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    Clinical Trial Results:
    A Phase II Multi-Center Study of BGB324 in Combination with Pembrolizumab in Patients with Previously Treated Advanced Adenocarcinoma of the Lung

    Summary
    EudraCT number
    		 2016-003609-32
    Trial protocol
    		 NO   GB   ES  
    Global end of trial date
    27 Oct 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Nov 2023
    First version publication date
    15 Nov 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BGBC008
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03184571
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 MSD: MK-3475 PN531
    Sponsors
    Sponsor organisation name
    BerGenBio ASA
    Sponsor organisation address
    Mollendalsbakken 9, Bergen, Norway, 5009
    Public contact
    Clinical Project Manager, BerGenBio ASA, +47 55961159, regulatory.bgbc008@bergenbio.com
    Scientific contact
    Clinical Project Manager, BerGenBio ASA, +47 55961159, regulatory.bgbc008@bergenbio.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    20 Feb 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Oct 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the anti-tumor activity of bemcentinib and pembrolizumab when given in combination.
    Protection of trial subjects
    The study was conducted in accordance with International Council for Harmonization , Good clinical practice (GCP), the Declaration of Helsinki, the European Union Clinical Trials Directive 2001/20/EC, the GCP Directive 2005/28/EC, the requirements of local , Institutional Ethics Committee/ Institutional Review Board and the United States (US) Code of Federal Regulations (CFR), Title 21 CFR Part 50.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Oct 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Norway: 10
    Country: Number of subjects enrolled
    Spain: 64
    Country: Number of subjects enrolled
    United Kingdom: 20
    Country: Number of subjects enrolled
    United States: 5
    Worldwide total number of subjects
    99
    EEA total number of subjects
    74
    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)
    46
    From 65 to 84 years
    52
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 138 subjects were enrolled in study, of these 39 subjects did not receive any treatment for the following reasons: 30 screen failures; 2 due to death; 2 due to voluntary withdrawal; 2 lost to follow-up and 3 due to an unspecified reason.

    Pre-assignment
    Screening details
    		 A total of 138 subjects were enrolled in the study, however, the subject information detailed in this record relates to the 99 subjects who received at least one dose of study treatment (bemcentinib and pembrolizumab).

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was an open label study, no randomization and blinding were used in this study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort A
    Arm description
    		 This arm included subjects who had a maximum of one prior line of platinum-containing chemotherapy and had not received prior immunotherapy of any kind. During the course of the study all subjects received at least one dose of bemcentinib and pembrolizumab.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bemcentinib
    Investigational medicinal product code
    BGB324
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Bemcentinib was administered as follows: a loading dose of 400 milligrams (mg) was administered on Days 1, 2, and 3, followed by a daily dose of 200 mg from Day 4 onwards.

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    Keytruda
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    A dose of 200 mg pembrolizumab was given to subjects by intravenous (IV) infusion over 30 minutes every 3 weeks.

    Arm title
    		 Cohort B
    Arm description
    		 This arm included subjects who had a maximum of one prior line of an anti-PD-(L)1 therapy (monotherapy). During the course of the study all subjects received at least one dose of bemcentinib and pembrolizumab.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bemcentinib
    Investigational medicinal product code
    BGB324
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Bemcentinib was administered as follows: a loading dose of 400 mg was administered on Days 1, 2, and 3, followed by a daily dose of 200 mg from Day 4 onwards.

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    Keytruda
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    A dose of 200 mg pembrolizumab was given to subjects by IV infusion over 30 minutes every 3 weeks.

    Arm title
    		 Cohort C
    Arm description
    		 This arm included subjects who had a maximum of one prior line of therapy with an anti-PD-(L)1 therapy in combination with a platinum-containing chemotherapy. During the course of the study all subjects received at least one dose of bemcentinib and pembrolizumab.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bemcentinib
    Investigational medicinal product code
    BGB324
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Bemcentinib was administered as follows: a loading dose of 400 mg was administered on Days 1, 2, and 3, followed by a daily dose of 200 mg from Day 4 onwards.

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    Keytruda
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    A dose of 200 mg pembrolizumab was given to subjects by IV infusion over 30 minutes every 3 weeks.

