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    Clinical Trial Results:
    A Phase II, open label, randomized, parallel arm study of NIS793 (with and without spartalizumab) in combination with SOC chemotherapy gemcitabine/nab-paclitaxel, and gemcitabine/nab-paclitaxel alone in first-line metastatic pancreatic ductal adenocarcinoma (mPDAC)

    Summary
    EudraCT number
    		 2020-000349-14
    Trial protocol
    		 FI   FR   GB   AT   BE   DE   IT  
    Global end of trial date
    02 May 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Mar 2025
    First version publication date
    20 Mar 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CNIS793B12201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04390763
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    Novartis campus, Basel, Switzerland, CH-4056
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.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
    02 May 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 May 2024
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objectives of the trial were: Safety run-in part: • To assess the safety and tolerability of NIS793+spartalizumab in combination with gemcitabine/nab-paclitaxel Randomized part: • To evaluate the progression free survival (PFS) of NIS793 with spartalizumab in combination with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel • To evaluate the PFS of NIS793 with gemcitabine/nab-paclitaxel versus gemcitabine /nab-paclitaxel
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Oct 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 11
    Country: Number of subjects enrolled
    Austria: 9
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    Czechia: 11
    Country: Number of subjects enrolled
    Finland: 2
    Country: Number of subjects enrolled
    France: 12
    Country: Number of subjects enrolled
    Germany: 11
    Country: Number of subjects enrolled
    Italy: 14
    Country: Number of subjects enrolled
    Singapore: 12
    Country: Number of subjects enrolled
    Spain: 15
    Country: Number of subjects enrolled
    Switzerland: 7
    Country: Number of subjects enrolled
    Taiwan: 23
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    United States: 22
    Worldwide total number of subjects
    164
    EEA total number of subjects
    80
    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)
    71
    From 65 to 84 years
    93
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants took part in 31 investigative sites in 14 countries.

    Pre-assignment
    Screening details
    		 Screening evaluations had to be completed within 21 days prior to the first dose of study treatment (≤ 28 days for baseline radiological assessments). After screening, the treatment period started on Cycle 1 Day 1. The study consisted of two parts: Safety run-in part and Randomized part (Arm 1, 2 and 3).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Run-in: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel
    Arm description
    		 NIS793 2100 mg every 2 weeks i.v. with spartalizumab 400 mg every 4 weeks i.v and standard of care chemotherapy in the safety run-in part
    Arm type
    		 Experimental

    Investigational medicinal product name
    NIS793
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    NIS793 was administered at a flat dose of 2100 mg every 2 weeks.

    Investigational medicinal product name
    Gemcitabine/nab-paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gemcitabine (1000 mg/m2 on Days 1, 8, and 15) and nab-paclitaxel (125 mg/m2 on Days 1, 8, and 15) were given as per label. 1 cycle=28 days.

    Investigational medicinal product name
    Spartalizumab
    Investigational medicinal product code
    PDR001
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Spartalizumab was administered at a flat dose of 400 mg every 4 weeks.

    Arm title
    		 Arm 1: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel
    Arm description
    		 NIS793 2100 mg every 2 weeks i.v. with spartalizumab 400 mg every 4 weeks i.v and standard of care chemotherapy in the randomized part
    Arm type
    		 Experimental

    Investigational medicinal product name
    NIS793
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    NIS793 was administered at a flat dose of 2100 mg every 2 weeks.

    Investigational medicinal product name
    Gemcitabine/nab-paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gemcitabine (1000 mg/m2 on Days 1, 8, and 15) and nab-paclitaxel (125 mg/m2 on Days 1, 8, and 15) were given as per label. 1 cycle=28 days.

    Investigational medicinal product name
    Spartalizumab
    Investigational medicinal product code
    PDR001
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Spartalizumab was administered at a flat dose of 400 mg every 4 weeks.

    Arm title
    		 Arm 2: NIS793 + gemcitabine/nab-paclitaxel
    Arm description
    		 NIS793 2100 mg every 2 weeks i.v. with standard of care chemotherapy in the randomized part
    Arm type
    		 Experimental

    Investigational medicinal product name
    Gemcitabine/nab-paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gemcitabine (1000 mg/m2 on Days 1, 8, and 15) and nab-paclitaxel (125 mg/m2 on Days 1, 8, and 15) were given as per label. 1 cycle=28 days.

    Investigational medicinal product name
    NIS793
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    NIS793 was administered at a flat dose of 2100 mg every 2 weeks.

    Arm title
    		 Arm 3: gemcitabine/nab-paclitaxel
    Arm description
    		 Standard of care chemotherapy in the randomized part
    Arm type
    		 Experimental

    Investigational medicinal product name
    Gemcitabine/nab-paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gemcitabine (1000 mg/m2 on Days 1, 8, and 15) and nab-paclitaxel (125 mg/m2 on Days 1, 8, and 15) were given as per label. 1 cycle=28 days.

    Number of subjects in period 1
    		Run-in: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel Arm 1: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel Arm 2: NIS793 + gemcitabine/nab-paclitaxel Arm 3: gemcitabine/nab-paclitaxel
    Started
    11
    50
    51
    52
    Full Analysis Set (FAS)
    0
    50
    51
    52
    Completed
    0
    0
    0
    0
    Not completed
    11
    50
    51
    52
         Participant Decision
    -
    5
    7
    6
         Physician decision
    1
    2
    2
    9
         Death
    -
    3
    4
    2
         Progressive Disease
    6
    24
    31
    23
         Adverse event
    4
    11
    5
    5
         Study terminated by sponsor
    -
    1
    -
    -
         Not treated
    -
    4
    2
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Run-in: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel
    Reporting group description
    		 NIS793 2100 mg every 2 weeks i.v. with spartalizumab 400 mg every 4 weeks i.v and standard of care chemotherapy in the safety run-in part

    Reporting group title
    Arm 1: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel
    Reporting group description
    		 NIS793 2100 mg every 2 weeks i.v. with spartalizumab 400 mg every 4 weeks i.v and standard of care chemotherapy in the randomized part

    Reporting group title
    Arm 2: NIS793 + gemcitabine/nab-paclitaxel
    Reporting group description
    		 NIS793 2100 mg every 2 weeks i.v. with standard of care chemotherapy in the randomized part

    Reporting group title
    Arm 3: gemcitabine/nab-paclitaxel
    Reporting group description
    		 Standard of care chemotherapy in the randomized part

    Reporting group values
    		 Run-in: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel Arm 1: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel Arm 2: NIS793 + gemcitabine/nab-paclitaxel Arm 3: gemcitabine/nab-paclitaxel Total
    Number of subjects
    		 11 50 51 52 164
    Age Categorical
    Units: participants
        18 - <65 years
    		 5 20 23 23 71
        65 - <85 years
    		 6 30 28 29 93
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.5 ( 8.77 ) 64.3 ( 10.91 ) 64.2 ( 9.90 ) 64.8 ( 8.25 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 5 21 21 20 67
        Male
    		 6 29 30 32 97
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 9 39 35 33 116
        Black or African American
    		 0 1 1 3 5
        Asian
    		 2 9 15 15 41
        Unknown
    		 0 1 0 1 2

    End points

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    End points reporting groups
    Reporting group title
    Run-in: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel
    Reporting group description
    		 NIS793 2100 mg every 2 weeks i.v. with spartalizumab 400 mg every 4 weeks i.v and standard of care chemotherapy in the safety run-in part

    Reporting group title
    Arm 1: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel
    Reporting group description
    		 NIS793 2100 mg every 2 weeks i.v. with spartalizumab 400 mg every 4 weeks i.v and standard of care chemotherapy in the randomized part

    Reporting group title
    Arm 2: NIS793 + gemcitabine/nab-paclitaxel
    Reporting group description
    		 NIS793 2100 mg every 2 weeks i.v. with standard of care chemotherapy in the randomized part

    Reporting group title
    Arm 3: gemcitabine/nab-paclitaxel
    Reporting group description
    		 Standard of care chemotherapy in the randomized part

    Primary: Safety run-in part: Number of participants with Dose-Limiting Toxicities (DLTs)

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    End point title
    		 Safety run-in part: Number of participants with Dose-Limiting Toxicities (DLTs) [1] [2]
    End point description
    A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value of Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3 where the relationship to study treatment cannot be ruled out and is not clearly related solely to disease, disease progression, inter-current illness or concomitant medications, which occurs within the DLT evaluation period. The DLT evaluation period is the first 28 days of treatment with NIS793 with spartalizumab in combination with gemcitabine/nab-paclitaxel. Other clinically significant toxicities may be considered to be DLTs, even if not CTCAE grade 3 or higher.
    End point type
    Primary
    End point timeframe
    First cycle of treatment (28 days)
    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: No statistical analysis were planned for this endpoint.
    [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 endpoint is applicable to the Safety run-in part only.
    End point values
    		 Run-in: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel
    Number of subjects analysed
    6
    Units: participants
        Any DLT
    1
        - Colitis
    1
    No statistical analyses for this end point

    Primary: Safety run-in part: Number of participants with AEs and SAEs during the on-treatment period

