.29%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    4 / 155 (2.58%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    4 / 155 (2.58%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 155 (1.94%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    2 / 155 (1.29%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal abscess
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Kidney infection
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection viral
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvic infection
         subjects affected / exposed
    1 / 155 (0.65%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 10 (10.00%)
    0 / 10 (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
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This adverse event was only experienced by female participants.
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This adverse event was only experienced by female participants.
    [3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This adverse event was only experienced by female participants.
    [4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This adverse event was only experienced by female participants.
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Phase 2: Zalifrelimab + Balstilimab Phase 1 – Dose 1: Zalifrelimab + Balstilimab Phase 1 – Dose 2: Zalifrelimab + Balstilimab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    145 / 155 (93.55%)
    10 / 10 (100.00%)
    9 / 10 (90.00%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    1 / 155 (0.65%)
    1 / 10 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    2
    1
    Flushing
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    30 / 155 (19.35%)
    6 / 10 (60.00%)
    5 / 10 (50.00%)
         occurrences all number
    43
    6
    8
    Pyrexia
         subjects affected / exposed
    25 / 155 (16.13%)
    2 / 10 (20.00%)
    2 / 10 (20.00%)
         occurrences all number
    36
    4
    3
    Asthenia
         subjects affected / exposed
    18 / 155 (11.61%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    23
    0
    0
    Oedema peripheral
         subjects affected / exposed
    10 / 155 (6.45%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    11
    0
    0
    Chills
         subjects affected / exposed
    2 / 155 (1.29%)
    3 / 10 (30.00%)
    2 / 10 (20.00%)
         occurrences all number
    2
    4
    2
    Influenza like illness
         subjects affected / exposed
    2 / 155 (1.29%)
    3 / 10 (30.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    5
    0
    Chest discomfort
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 10 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Chest pain
         subjects affected / exposed
    1 / 155 (0.65%)
    1 / 10 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    1
    Injection site pain
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 10 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Tenderness
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Application site rash
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Reproductive system and breast disorders
    Vaginal haemorrhage
         subjects affected / exposed [5]
    8 / 155 (5.16%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    10
    1
    0
    Breast pain
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    15 / 155 (9.68%)
    2 / 10 (20.00%)
    3 / 10 (30.00%)
         occurrences all number
    20
    3
    3
    Dyspnoea
         subjects affected / exposed
    5 / 155 (3.23%)
    1 / 10 (10.00%)
    2 / 10 (20.00%)
         occurrences all number
    5
    1
    2
    Haemoptysis
         subjects affected / exposed
    2 / 155 (1.29%)
    1 / 10 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    2
    5
    1
    Oropharyngeal pain
         subjects affected / exposed
    2 / 155 (1.29%)
    0 / 10 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    2
    0
    2
    Productive cough
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 10 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Pneumonitis
         subjects affected / exposed
    3 / 155 (1.94%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    3
    0
    1
    Nasal congestion
         subjects affected / exposed
    1 / 155 (0.65%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Wheezing
         subjects affected / exposed
    1 / 155 (0.65%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Asthma
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    2
    Orthopnoea
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Pleuritic pain
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    3 / 155 (1.94%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    3
    1
    0
    Depression
         subjects affected / exposed
    3 / 155 (1.94%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    3
    1
    0
    Sleep disorder
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    19 / 155 (12.26%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    31
    0
    1
    Blood creatinine increased
         subjects affected / exposed
    18 / 155 (11.61%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    42
    0
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    16 / 155 (10.32%)
    0 / 10 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    35
    0
    3
    Blood alkaline phosphatase increased
         subjects affected / exposed
    8 / 155 (5.16%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    16
    0
    0
    Transaminases increased
         subjects affected / exposed
    2 / 155 (1.29%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    7
    3
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    1
    Blood urea increased
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    1
    International normalised ratio increased
         subjects affected / exposed
    1 / 155 (0.65%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    C-reactive protein increased
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Injury, poisoning and procedural complications
    Wound
         subjects affected / exposed
    0 / 155 (0.00%)