    Number of subjects in period 1
    		Cohort A Cohort B Cohort C
    Started
    50
    29
    20
    Completed
    0
    0
    0
    Not completed
    50
    29
    20
         Consent withdrawn by subject
    2
    -
    -
         Death
    41
    22
    14
         Unknown
    6
    7
    6
         Lost to follow-up
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort A
    Reporting group description
    		 This arm included subjects who had a maximum of one prior line of platinum-containing chemotherapy and had not received prior immunotherapy of any kind. During the course of the study all subjects received at least one dose of bemcentinib and pembrolizumab.

    Reporting group title
    Cohort B
    Reporting group description
    		 This arm included subjects who had a maximum of one prior line of an anti-PD-(L)1 therapy (monotherapy). During the course of the study all subjects received at least one dose of bemcentinib and pembrolizumab.

    Reporting group title
    Cohort C
    Reporting group description
    		 This arm included subjects who had a maximum of one prior line of therapy with an anti-PD-(L)1 therapy in combination with a platinum-containing chemotherapy. During the course of the study all subjects received at least one dose of bemcentinib and pembrolizumab.

    Reporting group values
    		 Cohort A Cohort B Cohort C Total
    Number of subjects
    		 50 29 20 99
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 23 13 10 46
        From 65-84 years
    		 27 15 10 52
        85 years and over
    		 0 1 0 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.0 ( 9.27 ) 64.6 ( 9.41 ) 64.8 ( 9.33 ) -
    Gender categorical
    Units: Subjects
        Female
    		 20 8 6 34
        Male
    		 30 21 14 65
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 2 0 2 4
        Not Hispanic or Latino
    		 48 29 18 95
    Race
    Units: Subjects
        White
    		 47 27 20 94
        Asian
    		 2 0 0 2
        Black
    		 0 2 0 2
        Other
    		 1 0 0 1

    End points

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    End points reporting groups
    Reporting group title
    Cohort A
    Reporting group description
    		 This arm included subjects who had a maximum of one prior line of platinum-containing chemotherapy and had not received prior immunotherapy of any kind. During the course of the study all subjects received at least one dose of bemcentinib and pembrolizumab.

    Reporting group title
    Cohort B
    Reporting group description
    		 This arm included subjects who had a maximum of one prior line of an anti-PD-(L)1 therapy (monotherapy). During the course of the study all subjects received at least one dose of bemcentinib and pembrolizumab.

    Reporting group title
    Cohort C
    Reporting group description
    		 This arm included subjects who had a maximum of one prior line of therapy with an anti-PD-(L)1 therapy in combination with a platinum-containing chemotherapy. During the course of the study all subjects received at least one dose of bemcentinib and pembrolizumab.

    Primary: Percentage of Subjects with Objective Response Rate (ORR)

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    End point title
    		 Percentage of Subjects with Objective Response Rate (ORR) [1]
    End point description
    The ORR was defined as the percentage of evaluable subjects who had at least one (confirmed) overall response of complete response (CR) or partial response (PR) (defined by modified response evaluation criteria in solid tumors [RECIST] 1.1). The CR was defined as the disappearance of all target lesions (TLs) since baseline. Any pathological lymph nodes selected as TLs must have a reduction in the short axis to <10 millimeter (mm). And the PR was defined as at least a 30% decrease in the sum of the diameters of TLs, taking as reference the baseline sum of diameters. The Evaluable analysis set included all evaluable for efficacy subjects (EE), subjects that: (i) received at least one dose of pembrolizumab and bemcentinib, (ii) had measurable disease at study entry, as determined by the Investigator Site assessment, (iii) met the inclusion/exclusion criteria, and (iv) had at least one on-treatment scan.
    End point type
    Primary
    End point timeframe
    Approximately 61 months (From the date of first observation to the last observation)
    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 hypothesis was tested using statistical analysis.
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    44
    27
    19
    Units: Percentage of subjects
        number (confidence interval 90%)
    22.7 (12.9 to 35.5)
    0 (0 to 10.5)
    0 (0 to 14.6)
    No statistical analyses for this end point

    Secondary: Disease Control Rate (DCR)