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    End point title
    		 Safety run-in part: Number of participants with AEs and SAEs during the on-treatment period [3] [4]
    End point description
    Number of participants with AEs (any adverse events regardless of seriousness) and serious adverse events (SAEs), including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs. AE grades to characterize the severity of the AEs were based on the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. For CTCAE v5.0, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death related to AE. The on-treatment period is defined from the day of first administration of any study treatment up to 30 days after the date of the last actual administration of any study drug.
    End point type
    Primary
    End point timeframe
    Up to approximately 0.8 years
    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: No statistical analysis were planned for this endpoint.
    [4] - 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 endpoint is applicable to the Safety run-in part only.
    End point values
    		 Run-in: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel
    Number of subjects analysed
    11
    Units: participants
        AEs
    11
        Treatment-related AEs
    11
        AEs with grade>=3
    11
        Treatment-related AEs with grade>=3
    8
        SAEs
    8
        Treatment-related SAEs
    3
        Fatal SAEs
    1
        Treatment-related fatal SAEs
    0
    No statistical analyses for this end point

    Primary: Safety run-in part: Number of participants with dose reductions and dose interruptions of NIS793, spartalizumab, gemcitabine and nab-paclitaxel

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    End point title
    		 Safety run-in part: Number of participants with dose reductions and dose interruptions of NIS793, spartalizumab, gemcitabine and nab-paclitaxel [5] [6]
    End point description
    Number of participants with at least one dose reduction and at least one dose interruption of study drugs. Dose adjustments were permitted for patients who did not tolerate the protocol-specified dosing schedule. No dose reductions were allowed for NIS793 and spartalizumab beyond the first 28 days period of Safety run-in part.
    End point type
    Primary
    End point timeframe
    Up to approximately 0.7 years
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis were planned for this endpoint.
    [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: This endpoint is applicable to the Safety run-in part only.
    End point values
    		 Run-in: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel
    Number of subjects analysed
    11
    Units: participants
        NIS793: ≥1 dose reduction or interruption
    5
        NIS793: ≥1 dose reduction
    0
        NIS793: ≥1 dose interruption
    5
        Spartalizumab: ≥1 dose reduction or interruption
    3
        Spartalizumab: ≥1 dose reduction
    0
        Spartalizumab: ≥1 dose interruption
    3
        Gemcitabine: ≥1 dose reduction or interruption
    9
        Gemcitabine: ≥1 dose reduction
    2
        Gemcitabine: ≥1 dose interruption
    9
        Nab-paclitaxel: ≥1 dose reduction or interruption
    9
        Nab-paclitaxel: ≥1 dose reduction
    3
        Nab-paclitaxel: ≥1 dose interruption
    9
    No statistical analyses for this end point

    Primary: Safety run-in part: Dose intensity of NIS793 and spartalizumab

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    End point title
    		 Safety run-in part: Dose intensity of NIS793 and spartalizumab [7] [8]
    End point description
    Dose intensity of NIS973 and spartalizumab was calculated as cumulative actual dose in milligrams divided by duration of exposure in days and multiplied by 28 days.
    End point type
    Primary
    End point timeframe
    Cycle 1 and Cycle 3. The duration of each cycle was 28 days.
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis were planned for this endpoint.
    [8] - 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 endpoint is applicable to the Safety run-in part only.
    End point values
    		 Run-in: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel
    Number of subjects analysed
    11
    Units: mg per cycle
    arithmetic mean (standard deviation)
        NIS793 - cycle 1 (n=11)
    3627.3 ( 980.91 )
        NIS793 - cycle 3 (n=5)
    4200.0 ( 0.00 )
        Spartalizumab - cycle 1 (n=11)
    400.0 ( 0.00 )
        Spartalizumab - cycle 3 (n=5)
    400.0 ( 0.00 )
    No statistical analyses for this end point

    Primary: Safety run-in part: Dose intensity of gemcitabine and nab-paclitaxel

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    End point title
    		 Safety run-in part: Dose intensity of gemcitabine and nab-paclitaxel [9] [10]
    End point description
    Dose intensity of gemcitabine and nab-paclitaxel was calculated as cumulative actual dose in milligrams/m^2 divided by duration of exposure in days and multiplied by 28 days.
    End point type
    Primary
    End point timeframe
    Cycle 1 and Cycle 3. The duration of each cycle was 28 days.
    Notes
    [9] - 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: No statistical analysis were planned for this endpoint.
    [10] - 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 endpoint is applicable to the Safety run-in part only.
    End point values
    		 Run-in: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel
    Number of subjects analysed
    11
    Units: mg per m^2 per cycle
    arithmetic mean (standard deviation)
        Gemcitabine - cycle 1 (n=11)
    2425.4 ( 698.27 )
        Gemcitabine - cycle 3 (n=5)
    2619.1 ( 508.19 )
        Nab-paclitaxel - cycle 1 (n=11)
    303.3 ( 87.18 )
        Nab-paclitaxel - cycle 3 (n=5)
    327.6 ( 63.65 )
    No statistical analyses for this end point

    Primary: Randomized Part: Progression-Free Survival (PFS) per RECIST v1.1 – Bayesian model

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    End point title
    		 Randomized Part: Progression-Free Survival (PFS) per RECIST v1.1 – Bayesian model [11]
    End point description
    PFS was based on local review of tumor assessments, using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria. PFS is defined as the time from the date of randomization to the date of the first documented progression or death due to any cause. If a subject had not had an event, PFS was censored at the date of last adequate tumor assessment. PFS was estimated using a Bayesian model. For each comparison (arm 1 versus arm 3 and arm 2 versus arm 3), PFS was modeled using a two-piece hazard model, with specifying hazard rates before and after the possible delayed effect for arms 1 and 2 and constant hazard rate for arm 3. Results in the table as expressed as estimated posterior median hazard rate and one-sided 90% credible interval.
    End point type
    Primary
    End point timeframe
    Up to approximately 2 years. Risk changing timepoint=approximately 0.3 years.
    Notes
    [11] - 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 endpoint is applicable to the Randomized part only.
    End point values
    		 Arm 1: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel Arm 2: NIS793 + gemcitabine/nab-paclitaxel Arm 3: gemcitabine/nab-paclitaxel
    Number of subjects analysed
    50
    51
    52
    Units: events (progression, death) per year
    median (confidence interval 90%)
        Hazard rate before the risk changing timepoint
    2.54 (0 to 3.34)
    1.23 (0 to 1.79)
    2.09 (0 to 2.53)
        Hazard rate after the risk changing timepoint
    1.46 (0 to 2.06)
    2.94 (0 to 3.86)
    2.09 (0 to 2.53)
    Statistical analysis title
    		 Arm 2 vs. Arm 3
    Comparison groups
    Arm 2: NIS793 + gemcitabine/nab-paclitaxel v Arm 3: gemcitabine/nab-paclitaxel
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 Bayesian two-piece hazard model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.41
    Confidence interval
         level
    		 90%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 1.96
    Statistical analysis title
    		 Arm 1 vs. Arm 3
    Comparison groups
    Arm 1: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel v Arm 3: gemcitabine/nab-paclitaxel
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 Bayesian two-piece hazard model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.7
    Confidence interval
         level
    		 90%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 1.04

    Primary: Randomized Part: Progression-Free Survival (PFS) per RECIST v1.1 – Kaplan-Meier curves and Cox model

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    End point title
    		 Randomized Part: Progression-Free Survival (PFS) per RECIST v1.1 – Kaplan-Meier curves and Cox model [12]
    End point description
    PFS was based on local review of tumor assessments, using RECIST 1.1 criteria. PFS is defined as the time from the date of randomization to the date of the first documented progression or death due to any cause. If a subject had not had an event, PFS was censored at the date of last adequate tumor assessment. PFS was analyzed based on the Kaplan-Meier curves and the Cox model.
    End point type
    Primary
    End point timeframe
    Up to approximately 2 years
    Notes
    [12] - 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 endpoint is applicable to the Randomized part only.
    End point values
    		 Arm 1: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel Arm 2: NIS793 + gemcitabine/nab-paclitaxel Arm 3: gemcitabine/nab-paclitaxel
    Number of subjects analysed
    50
    51
    52
    Units: months
        median (confidence interval 95%)
    3.91 (3.06 to 6.93)
    5.52 (3.94 to 7.29)
    4.37 (3.55 to 7.20)
    Statistical analysis title
    		 Arm 2 vs. Arm 3
    Comparison groups
    Arm 2: NIS793 + gemcitabine/nab-paclitaxel v Arm 3: gemcitabine/nab-paclitaxel
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.38
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.08
    Confidence interval
         level
    		 90%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 1.44
    Statistical analysis title
    		 Arm 1 vs. Arm 3
    Comparison groups
    Arm 1: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel v Arm 3: gemcitabine/nab-paclitaxel
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.46
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.02
    Confidence interval
         level
    		 90%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 1.37

    Secondary: Randomized Part: Number of participants with AEs and SAEs during the on-treatment period