    3 / 10 (30.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    6
    0
    Nail injury
         subjects affected / exposed
    0 / 155 (0.00%)
    2 / 10 (20.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    2
    0
    Foot fracture
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Limb injury
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Muscle injury
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Muscle strain
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Radiation injury
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    2
    0
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    8 / 155 (5.16%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    8
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    11 / 155 (7.10%)
    1 / 10 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    12
    2
    1
    Headache
         subjects affected / exposed
    14 / 155 (9.03%)
    3 / 10 (30.00%)
    1 / 10 (10.00%)
         occurrences all number
    19
    3
    1
    Lethargy
         subjects affected / exposed
    2 / 155 (1.29%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    1
    0
    Hypoaesthesia
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    1
    Neuropathy peripheral
         subjects affected / exposed
    1 / 155 (0.65%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Somnolence
         subjects affected / exposed
    1 / 155 (0.65%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Dysarthria
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Dysgeusia
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Intention tremor
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Syncope
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    43 / 155 (27.74%)
    1 / 10 (10.00%)
    5 / 10 (50.00%)
         occurrences all number
    122
    1
    11
    Thrombocytopenia
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    1
    0
    2
    Iron deficiency anaemia
         subjects affected / exposed
    2 / 155 (1.29%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    2
    0
    1
    Eosinophilia
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Coagulopathy
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    2 / 155 (1.29%)
    2 / 10 (20.00%)
    0 / 10 (0.00%)
         occurrences all number
    3
    2
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    38 / 155 (24.52%)
    4 / 10 (40.00%)
    3 / 10 (30.00%)
         occurrences all number
    66
    7
    3
    Nausea
         subjects affected / exposed
    32 / 155 (20.65%)
    5 / 10 (50.00%)
    6 / 10 (60.00%)
         occurrences all number
    45
    6
    7
    Vomiting
         subjects affected / exposed
    30 / 155 (19.35%)
    3 / 10 (30.00%)
    3 / 10 (30.00%)
         occurrences all number
    36
    4
    7
    Constipation
         subjects affected / exposed
    19 / 155 (12.26%)
    1 / 10 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    25
    1
    1
    Abdominal pain
         subjects affected / exposed
    19 / 155 (12.26%)
    4 / 10 (40.00%)
    0 / 10 (0.00%)
         occurrences all number
    20
    4
    0
    Abdominal pain upper
         subjects affected / exposed
    3 / 155 (1.94%)
    1 / 10 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    3
    1
    1
    Dry mouth
         subjects affected / exposed
    5 / 155 (3.23%)
    1 / 10 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    5
    1
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    5 / 155 (3.23%)
    1 / 10 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    6
    1
    1
    Toothache
         subjects affected / exposed
    1 / 155 (0.65%)
    1 / 10 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    1
    Abdominal pain lower
         subjects affected / exposed
    5 / 155 (3.23%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    7
    1
    0
    Dysphagia
         subjects affected / exposed
    4 / 155 (2.58%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    4
    0
    1
    Abdominal discomfort
         subjects affected / exposed
    2 / 155 (1.29%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    1
    0
    Haemorrhoids
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    1
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    12 / 155 (7.74%)
    2 / 10 (20.00%)
    4 / 10 (40.00%)
         occurrences all number
    15
    4
    8
    Rash
         subjects affected / exposed
    11 / 155 (7.10%)
    3 / 10 (30.00%)
    3 / 10 (30.00%)
         occurrences all number
    14
    4
    4
    Rash maculo-papular
         subjects affected / exposed
    10 / 155 (6.45%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    10
    0
    1
    Dry skin
         subjects affected / exposed
    3 / 155 (1.94%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    3
    0
    1
    Hyperhidrosis
         subjects affected / exposed
    1 / 155 (0.65%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Alopecia
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Blister
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Psoriasis
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Blister rupture
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Rash papular
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 155 (0.65%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    1
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    23 / 155 (14.84%)
    1 / 10 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    28
    1
    1
    Hyperthyroidism
         subjects affected / exposed
    17 / 155 (10.97%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    19
    1
    0
    Adrenal insufficiency
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    16 / 155 (10.32%)
    5 / 10 (50.00%)
    1 / 10 (10.00%)
         occurrences all number
    24
    11
    1
    Arthralgia
         subjects affected / exposed
    11 / 155 (7.10%)
    2 / 10 (20.00%)
    2 / 10 (20.00%)
         occurrences all number
    16
    2
    2
    Muscle spasms
         subjects affected / exposed
    6 / 155 (3.87%)
    3 / 10 (30.00%)
    0 / 10 (0.00%)
         occurrences all number
    7