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    End point title
    		 Disease Control Rate (DCR)
    End point description
    The DCR was defined as the percentage of evaluable subjects with a confirmed CR, confirmed PR, or stable disease (out of number evaluable subjects evaluable) (defined by modified RECIST 1.1). The CR was defined as the disappearance of all TLs since baseline. Any pathological lymph nodes selected as TLs must have a reduction in the short axis to <10 mm. The PR was defined as at least a 30% decrease in the sum of the diameters of TLs, taking as reference the baseline sum of diameters. And SD Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progression of disease. The EE population was analyzed in this endpoint.
    End point type
    Secondary
    End point timeframe
    Approximately 61 months (From the date of first observation to the last observation)
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    44
    27
    19
    Units: Percentage of subjects
        number (confidence interval 95%)
    54.5 (38.8 to 69.6)
    44.4 (25.5 to 64.7)
    52.6 (28.9 to 75.6)
    No statistical analyses for this end point

    Secondary: Median Duration of Response (DoR)

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    End point title
    		 Median Duration of Response (DoR)
    End point description
    The DoR was defined as the time from the date of first documented response until the date of documented progression or death (in the absence of disease progression). The DoR was calculated only for the subjects who had an objective response. Kaplan-Meier technique was used for calculation. In data table below, "00000" suggests that median and 95% confidence interval (CI) was not estimable for cohorts B and C. In both cohorts no subject had a confirmed objective response, required for DOR analysis. The EE population was analyzed in this endpoint.
    End point type
    Secondary
    End point timeframe
    Approximately 61 months (From the date of first observation to the last observation)
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    44
    27
    19
    Units: Months
        median (confidence interval 95%)
    8.1 (3.9 to 25.6)
    00000 (00000 to 00000)
    00000 (00000 to 00000)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Who Were Progression Free at 12 Months

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    End point title
    		 Percentage of Subjects Who Were Progression Free at 12 Months
    End point description
    The progression free survival (PFS) was defined as the time from start of treatment until the date of radiological disease progression (the date on which the confirmed progression was initially observed) or the date of death (whichever was earlier). Kaplan-Meier technique was used for calculation. The EE population was analyzed in this endpoint.
    End point type
    Secondary
    End point timeframe
    Up to 12 months following treatment initiation
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    44
    27
    19
    Units: Percentage of subjects
        number (confidence interval 95%)
    43.2 (28.4 to 57.1)
    16.7 (5.4 to 33.3)
    31.6 (12.9 to 52.2)
    No statistical analyses for this end point

    Secondary: Number of Subjects With Clinically Significant Laboratory Abnormalities

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    End point title
    		 Number of Subjects With Clinically Significant Laboratory Abnormalities
    End point description
    The number of subjects with clinically significant laboratory abnormality was assessed by physician, and were reported here. Laboratory tests included clinical chemistry, hematology, coagulation, and urinalysis. The safety set included all subjects who were enrolled in the study and were evaluable for safety (ES); subjects who received at least one dose of study treatment (bemcentinib and pembrolizumab). In below results: AST =aspartate aminotransferase, ALT = alanine aminotransferase, and GGT= Gamma-glutamyl transferase.
    End point type
    Secondary
    End point timeframe
    Approximately 61 months (From the date of first observation to the last observation)
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    50
    29
    20
    Units: Subjects
        Platelet count decreased (Hematology)
    2
    2
    0
        Neutrophil count decreased (Hematology)
    2
    1
    0
        Lymphocyte count decreased (Hematology)
    2
    0
    0
        White blood cell count decreased (Hematology)
    2
    0
    0
        Blood creatinine increased (Clinical Chemistry)
    11
    11
    8
        GGT increased (Clinical Chemistry)
    5
    2
    0
        Blood cholesterol increased (Clinical Chemistry)
    2
    3
    0
        Blood bilirubin increased (Clinical Chemistry)
    2
    1
    1
        Lipase increased (Clinical Chemistry)
    0
    1
    2
        AST increased (Clinical Chemistry)
    15
    7
    7
        ALT increased (Clinical Chemistry)
    17
    8
    4
    No statistical analyses for this end point

    Secondary: Median Overall Survival (OS)

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    End point title
    		 Median Overall Survival (OS)
    End point description
    The OS was defined as the time from the first dose of study treatment until the date of death (from any cause and irrespective of any subsequent anti-cancer treatment given). Kaplan-Meier technique was used for calculation. The EE population was analyzed in this endpoint.
    End point type
    Secondary
    End point timeframe
    Approximately 61 months (From the date of first observation to the last observation)
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    44
    27
    19
    Units: Months
        median (confidence interval 95%)
    14.0 (10.6 to 17.4)
    10.0 (6.7 to 16.1)
    14.8 (6.4 to 25.4)
    No statistical analyses for this end point