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    End point title
    		 Randomized Part: Number of participants with AEs and SAEs during the on-treatment period [13]
    End point description
    Number of participants with AEs (any adverse events regardless of seriousness) and serious adverse events (SAEs), including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs. AE grades to characterize the severity of the AEs were based on the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. For CTCAE v5.0, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death related to AE. The on-treatment period is defined from the day of first administration of any study treatment up to 30 days after the date of the last actual administration of any study drug.
    End point type
    Secondary
    End point timeframe
    Up to approximately 1.8 years
    Notes
    [13] - 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 endpoint is applicable to the Randomized part only.
    End point values
    		 Arm 1: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel Arm 2: NIS793 + gemcitabine/nab-paclitaxel Arm 3: gemcitabine/nab-paclitaxel
    Number of subjects analysed
    46
    49
    45
    Units: participants
        AEs
    45
    49
    43
        Treatment-related AEs
    45
    45
    38
        AEs with grade>=3
    42
    42
    35
        Treatment-related AEs with grade>=3
    34
    37
    24
        SAEs
    32
    26
    26
        Treatment-related SAEs
    19
    12
    12
        Fatal SAEs
    3
    1
    4
        Treatment-related fatal SAEs
    1
    0
    0
    No statistical analyses for this end point

    Secondary: Randomized Part: Number of participants with dose reductions and dose interruptions of NIS793, spartalizumab, gemcitabine and nab-paclitaxel

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    End point title
    		 Randomized Part: Number of participants with dose reductions and dose interruptions of NIS793, spartalizumab, gemcitabine and nab-paclitaxel [14]
    End point description
    Number of participants with at least one dose reduction and at least one dose interruption of study drugs. Dose adjustments were permitted for patients who did not tolerate the protocol-specified dosing schedule. No dose reductions were allowed for NIS793 and spartalizumab in the Randomized part. Due to EudraCT system limitations, data fields in the table cannot be empty or contain letters (e.g. NA indicating ‘not applicable’). Therefore, not applicable values are indicated as ‘999’.
    End point type
    Secondary
    End point timeframe
    Up to approximately 1.7 years
    Notes
    [14] - 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 endpoint is applicable to the Randomized part only.
    End point values
    		 Arm 1: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel Arm 2: NIS793 + gemcitabine/nab-paclitaxel Arm 3: gemcitabine/nab-paclitaxel
    Number of subjects analysed
    46
    49 [15]
    45 [16]
    Units: participants
        NIS793: ≥1 dose reduction or interruption
    35
    31
    999
        NIS793: ≥1 dose reduction
    0
    0
    999
        NIS793: ≥1 dose interruption
    35
    31
    999
        Spartalizumab: ≥1 dose reduction or interruption
    21
    999
    999
        Spartalizumab: ≥1 dose reduction
    0
    999
    999
        Spartalizumab: ≥1 dose interruption
    21
    999
    999
        Gemcitabine: ≥1 dose reduction or interruption
    38
    41
    32
        Gemcitabine: ≥1 dose reduction
    25
    23
    19
        Gemcitabine: ≥1 dose interruption
    35
    36
    29
        Nab-paclitaxel: ≥1 dose reduction or interruption
    39
    43
    34
        Nab-paclitaxel: ≥1 dose reduction
    26
    27
    19
        Nab-paclitaxel: ≥1 dose interruption
    34
    37
    32
    Notes
    [15] - The dose reductions and interruptions of spartalizumab are not applicable.
    [16] - The dose reductions and interruptions of spartalizumab and NIS793 are not applicable.
    No statistical analyses for this end point

    Secondary: Randomized Part: Dose intensity of NIS973 and spartalizumab

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    End point title
    		 Randomized Part: Dose intensity of NIS973 and spartalizumab [17]
    End point description
    Dose intensity of NIS973 and spartalizumab was calculated as cumulative actual dose in milligrams divided by duration of exposure in days and multiplied by 28 days. Due to EudraCT system limitations, data fields in the table cannot be empty or contain letters (e.g. NA indicating ‘not applicable’). Therefore, not applicable values are indicated as ‘999’.
    End point type
    Secondary
    End point timeframe
    Cycle 1 and Cycle 3. The duration of each cycle was 28 days
    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 endpoint is applicable to the Randomized part only.
    End point values
    		 Arm 1: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel Arm 2: NIS793 + gemcitabine/nab-paclitaxel
    Number of subjects analysed
    46
    49 [18]
    Units: mg per cycle
    arithmetic mean (standard deviation)
        NIS793 - cycle 1 (n=46,49)
    3515.2 ( 995.32 )
    3857.1 ( 784.22 )
        NIS793 - cycle 3 (n=26,42)
    3796.2 ( 844.03 )
    3550.0 ( 982.59 )
        Spartalizumab - cycle 1 (n=46,0)
    400.0 ( 0.00 )
    999 ( 999 )
        Spartalizumab - cycle 3 (n=24,0)
    400.0 ( 0.00 )
    999 ( 999 )
    Notes
    [18] - Dose intensity of spartalizumab is not applicable.
    No statistical analyses for this end point

    Secondary: Randomized Part: Dose intensity of gemcitabine and nab-paclitaxel

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    End point title
    		 Randomized Part: Dose intensity of gemcitabine and nab-paclitaxel [19]
    End point description
    Dose intensity of gemcitabine and nab-paclitaxel was calculated as cumulative actual dose in milligrams/m^2 divided by duration of exposure in days and multiplied by 28 days.
    End point type
    Secondary
    End point timeframe
    Cycle 1 and Cycle 3. The duration of each cycle was 28 days
    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 endpoint is applicable to the Randomized part only.
    End point values
    		 Arm 1: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel Arm 2: NIS793 + gemcitabine/nab-paclitaxel Arm 3: gemcitabine/nab-paclitaxel
    Number of subjects analysed
    46
    49
    45
    Units: mg per m^2 per cycle
    arithmetic mean (standard deviation)
        Gemcitabine - cycle 1 (n=46,49,45)
    2442.3 ( 675.34 )
    2644.8 ( 543.43 )
    2392.1 ( 651.00 )
        Gemcitabine - cycle 3 (n=29,42,29)
    2293.9 ( 710.08 )
    2426.5 ( 696.10 )
    2445.3 ( 561.36 )
        Nab-paclitaxel - cycle 1 (n=46,49,45)
    307.5 ( 84.91 )
    330.7 ( 67.95 )
    298.8 ( 80.96 )
        Nab-paclitaxel - cycle 3 (n=29,42,29)
    286.2 ( 86.45 )
    296.2 ( 88.06 )
    299.1 ( 70.08 )
    No statistical analyses for this end point

    Secondary: Randomized Part: Overall Response Rate (ORR) per RECIST v1.1

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    End point title
    		 Randomized Part: Overall Response Rate (ORR) per RECIST v1.1 [20]
    End point description
    ORR is the percentage of patients with a confirmed best overall response of complete response (CR) or partial response (PR), based on local investigator assessment per Response Evaluation Criteria for Solid Tumors (RECIST) v1.1. For RECIST v1.1, CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm; PR= At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
    End point type
    Secondary
    End point timeframe
    Up to approximately 1.7 years
    Notes
    [20] - 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 endpoint is applicable to the Randomized part only.
    End point values
    		 Arm 1: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel Arm 2: NIS793 + gemcitabine/nab-paclitaxel Arm 3: gemcitabine/nab-paclitaxel
    Number of subjects analysed
    50
    51
    52
    Units: percentage of participants
        number (confidence interval 95%)
    22.0 (11.5 to 36.0)
    31.4 (19.1 to 45.9)
    15.4 (6.9 to 28.1)
    No statistical analyses for this end point

    Secondary: Randomized Part: Duration of Response (DOR) per RECIST v1.1

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    End point title
    		 Randomized Part: Duration of Response (DOR) per RECIST v1.1 [21]
    End point description
    DOR per RECIST v1.1 is defined as the time from the first documented response of CR or PR to the date of the first documented progression or death. DOR only applies to patients with a best overall response of CR or PR by investigator assessment per RECIST v1.1. Participants continuing without progression or death were censored at the date of their last adequate tumor assessment. DOR was analyzed using the Kaplan-Meier method.
    End point type
    Secondary
    End point timeframe
    Up to approximately 1.7 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 endpoint is applicable to the Randomized part only.
    End point values
    		 Arm 1: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel Arm 2: NIS793 + gemcitabine/nab-paclitaxel Arm 3: gemcitabine/nab-paclitaxel
    Number of subjects analysed
    16
    18
    15
    Units: months
        arithmetic mean (confidence interval 95%)
    5.85 (2.43 to 9.43)
    4.32 (3.61 to 6.37)
    3.73 (1.84 to 12.91)
    No statistical analyses for this end point

    Secondary: Randomized Part: Time to Progression (TTP) per RECIST v1.1

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    End point title
    		 Randomized Part: Time to Progression (TTP) per RECIST v1.1 [22]
    End point description
    TTP per RECIST v1.1 is defined as the time from the date of randomization to the date of event defined as the first documented progression per RECIST v1.1 or death due to underlying cancer. If a participant had no progression or death, the participant was censored at the date of last adequate tumor assessment. DOR was analyzed using the Kaplan-Meier method.
    End point type
    Secondary
    End point timeframe
    Up to approximately 1.7 years
    Notes
    [22] - 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 endpoint is applicable to the Randomized part only.
    End point values
    		 Arm 1: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel Arm 2: NIS793 + gemcitabine/nab-paclitaxel Arm 3: gemcitabine/nab-paclitaxel
    Number of subjects analysed
    50
    51
    52
    Units: months
        median (confidence interval 95%)
    3.94 (3.55 to 7.03)
    5.59 (4.57 to 7.36)
    5.36 (3.68 to 8.61)
    No statistical analyses for this end point