    3
    0
    Groin pain
         subjects affected / exposed
    4 / 155 (2.58%)
    2 / 10 (20.00%)
    0 / 10 (0.00%)
         occurrences all number
    6
    2
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    3 / 155 (1.94%)
    1 / 10 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    3
    1
    1
    Musculoskeletal pain
         subjects affected / exposed
    3 / 155 (1.94%)
    2 / 10 (20.00%)
    0 / 10 (0.00%)
         occurrences all number
    3
    3
    0
    Myalgia
         subjects affected / exposed
    7 / 155 (4.52%)
    1 / 10 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    10
    1
    2
    Pain in extremity
         subjects affected / exposed
    3 / 155 (1.94%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    3
    1
    0
    Bone pain
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    2
    Musculoskeletal discomfort
         subjects affected / exposed
    1 / 155 (0.65%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Bursitis
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Muscle twitching
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    26 / 155 (16.77%)
    1 / 10 (10.00%)
    3 / 10 (30.00%)
         occurrences all number
    40
    1
    4
    Upper respiratory tract infection
         subjects affected / exposed
    9 / 155 (5.81%)
    1 / 10 (10.00%)
    2 / 10 (20.00%)
         occurrences all number
    11
    1
    3
    Sinusitis
         subjects affected / exposed
    4 / 155 (2.58%)
    2 / 10 (20.00%)
    1 / 10 (10.00%)
         occurrences all number
    4
    5
    1
    Pneumonia
         subjects affected / exposed
    5 / 155 (3.23%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    5
    0
    1
    Cystitis
         subjects affected / exposed
    4 / 155 (2.58%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    5
    1
    0
    Fungal skin infection
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    1
    Influenza
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    1
    Rhinitis
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    1
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 155 (0.65%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    1
    0
    Nail bed infection
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Lymphangitis
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Metabolism and nutrition disorders
    Hypomagnesaemia
         subjects affected / exposed
    14 / 155 (9.03%)
    2 / 10 (20.00%)
    0 / 10 (0.00%)
         occurrences all number
    22
    2
    0
    Decreased appetite
         subjects affected / exposed
    11 / 155 (7.10%)
    2 / 10 (20.00%)
    0 / 10 (0.00%)
         occurrences all number
    13
    2
    0
    Hyponatraemia
         subjects affected / exposed
    8 / 155 (5.16%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    12
    0
    0
    Hypercalcaemia
         subjects affected / exposed
    2 / 155 (1.29%)
    1 / 10 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    3
    2
    1
    Hypoalbuminaemia
         subjects affected / exposed
    4 / 155 (2.58%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    7
    1
    0
    Iron deficiency
         subjects affected / exposed
    2 / 155 (1.29%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    1
    0
    Notes
    [5] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This adverse event was only experienced by female participants.

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Nov 2017
    - Added the following language in the 5.4 Dosage and Administration “Relevant clinical laboratory results essential for subject management decisions (hematology, biochemistry, liver function tests) must be available and reviewed before administration of AGEN1884 and/or AGEN2034.”
    09 Mar 2018
    - Addition of best overall response, duration of response, and progression-free survival per immune-RECIST as secondary end points, including the requirement for a repeat scan to be performed 4-8 weeks after initial diagnosis of progressive disease - Screening period shortened from 42 days to 28 days
    22 Aug 2018
    - A 2-week washout was permitted for palliative radiation to non-central nervous system disease with sponsor approval - Infusion times and waiting period were shortened in dosage and administration of zalifrelimab and balstilimab
    15 Apr 2019
    - Reorganized and refined the trial objectives and endpoints for Phase 1 versus Phase 2 - Added information from Phase 1 part of the trial that was not available at the time of the previous amendment to support Phase 2 part - Increased sample size to 100 participants in Phase 2 - Changed tumor assessments to continue at 6-week intervals rather than 9-week intervals after Week 18 in order to collect more comprehensive data and consistent tumor response data - Modified the schedule of assessments to align with Study C-700-01 and to increase and enhance data collected to support registration - Updated the planned trial duration from 60 months to 73 months - Updated that administration of balstilimab and zalifrelimab was over 30 minutes - Updated duration of the Follow-up Phase and overall trial duration - Added that response assessment was to be done according to RECIST 1.1 in both phases - The primary end point changed from BOR to ORR to align with change in objectives
    29 Sep 2019
    - The Phase 2 sample size was increased from approximately 100 to 150 participants to allow for a more robust analysis of safety and PK data - Eligible participants required to have measurable disease per RECIST 1.1 confirmed by an independent central review prior to trial entry; the prior version of the protocol did not specify central review of measurable disease - Statistical assumptions were updated to accommodate the change in sample size - The planned interim analyses were updated, with a second interim analysis added for 3 months after 100 participants have been treated - New information (per RECIST 1.1) on what constitutes clinical disease progression in the absence of radiologic progression was added

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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