    Secondary: Cmax of Bemcentinib at Cycle 1 Day 1

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    End point title
    		 Cmax of Bemcentinib at Cycle 1 Day 1
    End point description
    The Cmax was defined as maximum observed concentration of bemcentinib. The PK datasets were analyzed.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0h) at Cycle Day 1 and 2 (24h post dose for Day 1), and 2, 4, 6, and 8h post dose at Cycle 1 Day 1
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    50
    29
    20
    Units: ng/mL
        arithmetic mean (standard deviation)
    70.1 ( 42.0 )
    65.1 ( 34.0 )
    67.0 ( 34.0 )
    No statistical analyses for this end point

    Secondary: OS at 12 Months

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    End point title
    		 OS at 12 Months
    End point description
    The OS was defined as the time from the first dose of study treatment until the date of death (from any cause and irrespective of any subsequent anti-cancer treatment given). The EE population was analyzed in this endpoint.
    End point type
    Secondary
    End point timeframe
    Up to 12 months following treatment initiation
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    44
    27
    19
    Units: Percentage of subjects
        number (confidence interval 95%)
    65.9 (50.0 to 77.8)
    41.4 (22.4 to 59.5)
    50.5 (26.4 to 70.5)
    No statistical analyses for this end point

    Secondary: Maximum Observed Concentration (Cmax) of Bemcentinib at Cycle 1 Day 3

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    End point title
    		 Maximum Observed Concentration (Cmax) of Bemcentinib at Cycle 1 Day 3
    End point description
    The Cmax was defined as maximum observed concentration of bemcentinib. The pharmacokinetics (PK) datasets were analyzed.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hours [h]) at Cycle 1 Day 3 and 4 (24h post dose for Day 3), and 2, 4, 6, and 8h post dose at Cycle 1 Day 3
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    47
    29
    20
    Units: Nanograms per milliliter (ng/mL)
        arithmetic mean (standard deviation)
    187 ( 108 )
    178 ( 90.9 )
    169 ( 81.1 )
    No statistical analyses for this end point

    Secondary: Cmax of Bemcentinib at Steady State

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    End point title
    		 Cmax of Bemcentinib at Steady State
    End point description
    The Cmax was defined as maximum observed concentration of bemcentinib. The PK datasets were analyzed.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0h) at Cycle 1 Day 1, 2 (24h post dose for Day 1), 3, and 4 (24h post-dose for Day 3), and 2, 4, 6, and 8h post dose at Cycle 1 Day 1 and 3
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    50
    29
    20
    Units: ng/mL
        arithmetic mean (standard deviation)
    270 ( 165 )
    304 ( 153 )
    244 ( 134 )
    No statistical analyses for this end point

    Secondary: Time to Cmax (Tmax) of Bemcentinib at Cycle 1 Day 1

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    End point title
    		 Time to Cmax (Tmax) of Bemcentinib at Cycle 1 Day 1
    End point description
    The Tmax was defined as the time taken by bemcentinib to reach Cmax. The PK datasets were analyzed.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0h) at Cycle Day 1 and 2 (24h post dose for Day 1), and 2, 4, 6, and 8h post dose at Cycle 1 Day 1
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    50
    29
    20
    Units: Hour
        median (full range (min-max))
    13.0 (3.99 to 24.0)
    14.6 (4.35 to 23.1)
    12.0 (4.57 to 23.2)
    No statistical analyses for this end point

    Secondary: Tmax of Bemcentinib at Cycle 1 Day 3

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    End point title
    		 Tmax of Bemcentinib at Cycle 1 Day 3
    End point description
    The Tmax was defined as the time taken by bemcentinib to reach Cmax. The PK datasets were analyzed.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0h) at Cycle 1 Day 3 and 4 (24h post dose for Day 3), and 2, 4, 6, and 8h post dose at Cycle 1 Day 3
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    47
    29
    20
    Units: Hour
        median (full range (min-max))
    10.3 (3.37 to 26.2)
    11.2 (3.87 to 24.2)
    9.86 (4.06 to 24.2)
    No statistical analyses for this end point