    Secondary: Randomized Part: Overall Survival (OS)

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    End point title
    		 Randomized Part: Overall Survival (OS) [23]
    End point description
    Overall survival is defined as the time from the date of randomization to the date of death due to any cause. OS was analyzed using the Kaplan-Meier method.
    End point type
    Secondary
    End point timeframe
    Up to approximately 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 endpoint is applicable to the Randomized part only.
    End point values
    		 Arm 1: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel Arm 2: NIS793 + gemcitabine/nab-paclitaxel Arm 3: gemcitabine/nab-paclitaxel
    Number of subjects analysed
    50
    51
    52
    Units: months
        median (confidence interval 95%)
    10.7 (7.2 to 12.7)
    8.5 (7.7 to 9.9)
    10.1 (6.5 to 13.4)
    No statistical analyses for this end point

    Secondary: Randomized Part: Change from baseline in PD-L1 expression

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    End point title
    		 Randomized Part: Change from baseline in PD-L1 expression [24]
    End point description
    The tumor expression of programmed cell death-ligand 1 (PD-L1) was measured by immunohistochemical methods. Results are expressed as absolute change from baseline in PD-L1 expression.
    End point type
    Secondary
    End point timeframe
    Baseline (Screening), on-treatment (anytime between Cycle 3 Day 2 and Day 4). The duration of each cycle was 28 days.
    Notes
    [24] - 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 endpoint is applicable to the Randomized part only.
    End point values
    		 Arm 1: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel Arm 2: NIS793 + gemcitabine/nab-paclitaxel Arm 3: gemcitabine/nab-paclitaxel
    Number of subjects analysed
    4
    12
    5
    Units: PD-L1 positivity percentage
        arithmetic mean (standard deviation)
    7.625 ( 10.4193 )
    7.917 ( 17.0572 )
    4.000 ( 8.9443 )
    No statistical analyses for this end point

    Secondary: Randomized Part: Change from baseline in CD8 expression

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    End point title
    		 Randomized Part: Change from baseline in CD8 expression [25]
    End point description
    The tumor expression of CD8 was measured by immunohistochemical methods. Results are expressed as absolute change from baseline in CD8 expression.
    End point type
    Secondary
    End point timeframe
    Baseline (Screening), on-treatment (anytime between Cycle 3 Day 2 and Day 4). The duration of each cycle was 28 days.
    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 endpoint is applicable to the Randomized part only.
    End point values
    		 Arm 1: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel Arm 2: NIS793 + gemcitabine/nab-paclitaxel Arm 3: gemcitabine/nab-paclitaxel
    Number of subjects analysed
    3
    14
    6
    Units: percent marker area expression of CD8
        arithmetic mean (standard deviation)
    10.1 ( 11.01 )
    1.4 ( 2.64 )
    2.1 ( 1.82 )
    No statistical analyses for this end point

    Secondary: Randomized Part: Number of participants with anti-NIS793 antibodies

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    End point title
    		 Randomized Part: Number of participants with anti-NIS793 antibodies [26]
    End point description
    The immunogenicity (IG) against NIS793 was assessed in serum using a validated enhanced electrochemiluminescence immunoassay (ECLIA). Patient anti-drug antibodies (ADA) status was defined as follows: • ADA-negative at baseline: ADA-negative sample at baseline • ADA-positive at baseline: ADA-positive sample at baseline • ADA-negative post-baseline: patient with ADA-negative sample at baseline and at least 1 post baseline sample, all of which are ADA-negative samples • ADA-inconclusive post-baseline = patient who does not qualify as ADA-positive or ADA-negative post-baseline • Treatment-induced ADA-positive = ADA-negative sample at baseline and at least 1 treatment-induced ADA-positive sample
    End point type
    Secondary
    End point timeframe
    Baseline (before first dose) and post-baseline (assessed throughout the treatment up to approximately 1.7 years)
    Notes
    [26] - 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 endpoint is applicable to the Randomized part only.
    End point values
    		 Arm 1: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel Arm 2: NIS793 + gemcitabine/nab-paclitaxel
    Number of subjects analysed
    41
    44
    Units: participants
        ADA-negative at baseline
    41
    44
        ADA-positive at baseline
    0
    0
        ADA-negative post-baseline
    41
    44
        ADA- inconclusive post-baseline
    0
    0
        Treatment-induced ADA-positive
    0
    0
    No statistical analyses for this end point

    Secondary: Randomized Part: Number of participants with anti-spartalizumab antibodies

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    End point title
    		 Randomized Part: Number of participants with anti-spartalizumab antibodies [27]
    End point description
    The immunogenicity (IG) against spartalizumab was assessed in serum using a validated a validated homogenous enzyme-linked immunosorbent assay (ELISA). Patient anti-drug antibodies (ADA) status was defined as follows: • ADA-negative at baseline: ADA-negative sample at baseline • ADA-inconclusive at baseline: patient who does not qualify as ADA-positive or ADA-negative at baseline • ADA-positive at baseline: ADA-positive sample at baseline • ADA-negative post-baseline: patient with ADA-negative sample at baseline and at least 1 post baseline sample, all of which are ADA-negative samples • ADA-inconclusive post-baseline = patient who does not qualify as ADA-positive or ADA-negative post-baseline • Treatment-induced ADA-positive = ADA-negative sample at baseline and at least 1 treatment-induced ADA-positive sample
    End point type
    Secondary
    End point timeframe
    Cycle 1 and Cycle 3. The duration of each cycle was 28 days
    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 endpoint is applicable to the Randomized part only.
    End point values
    		 Arm 1: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel
    Number of subjects analysed
    41
    Units: participants
        ADA-negative at baseline
    40
        ADA- inconclusive at baseline
    1
        ADA-positive at baseline
    0
        ADA-negative post-baseline
    35
        ADA- inconclusive post-baseline
    2
        Treatment-induced ADA-positive
    4
    No statistical analyses for this end point

    Secondary: Randomized Part: Maximum observed serum concentration (Cmax) of NIS793

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    End point title
    		 Randomized Part: Maximum observed serum concentration (Cmax) of NIS793 [28]
    End point description
    Pharmacokinetic (PK) parameters were calculated based on NIS793 serum concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed concentration following a dose.
    End point type
    Secondary
    End point timeframe
    Cycle 1 and Cycle 3: pre-dose, 1, 24, 168 and 336 hours after the end of the infusion on Day 1. The duration of the infusion was 30 minutes. One cycle=28 days
    Notes
    [28] - 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 endpoint is applicable to the Randomized part only.
    End point values
    		 Arm 1: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel Arm 2: NIS793 + gemcitabine/nab-paclitaxel
    Number of subjects analysed
    42
    39
    Units: ng/mL
    arithmetic mean (standard deviation)
        Cycle 1 (n=42,39)
    603000 ( 181000 )
    622000 ( 192000 )
        Cycle 3 (n=21,31)
    821000 ( 235000 )
    784000 ( 286000 )
    No statistical analyses for this end point

    Secondary: Randomized Part: Area under the serum concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) of NIS793

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    End point title
    		 Randomized Part: Area under the serum concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) of NIS793 [29]
    End point description
    PK parameters were calculated based on NIS793 serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUClast calculation.
    End point type
    Secondary
    End point timeframe
    Cycle 1 and Cycle 3: pre-dose, 1, 24, 168 and 336 hours after the end of the infusion on Day 1. The duration of the infusion was 30 minutes. One cycle=28 days
    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 endpoint is applicable to the Randomized part only.
    End point values
    		 Arm 1: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel Arm 2: NIS793 + gemcitabine/nab-paclitaxel
    Number of subjects analysed
    42
    39
    Units: h*ng/mL
    arithmetic mean (standard deviation)
        Cycle 1 (n=42,39)
    84700000 ( 29300000 )
    96000000 ( 26100000 )
        Cycle 3 (n=21,31)
    153000000 ( 52300000 )
    151000000 ( 55000000 )
    No statistical analyses for this end point

    Secondary: Randomized Part: Trough serum concentration (Ctrough) of NIS793

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    End point title
    		 Randomized Part: Trough serum concentration (Ctrough) of NIS793 [30]
    End point description
    Ctrough is defined as the concentration reached immediately before the next dose is administered. All drug concentrations below the lower limit of quantification were treated as zero for the calculation of PK parameters.
    End point type
    Secondary
    End point timeframe
    Cycle 1: pre-dose on Day 1. Cycle 3: pre-dose on Day 1 and Day 15 (combined). One cycle=28 days
    Notes
    [30] - 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 endpoint is applicable to the Randomized part only.
    End point values
    		 Arm 1: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel Arm 2: NIS793 + gemcitabine/nab-paclitaxel
    Number of subjects analysed
    26
    34
    Units: ng/mL
    arithmetic mean (standard deviation)
        Cycle 1 (n=26,34)
    137000 ( 51700 )
    156000 ( 50100 )
        Cycle 3 (n=22,34)
    289000 ( 121000 )
    291000 ( 126000 )
    No statistical analyses for this end point

    Secondary: Randomized Part: Maximum observed serum concentration (Cmax) of spartalizumab

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    End point title
    		 Randomized Part: Maximum observed serum concentration (Cmax) of spartalizumab [31]
    End point description
    PK parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed concentration following a dose.
    End point type
    Secondary
    End point timeframe
    Cycle 1 and Cycle 3: pre-dose, 1, 24, 168 and 648 hours after the end of the infusion on Day 1. The duration of the infusion was 30 minutes. One cycle=28 days
    Notes
    [31] - 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 endpoint is applicable to the Randomized part only.
    End point values
    		 Arm 1: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel
    Number of subjects analysed
    42
    Units: µg/mL
    arithmetic mean (standard deviation)
        Cycle 1 (n=42)
    109 ( 22.4 )
        Cycle 3 (n=21)
    120 ( 38.0 )
    No statistical analyses for this end point

    Secondary: Randomized Part: Area under the serum concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) of spartalizumab

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    End point title
    		 Randomized Part: Area under the serum concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) of spartalizumab [32]
    End point description
    PK parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUClast calculation.
    End point type
    Secondary
    End point timeframe
    Cycle 1 and Cycle 3: pre-dose, 1, 24, 168 and 648 hours after the end of the infusion on Day 1. The duration of the infusion was 30 minutes. One cycle=28 days
    Notes
    [32] - 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 endpoint is applicable to the Randomized part only.
    End point values
    		 Arm 1: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel
    Number of subjects analysed
    42
    Units: h*µg/mL
    arithmetic mean (standard deviation)
        Cycle 1 (n=42)
    10800 ( 4900 )
        Cycle 3 (n=21)
    3240 ( 1900 )
    No statistical analyses for this end point

    Secondary: Randomized Part: Trough serum concentration (Ctrough) of spartalizumab

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    End point title
    		 Randomized Part: Trough serum concentration (Ctrough) of spartalizumab [33]
    End point description
    Ctrough is defined as the concentration reached immediately before the next dose is administered. All drug concentrations below the lower limit of quantification were treated as zero for the calculation of PK parameters.
    End point type
    Secondary
    End point timeframe
    Cycle 2, 3 and 4: pre-dose on Day 1. One cycle=28 days
    Notes
    [33] - 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 endpoint is applicable to the Randomized part only.
    End point values
    		 Arm 1: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel
    Number of subjects analysed
    32
    Units: µg/mL
    arithmetic mean (standard deviation)
        Cycle 2 (n=32)
    22.3 ( 8.67 )
        Cycle 3 (n=21)
    31.9 ( 11.7 )
        Cycle 4 (n=23)
    30.5 ( 14.3 )
    No statistical analyses for this end point

    Secondary: Randomized Part: Maximum observed plasma concentration (Cmax) of gemcitabine

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    End point title
    		 Randomized Part: Maximum observed plasma concentration (Cmax) of gemcitabine [34]
    End point description
    PK parameters were calculated based on gemcitabine plasma concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed concentration following a dose.
    End point type
    Secondary
    End point timeframe
    Cycle 1 and Cycle 4: pre-dose, end of infusion, and 2, 3, 5 and 24 hours after the start of infusion on Day 1. The duration of the infusion was according to the product labelling and local guidance. One cycle=28 days
    Notes
    [34] - 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 endpoint is applicable to the Randomized part only.
    End point values
    		 Arm 1: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel Arm 2: NIS793 + gemcitabine/nab-paclitaxel Arm 3: gemcitabine/nab-paclitaxel
    Number of subjects analysed
    42
    40
    44
    Units: ng/mL
    arithmetic mean (standard deviation)
        Cycle 1 (n=42,40,44)
    9830 ( 8580 )
    12000 ( 6850 )
    10600 ( 6170 )
        Cycle 4 (n=23,28,24)
    7950 ( 5650 )
    8830 ( 6150 )
    7000 ( 4210 )
    No statistical analyses for this end point

    Secondary: Randomized Part: Area under the serum concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) of gemcitabine

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    End point title
    		 Randomized Part: Area under the serum concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) of gemcitabine [35]
    End point description
    PK parameters were calculated based on gemcitabine plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUClast calculation.
    End point type
    Secondary
    End point timeframe
    Cycle 1 and Cycle 4: pre-dose, end of infusion, and 2, 3, 5 and 24 hours after the start of infusion on Day 1. The duration of the infusion was according to the product labelling and local guidance. One cycle=28 days
    Notes
    [35] - 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 endpoint is applicable to the Randomized part only.
    End point values
    		 Arm 1: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel Arm 2: NIS793 + gemcitabine/nab-paclitaxel Arm 3: gemcitabine/nab-paclitaxel
    Number of subjects analysed
    42
    40
    44
    Units: h*ng/mL
    arithmetic mean (standard deviation)
        Cycle 1 (n=42,40,44)
    7270 ( 6950 )
    9900 ( 6140 )
    8040 ( 4490 )
        Cycle 4 (n=23,28,24)
    5270 ( 4730 )
    5980 ( 4410 )
    4920 ( 2830 )
    No statistical analyses for this end point

    Secondary: Randomized Part: Trough serum concentration (Ctrough) of gemcitabine

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    End point title
    		 Randomized Part: Trough serum concentration (Ctrough) of gemcitabine [36]
    End point description
    Ctrough is defined as the concentration reached immediately before the next dose is administered. All drug concentrations below the lower limit of quantification were treated as zero for the calculation of PK parameters.
    End point type
    Secondary
    End point timeframe
    Cycle 4: pre-dose on Day 1. One cycle=28 days
    Notes
    [36] - 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 endpoint is applicable to the Randomized part only.
    End point values
    		 Arm 1: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel Arm 2: NIS793 + gemcitabine/nab-paclitaxel Arm 3: gemcitabine/nab-paclitaxel
    Number of subjects analysed
    24
    30
    23
    Units: ng/mL
        arithmetic mean (standard deviation)
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
    No statistical analyses for this end point

    Secondary: Randomized Part: Maximum observed plasma concentration (Cmax) of nab-paclitaxel

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    End point title
    		 Randomized Part: Maximum observed plasma concentration (Cmax) of nab-paclitaxel [37]
    End point description
    PK parameters were calculated based on nab-paclitaxel plasma concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed concentration following a dose.
    End point type
    Secondary
    End point timeframe
    Cycle 1 and Cycle 4: pre-dose, end of infusion, and 2, 3, 5 and 24 hours after the start of infusion on Day 1. The duration of the infusion was according to the product labelling and local guidance. One cycle=28 days
    Notes
    [37] - 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 endpoint is applicable to the Randomized part only.
    End point values
    		 Arm 1: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel Arm 2: NIS793 + gemcitabine/nab-paclitaxel Arm 3: gemcitabine/nab-paclitaxel
    Number of subjects analysed
    37
    38
    43
    Units: ng/mL
    arithmetic mean (standard deviation)
        Cycle 1 (n=37,38,43)
    9990 ( 37100 )
    4120 ( 3370 )
    3490 ( 1760 )
        Cycle 4 (n=19,28,24)
    4570 ( 4910 )
    4050 ( 2410 )
    2900 ( 1370 )
    No statistical analyses for this end point

    Secondary: Randomized Part: Area under the serum concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) of nab-paclitaxel

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    End point title
    		 Randomized Part: Area under the serum concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) of nab-paclitaxel [38]
    End point description
    PK parameters were calculated based on nab-paclitaxel plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUClast calculation.
    End point type
    Secondary
    End point timeframe
    Cycle 1 and Cycle 4: pre-dose, end of infusion, and 2, 3, 5 and 24 hours after the start of infusion on Day 1. The duration of the infusion was according to the product labelling and local guidance. One cycle=28 days
    Notes
    [38] - 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 endpoint is applicable to the Randomized part only.
    End point values
    		 Arm 1: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel Arm 2: NIS793 + gemcitabine/nab-paclitaxel Arm 3: gemcitabine/nab-paclitaxel
    Number of subjects analysed
    37
    38
    43
    Units: h*ng/mL
    arithmetic mean (standard deviation)
        Cycle 1 (n=37,38,43)
    15700 ( 52400 )
    5080 ( 2820 )
    4820 ( 2500 )
        Cycle 4 (n=19,28,24)
    5960 ( 3650 )
    5020 ( 3050 )
    4250 ( 2550 )
    No statistical analyses for this end point

    Secondary: Randomized Part: Trough serum concentration (Ctrough) of nab-paclitaxel

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    End point title
    		 Randomized Part: Trough serum concentration (Ctrough) of nab-paclitaxel [39]
    End point description
    Ctrough is defined as the concentration reached immediately before the next dose is administered. All drug concentrations below the lower limit of quantification were treated as zero for the calculation of PK parameters.
    End point type
    Secondary
    End point timeframe
    Cycle 4: pre-dose on Day 1. One cycle=28 days
    Notes
    [39] - 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 endpoint is applicable to the Randomized part only.
    End point values
    		 Arm 1: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel Arm 2: NIS793 + gemcitabine/nab-paclitaxel Arm 3: gemcitabine/nab-paclitaxel
    Number of subjects analysed
    19
    30
    23
    Units: ng/mL
        arithmetic mean (standard deviation)
    455 ( 1320 )
    2.13 ( 10.4 )
    3.25 ( 5.08 )
    No statistical analyses for this end point

    Post-hoc: All-Collected Deaths

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    End point title
    		 All-Collected Deaths
    End point description
    On-treatment and post-treatment safety follow-up (FU) deaths were collected from first dose of study treatment to 90 days after last dose of NIS793, 150 days after last dose of spartalizumab and 30 days after last dose of gemcitabine and nab-paclitaxel, whichever was longer. Survival FU deaths were collected from 91 days after last dose of NIS793, 151 days after last dose of spartalizumab and 31 days after last dose of gemcitabine and nab-paclitaxel, whichever was longer, until end of study. All deaths refer to the sum of pre-treatment deaths, on-treatment and post-treatment safety FU deaths, and survival FU deaths.
    End point type
    Post-hoc
    End point timeframe
    On-treatment and post-treatment safety FU deaths: up to approximately 1 year (run-in part) and 1.9 years (randomized part). Survival FU deaths: up to approximately 1.8 years (run-in part) and 2 years (randomized part)
    End point values
    		 Run-in: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel Arm 1: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel Arm 2: NIS793 + gemcitabine/nab-paclitaxel Arm 3: gemcitabine/nab-paclitaxel
    Number of subjects analysed
    11
    50
    51
    52
    Units: Participants
        On/post-treatment safety FU deaths (n=11,50,51,52)
    5
    18
    19
    4
        Survival FU deaths (n=6,28,30,41)
    5
    15
    22
    35
        All deaths (n=11,50,51,52)
    10
    33
    41
    39
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs: up to approximately 1 year (run-in part) and 1.9 years (randomized part). Deaths: up to approximately 1.8 years (run-in part) and 2 years (randomized part).
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.0
    Reporting groups
    Reporting group title
    Run-in: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel
    Reporting group description
    		 NIS793 2100 mg every 2 weeks i.v. with spartalizumab 400 mg every 4 weeks i.v and standard of care chemotherapy in the safety run-in part

    Reporting group title
    Arm 1: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel
    Reporting group description
    		 NIS793 2100 mg every 2 weeks i.v. with spartalizumab 400 mg every 4 weeks i.v and standard of care chemotherapy in the randomized part

    Reporting group title
    Arm 2: NIS793 + gemcitabine/nab-paclitaxel
    Reporting group description
    		 NIS793 2100 mg every 2 weeks i.v. with standard of care chemotherapy in the randomized part

    Reporting group title
    Arm 3: gemcitabine/nab-paclitaxel
    Reporting group description
    		 Standard of care chemotherapy in the randomized part

    Serious adverse events
    		 Run-in: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel Arm 1: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel Arm 2: NIS793 + gemcitabine/nab-paclitaxel Arm 3: gemcitabine/nab-paclitaxel
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 11 (72.73%)
    34 / 46 (73.91%)
    28 / 49 (57.14%)
    26 / 45 (57.78%)
         number of deaths (all causes)
    10
    33
    41
    39
         number of deaths resulting from adverse events
    1
    2
    4
    4
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour obstruction
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    1 / 49 (2.04%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    1 / 49 (2.04%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    2 / 49 (4.08%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    0 / 49 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    0 / 49 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    1 / 49 (2.04%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Gait inability
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    1 / 49 (2.04%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 11 (0.00%)
    3 / 46 (6.52%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    0 / 49 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 11 (18.18%)
    5 / 46 (10.87%)
    3 / 49 (6.12%)
    5 / 45 (11.11%)
         occurrences causally related to treatment / all
    2 / 2
    8 / 8
    4 / 4
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 46 (2.17%)
    1 / 49 (2.04%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Orchitis noninfective
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    2 / 49 (4.08%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    1 / 49 (2.04%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    0 / 49 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumomediastinum
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    1 / 49 (2.04%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    1 / 49 (2.04%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    1 / 49 (2.04%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    2 / 49 (4.08%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    1 / 49 (2.04%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    1 / 49 (2.04%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
    1 / 49 (2.04%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial necrosis marker increased
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical condition abnormal
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
    1 / 49 (2.04%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    1 / 49 (2.04%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Craniofacial fracture
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    0 / 49 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acetabulum fracture
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    1 / 49 (2.04%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Scapula fracture
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    0 / 49 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Demyelinating polyneuropathy
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    1 / 49 (2.04%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    1 / 49 (2.04%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 46 (4.35%)
    6 / 49 (12.24%)
    2 / 45 (4.44%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
    7 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood loss anaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemolysis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    1 / 49 (2.04%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 46 (4.35%)
    1 / 49 (2.04%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemolytic uraemic syndrome
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    1 / 49 (2.04%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain lower
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    1 / 49 (2.04%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 11 (9.09%)
    2 / 46 (4.35%)
    0 / 49 (0.00%)
    3 / 45 (6.67%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    1 / 49 (2.04%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 11 (9.09%)
    2 / 46 (4.35%)
    1 / 49 (2.04%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    1 / 49 (2.04%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 11 (0.00%)
    5 / 46 (10.87%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    6 / 6
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea haemorrhagic
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal obstruction
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal perforation
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    1 / 49 (2.04%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis haemorrhagic
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Gastrointestinal pain
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal toxicity
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    0 / 49 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    0 / 49 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    1 / 49 (2.04%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Immune-mediated enterocolitis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    2 / 49 (4.08%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    1 / 49 (2.04%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    1 / 49 (2.04%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    1 / 49 (2.04%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Impaired gastric emptying
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    1 / 49 (2.04%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    2 / 49 (4.08%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal haemorrhage
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    2 / 49 (4.08%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    1 / 49 (2.04%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 46 (4.35%)
    2 / 49 (4.08%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Biliary obstruction
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    2 / 49 (4.08%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated hepatitis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gallbladder rupture
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    0 / 49 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Hepatitis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertransaminasaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    0 / 49 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    0 / 49 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Proteinuria
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder tamponade
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    0 / 11 (0.00%)
    3 / 46 (6.52%)
    1 / 49 (2.04%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Glucocorticoid deficiency
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypopituitarism
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Degenerative bone disease
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    1 / 49 (2.04%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal infection
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    1 / 49 (2.04%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acarodermatitis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    0 / 49 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    1 / 49 (2.04%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Biliary sepsis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    0 / 49 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Biliary tract infection
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    1 / 49 (2.04%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Campylobacter infection
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    2 / 49 (4.08%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 11 (0.00%)
    3 / 46 (6.52%)
    1 / 49 (2.04%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine infection
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    1 / 49 (2.04%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    3 / 49 (6.12%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 11 (9.09%)
    4 / 46 (8.70%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia pseudomonal
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 11 (0.00%)
    4 / 46 (8.70%)
    3 / 49 (6.12%)
    3 / 45 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
    4 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    2 / 2
    Relapsing fever
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    1 / 49 (2.04%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    1 / 49 (2.04%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    1 / 49 (2.04%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    1 / 49 (2.04%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    2 / 49 (4.08%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    1 / 49 (2.04%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Run-in: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel Arm 1: NIS793 + spartalizumab + gemcitabine/nab-paclitaxel Arm 2: NIS793 + gemcitabine/nab-paclitaxel Arm 3: gemcitabine/nab-paclitaxel
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 11 (100.00%)
    45 / 46 (97.83%)
    48 / 49 (97.96%)
    40 / 45 (88.89%)
    Vascular disorders
    Jugular vein thrombosis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 46 (4.35%)
    2 / 49 (4.08%)
    3 / 45 (6.67%)
         occurrences all number
    0
    2
    3
    3
    Hypertension
         subjects affected / exposed
    1 / 11 (9.09%)
    3 / 46 (6.52%)
    4 / 49 (8.16%)
    2 / 45 (4.44%)
         occurrences all number
    2
    4
    4
    4
    Hypotension
         subjects affected / exposed
    0 / 11 (0.00%)
    4 / 46 (8.70%)
    6 / 49 (12.24%)
    4 / 45 (8.89%)
         occurrences all number
    0
    4
    7
    4
    Vein rupture
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    2
    0
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    5 / 11 (45.45%)
    12 / 46 (26.09%)
    16 / 49 (32.65%)
    11 / 45 (24.44%)
         occurrences all number
    5
    19
    36
    22
    Chills
         subjects affected / exposed
    1 / 11 (9.09%)
    3 / 46 (6.52%)
    2 / 49 (4.08%)
    5 / 45 (11.11%)
         occurrences all number
    1
    4
    2
    5
    Fatigue
         subjects affected / exposed
    7 / 11 (63.64%)
    23 / 46 (50.00%)
    18 / 49 (36.73%)
    14 / 45 (31.11%)
         occurrences all number
    8
    29
    22
    18
    Mucosal inflammation
         subjects affected / exposed
    1 / 11 (9.09%)
    5 / 46 (10.87%)
    4 / 49 (8.16%)
    1 / 45 (2.22%)
         occurrences all number
    1
    5
    4
    1
    Oedema
         subjects affected / exposed
    1 / 11 (9.09%)
    3 / 46 (6.52%)
    0 / 49 (0.00%)
    2 / 45 (4.44%)
         occurrences all number
    1
    5
    0
    2
    Oedema peripheral
         subjects affected / exposed
    4 / 11 (36.36%)
    11 / 46 (23.91%)
    15 / 49 (30.61%)
    8 / 45 (17.78%)
         occurrences all number
    5
    15
    19
    10
    Pain
         subjects affected / exposed
    1 / 11 (9.09%)
    2 / 46 (4.35%)
    1 / 49 (2.04%)
    1 / 45 (2.22%)
         occurrences all number
    1
    2
    1
    3
    Pyrexia
         subjects affected / exposed
    7 / 11 (63.64%)
    19 / 46 (41.30%)
    11 / 49 (22.45%)
    14 / 45 (31.11%)
         occurrences all number
    12
    36
    28
    30
    Reproductive system and breast disorders
    Prostatomegaly
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Nasal dryness
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    3 / 49 (6.12%)
    1 / 45 (2.22%)
         occurrences all number
    0
    0
    3
    1
    Epistaxis
         subjects affected / exposed
    2 / 11 (18.18%)
    11 / 46 (23.91%)
    14 / 49 (28.57%)
    1 / 45 (2.22%)
         occurrences all number
    3
    13
    17
    1
    Dyspnoea
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 46 (2.17%)
    8 / 49 (16.33%)
    7 / 45 (15.56%)
         occurrences all number
    1
    1
    9
    7
    Cough
         subjects affected / exposed
    1 / 11 (9.09%)
    3 / 46 (6.52%)
    11 / 49 (22.45%)
    12 / 45 (26.67%)
         occurrences all number
    1
    5
    12
    12
    Pulmonary embolism
         subjects affected / exposed
    1 / 11 (9.09%)
    4 / 46 (8.70%)
    3 / 49 (6.12%)
    1 / 45 (2.22%)
         occurrences all number
    1
    4
    3
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 11 (9.09%)
    4 / 46 (8.70%)
    3 / 49 (6.12%)
    7 / 45 (15.56%)
         occurrences all number
    1
    4
    3
    7
    Anxiety
         subjects affected / exposed
    0 / 11 (0.00%)
    3 / 46 (6.52%)
    4 / 49 (8.16%)
    0 / 45 (0.00%)
         occurrences all number
    0
    3
    4
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 11 (36.36%)
    14 / 46 (30.43%)
    10 / 49 (20.41%)
    10 / 45 (22.22%)
         occurrences all number
    7
    14
    15
    13
    Amylase increased
         subjects affected / exposed
    1 / 11 (9.09%)
    5 / 46 (10.87%)
    2 / 49 (4.08%)
    2 / 45 (4.44%)
         occurrences all number
    2
    6
    2
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 11 (36.36%)
    13 / 46 (28.26%)
    9 / 49 (18.37%)
    7 / 45 (15.56%)
         occurrences all number
    6
    15
    17
    11
    Blood alkaline phosphatase increased
         subjects affected / exposed
    2 / 11 (18.18%)
    4 / 46 (8.70%)
    2 / 49 (4.08%)
    3 / 45 (6.67%)
         occurrences all number
    2
    4
    3
    3
    Blood bilirubin increased
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    5 / 49 (10.20%)
    4 / 45 (8.89%)
         occurrences all number
    0
    1
    5
    4
    Blood creatinine increased
         subjects affected / exposed
    0 / 11 (0.00%)
    3 / 46 (6.52%)
    1 / 49 (2.04%)
    0 / 45 (0.00%)
         occurrences all number
    0
    3
    1
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 46 (4.35%)
    3 / 49 (6.12%)
    1 / 45 (2.22%)
         occurrences all number
    0
    2
    6
    2
    C-reactive protein increased
         subjects affected / exposed
    0 / 11 (0.00%)
    4 / 46 (8.70%)
    2 / 49 (4.08%)
    0 / 45 (0.00%)
         occurrences all number
    0
    4
    3
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    4 / 11 (36.36%)
    1 / 46 (2.17%)
    1 / 49 (2.04%)
    2 / 45 (4.44%)
         occurrences all number
    5
    1
    1
    2
    Lipase increased
         subjects affected / exposed
    2 / 11 (18.18%)
    5 / 46 (10.87%)
    3 / 49 (6.12%)
    2 / 45 (4.44%)
         occurrences all number
    3
    6
    3
    3
    Tri-iodothyronine decreased
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Platelet count decreased
         subjects affected / exposed
    1 / 11 (9.09%)
    8 / 46 (17.39%)
    10 / 49 (20.41%)
    9 / 45 (20.00%)
         occurrences all number
    1
    16
    14
    10
    White blood cell count decreased
         subjects affected / exposed
    0 / 11 (0.00%)
    3 / 46 (6.52%)
    3 / 49 (6.12%)
    3 / 45 (6.67%)
         occurrences all number
    0
    4
    5
    5
    Weight decreased
         subjects affected / exposed
    2 / 11 (18.18%)
    2 / 46 (4.35%)
    6 / 49 (12.24%)
    5 / 45 (11.11%)
         occurrences all number
    2
    3
    7
    5
    Neutrophil count decreased
         subjects affected / exposed
    2 / 11 (18.18%)
    7 / 46 (15.22%)
    8 / 49 (16.33%)
    9 / 45 (20.00%)
         occurrences all number
    2
    20
    16
    21
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 46 (2.17%)
    1 / 49 (2.04%)
    1 / 45 (2.22%)
         occurrences all number
    1
    1
    3
    1
    Infusion related reaction
         subjects affected / exposed
    1 / 11 (9.09%)
    2 / 46 (4.35%)
    0 / 49 (0.00%)
    2 / 45 (4.44%)
         occurrences all number
    1
    3
    0
    2
    Wound dehiscence
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
    1 / 49 (2.04%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 11 (9.09%)
    2 / 46 (4.35%)
    1 / 49 (2.04%)
    2 / 45 (4.44%)
         occurrences all number
    1
    2
    2
    2
    Dysgeusia
         subjects affected / exposed
    1 / 11 (9.09%)
    6 / 46 (13.04%)
    5 / 49 (10.20%)
    4 / 45 (8.89%)
         occurrences all number
    1
    6
    5
    4
    Dizziness
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    3 / 49 (6.12%)
    4 / 45 (8.89%)
         occurrences all number
    0
    1
    5
    4
    Hypoaesthesia
         subjects affected / exposed
    0 / 11 (0.00%)
    3 / 46 (6.52%)
    3 / 49 (6.12%)
    3 / 45 (6.67%)
         occurrences all number
    0
    3
    3
    3
    Paraesthesia
         subjects affected / exposed
    2 / 11 (18.18%)
    4 / 46 (8.70%)
    3 / 49 (6.12%)
    6 / 45 (13.33%)
         occurrences all number
    3
    6
    4
    9
    Neurotoxicity
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    4 / 45 (8.89%)
         occurrences all number
    0
    1
    0
    5
    Neuropathy peripheral
         subjects affected / exposed
    0 / 11 (0.00%)
    5 / 46 (10.87%)
    11 / 49 (22.45%)
    5 / 45 (11.11%)
         occurrences all number
    0
    5
    11
    5
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 11 (0.00%)
    4 / 46 (8.70%)
    2 / 49 (4.08%)
    4 / 45 (8.89%)
         occurrences all number
    0
    6
    2
    5
    Polyneuropathy
         subjects affected / exposed
    1 / 11 (9.09%)
    5 / 46 (10.87%)
    5 / 49 (10.20%)
    1 / 45 (2.22%)
         occurrences all number
    1
    5
    7
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 11 (45.45%)
    29 / 46 (63.04%)
    33 / 49 (67.35%)
    20 / 45 (44.44%)
         occurrences all number
    8
    40
    52
    33
    Leukopenia
         subjects affected / exposed
    1 / 11 (9.09%)
    4 / 46 (8.70%)
    2 / 49 (4.08%)
    3 / 45 (6.67%)
         occurrences all number
    1
    4
    5
    5
    Leukocytosis
         subjects affected / exposed
    1 / 11 (9.09%)
    3 / 46 (6.52%)
    0 / 49 (0.00%)
    2 / 45 (4.44%)
         occurrences all number
    1
    4
    0
    3
    Neutrophilia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Neutropenia
         subjects affected / exposed
    5 / 11 (45.45%)
    11 / 46 (23.91%)
    9 / 49 (18.37%)
    9 / 45 (20.00%)
         occurrences all number
    8
    24
    16
    26
    Thrombocytopenia
         subjects affected / exposed
    2 / 11 (18.18%)
    7 / 46 (15.22%)
    4 / 49 (8.16%)
    4 / 45 (8.89%)
         occurrences all number
    6
    7
    7
    13
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 11 (9.09%)
    4 / 46 (8.70%)
    9 / 49 (18.37%)
    4 / 45 (8.89%)
         occurrences all number
    1
    4
    9
    6
    Abdominal discomfort
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    3 / 49 (6.12%)
    1 / 45 (2.22%)
         occurrences all number
    0
    0
    5
    1
    Abdominal pain upper
         subjects affected / exposed
    1 / 11 (9.09%)
    4 / 46 (8.70%)
    8 / 49 (16.33%)
    5 / 45 (11.11%)
         occurrences all number
    1
    4
    10
    6
    Aphthous ulcer
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
    1 / 49 (2.04%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Constipation
         subjects affected / exposed
    1 / 11 (9.09%)
    16 / 46 (34.78%)
    16 / 49 (32.65%)
    12 / 45 (26.67%)
         occurrences all number
    1
    18
    22
    13
    Dyspepsia
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 46 (0.00%)
    1 / 49 (2.04%)
    0 / 45 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Dry mouth
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    4 / 49 (8.16%)
    3 / 45 (6.67%)
         occurrences all number
    0
    1
    4
    3
    Diarrhoea
         subjects affected / exposed
    5 / 11 (45.45%)
    26 / 46 (56.52%)
    19 / 49 (38.78%)
    18 / 45 (40.00%)
         occurrences all number
    11
    38
    28
    28
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    5 / 49 (10.20%)
    4 / 45 (8.89%)
         occurrences all number
    0
    2
    5
    5
    Ileal perforation
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Haemorrhoids
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 46 (2.17%)
    3 / 49 (6.12%)
    0 / 45 (0.00%)
         occurrences all number
    1
    2
    3
    0
    Gingival swelling
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 46 (0.00%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Gingival hypertrophy
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gingival bleeding
         subjects affected / exposed
    2 / 11 (18.18%)
    1 / 46 (2.17%)
    6 / 49 (12.24%)
    0 / 45 (0.00%)
         occurrences all number
    2
    1
    7
    0
    Ileus
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 46 (2.17%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Vomiting
         subjects affected / exposed
    3 / 11 (27.27%)
    10 / 46 (21.74%)
    18 / 49 (36.73%)
    12 / 45 (26.67%)
         occurrences all number
    3
    15
    24
    14
    Tongue disorder
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Tongue coated
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Stomatitis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 46 (2.17%)
    4 / 49 (8.16%)
    0 / 45 (0.00%)
         occurrences all number
    0
    1
    4
    0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
    1 / 49 (2.04%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Nausea
         subjects affected / exposed
    7 / 11 (63.64%)
    20 / 46 (43.48%)
    27 / 49 (55.10%)
    20 / 45 (44.44%)
         occurrences all number
    9
    28
    42
    31
    Hepatobiliary disorders
    Immune-mediated hepatitis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hepatobiliary disease
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pruritus
         subjects affected / exposed
    2 / 11 (18.18%)
    14 / 46 (30.43%)
    8 / 49 (16.33%)
    1 / 45 (2.22%)
         occurrences all number
    4
    25
    9
    1
    Rash
         subjects affected / exposed
    6 / 11 (54.55%)
    13 / 46 (28.26%)
    18 / 49 (36.73%)
    5 / 45 (11.11%)
         occurrences all number
    7
    17
    24
    5
    Rash macular
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Onycholysis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Night sweats
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
    2 / 49 (4.08%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Erythema
         subjects affected / exposed
    1 / 11 (9.09%)
    4 / 46 (8.70%)
    3 / 49 (6.12%)
    1 / 45 (2.22%)
         occurrences all number
    1
    5
    3
    1
    Alopecia
         subjects affected / exposed
    3 / 11 (27.27%)
    11 / 46 (23.91%)
    15 / 49 (30.61%)
    7 / 45 (15.56%)
         occurrences all number
    3
    11
    15
    7
    Dry skin
         subjects affected / exposed
    0 / 11 (0.00%)
    3 / 46 (6.52%)
    3 / 49 (6.12%)
    1 / 45 (2.22%)
         occurrences all number
    0
    3
    3
    1
    Rash maculo-papular
         subjects affected / exposed
    2 / 11 (18.18%)
    10 / 46 (21.74%)
    1 / 49 (2.04%)
    0 / 45 (0.00%)
         occurrences all number
    3
    15
    1
    0
    Skin toxicity
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 11 (0.00%)
    3 / 46 (6.52%)
    1 / 49 (2.04%)
    0 / 45 (0.00%)
         occurrences all number
    0
    4
    1
    0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    5 / 49 (10.20%)
    2 / 45 (4.44%)
         occurrences all number
    0
    0
    5
    2
    Neck pain
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 46 (2.17%)
    1 / 49 (2.04%)
    1 / 45 (2.22%)
         occurrences all number
    1
    1
    1
    1
    Myalgia
         subjects affected / exposed
    0 / 11 (0.00%)
    3 / 46 (6.52%)
    1 / 49 (2.04%)
    4 / 45 (8.89%)
         occurrences all number
    0
    4
    1
    4
    Back pain
         subjects affected / exposed
    1 / 11 (9.09%)
    6 / 46 (13.04%)
    5 / 49 (10.20%)
    2 / 45 (4.44%)
         occurrences all number
    1
    7
    6
    2
    Arthralgia
         subjects affected / exposed
    1 / 11 (9.09%)
    4 / 46 (8.70%)
    5 / 49 (10.20%)
    8 / 45 (17.78%)
         occurrences all number
    1
    5
    7
    11
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 46 (0.00%)
    2 / 49 (4.08%)
    3 / 45 (6.67%)
         occurrences all number
    0
    0
    2
    3
    Infection
         subjects affected / exposed
    1 / 11 (9.09%)
    2 / 46 (4.35%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    1
    2
    0
    0
    COVID-19
         subjects affected / exposed
    1 / 11 (9.09%)
    13 / 46 (28.26%)
    6 / 49 (12.24%)
    5 / 45 (11.11%)
         occurrences all number
    1
    13
    6
    6
    Urinary tract infection
         subjects affected / exposed
    0 / 11 (0.00%)
    7 / 46 (15.22%)
    6 / 49 (12.24%)
    1 / 45 (2.22%)
         occurrences all number
    0
    11
    6
    1
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 11 (9.09%)
    8 / 46 (17.39%)
    6 / 49 (12.24%)
    9 / 45 (20.00%)
         occurrences all number
    1
    12
    9
    12
    Hypochloraemia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 46 (0.00%)
    0 / 49 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hypocalcaemia
         subjects affected / exposed
    2 / 11 (18.18%)
    1 / 46 (2.17%)
    1 / 49 (2.04%)
    1 / 45 (2.22%)
         occurrences all number
    2
    2
    1
    1
    Decreased appetite
         subjects affected / exposed
    4 / 11 (36.36%)
    10 / 46 (21.74%)
    17 / 49 (34.69%)
    15 / 45 (33.33%)
         occurrences all number
    7
    11
    25
    17
    Hyperglycaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    4 / 46 (8.70%)
    1 / 49 (2.04%)
    3 / 45 (6.67%)
         occurrences all number
    0
    4
    1
    3
    Hypophosphataemia
         subjects affected / exposed
    3 / 11 (27.27%)
    9 / 46 (19.57%)
    7 / 49 (14.29%)
    2 / 45 (4.44%)
         occurrences all number
    4
    12
    9
    2
    Hyponatraemia
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 46 (2.17%)
    2 / 49 (4.08%)
    2 / 45 (4.44%)
         occurrences all number
    1
    1
    6
    2
    Hypomagnesaemia
         subjects affected / exposed
    1 / 11 (9.09%)
    4 / 46 (8.70%)
    2 / 49 (4.08%)
    3 / 45 (6.67%)
         occurrences all number
    1
    6
    2
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Jul 2020
    Amendment 1 introduced changes to address Health Authorities request to incorporate grade 3 diarrhea lasting for >72 hours as a DLT.
    31 Aug 2020
    Amendment 2 introduced changes to address Health Authorities request to state that sexually active males have to use a condom while taking study treatment and for 180 days after stopping treatment and to include instruction to follow contraception recommendations and other precautionary measures required by locally approved SmPC of gemcitabine and nab-paclitaxel.
    16 Apr 2021
    Amendment 3 was made to address the following: • Additional precautionary measures were implemented to enhance cardio-vascular and renal risks mitigation. • Additional clarification on the mitigation of risks already described in the NIS793 Investigator Brochure including exclusion criterion related to bleeding risk was added and drug-induced liver injury (DILI) was included in the dose modification recommendation. • Primary estimands were revised and secondary estimands related to efficacy objectives (anti-tumor response, overall survival) were introduced. • In order to mitigate the risks for participant safety and data integrity due to disruptions (e.g. COVID-19), disruption proofing language was added throughout the protocol. • Maximum permitted duration of study treatment interruption or delay was extended to 12 weeks to account for potential immune related toxicity and allow more time for recovery in case of toxicity. • For consistency between both study treatments, spartalizumab and NIS793, the 2h observation period was aligned to the first cycle.
    18 Apr 2022
    Amendment 4 was made to allow for potential interim analysis (IA) where statistical analyses by treatment arm can be conducted.

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

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

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