    Secondary: Tmax of Bemcentinib at Steady State

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    End point title
    		 Tmax of Bemcentinib at Steady State
    End point description
    The Tmax was defined as the time taken by bemcentinib to reach Cmax. The PK datasets were analyzed.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0h) at Cycle 1 Day 1, 2 (24h post dose for Day 1), 3, and 4 (24h post-dose for Day 3), and 2, 4, 6, and 8h post dose at Cycle 1 Day 1 and 3
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    50
    29
    20
    Units: Hour
        median (full range (min-max))
    7.55 (2.80 to 13.9)
    7.70 (3.40 to 11.5)
    7.75 (3.30 to 10.7)
    No statistical analyses for this end point

    Secondary: Area Under the Concentration Versus Time Curve From Time 0 to 24h Post dose (AUC0-24h) of Bemcentinib at Cycle 1 Day 1

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    End point title
    		 Area Under the Concentration Versus Time Curve From Time 0 to 24h Post dose (AUC0-24h) of Bemcentinib at Cycle 1 Day 1
    End point description
    The AUC0-24h post-dose; that was, within a dosing interval. The PK datasets were analyzed.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0h) at Cycle Day 1 and 2 (24h post dose for Day 1), and 2, 4, 6, and 8h post dose at Cycle 1 Day 1
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    50
    29
    20
    Units: Nanograms*hour per milliliter (ng*h/mL)
        arithmetic mean (standard deviation)
    1190 ( 773 )
    1070 ( 583 )
    1170 ( 599 )
    No statistical analyses for this end point

    Secondary: AUC0-24h of Bemcentinib at Steady State

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    End point title
    		 AUC0-24h of Bemcentinib at Steady State
    End point description
    The AUC0-24h post-dose; that was, within a dosing interval. The PK datasets were analyzed.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0h) at Cycle 1 Day 1, 2 (24h post dose for Day 1), 3, and 4 (24h post-dose for Day 3), and 2, 4, 6, and 8h post dose at Cycle 1 Day 1 and 3
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    50
    29
    20
    Units: ng*h/mL
        arithmetic mean (standard deviation)
    6250 ( 3880 )
    7090 ( 3620 )
    5640 ( 3200 )
    No statistical analyses for this end point

    Secondary: AUC0-24h of Bemcentinib at Cycle 1 Day 3

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    End point title
    		 AUC0-24h of Bemcentinib at Cycle 1 Day 3
    End point description
    The AUC0-24h post-dose; that was, within a dosing interval. The PK datasets were analyzed.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0h) at Cycle 1 Day 3 and 4 (24h post dose for Day 3), and 2, 4, 6, and 8h post dose at Cycle 1 Day 3
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    47
    29
    20
    Units: ng*h/mL
        arithmetic mean (standard deviation)
    4210 ( 2480 )
    4120 ( 2210 )
    3570 ( 1820 )
    No statistical analyses for this end point

    Secondary: Number of Subjects With Shift From a Normal Baseline to an Abnormal Clinically Significant Electrocardiogram (ECG) Result

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    End point title
    		 Number of Subjects With Shift From a Normal Baseline to an Abnormal Clinically Significant Electrocardiogram (ECG) Result
    End point description
    The number of subjects with abnormal clinically significant ECG result as assessed by physician were reported. All subjects who had a shift from an overall normal ECG result at Baseline to an abnormal clinically significant ECG result as worst post-Baseline value on at least one time point during the study were reported in this endpoint. The ES population was analyzed in this endpoint.
    End point type
    Secondary
    End point timeframe
    At baseline and up to end of the study (Approximately 61 months)
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    50
    29
    20
    Units: Subjects
    3
    2
    2
    No statistical analyses for this end point

    Secondary: Number of Subjects with Clinically Significant Vital Signs Abnormalities

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    End point title
    		 Number of Subjects with Clinically Significant Vital Signs Abnormalities
    End point description
    Vital sign parameters consisted of measurements of temperature, resting heart rate, seated blood pressure and respiratory rate. The number of subjects with clinically significant trend in vital signs as assessed by physician were reported. The ES population was analyzed in this endpoint.
    End point type
    Secondary
    End point timeframe
    Approximately 61 months (From the date of first observation to the last observation)
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    50
    29
    20
    Units: Subjects
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number Subjects with Adverse Events (AEs)

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    End point title
    		 Number Subjects with Adverse Events (AEs)
    End point description
    An AE was any untoward medical occurrence in a subject administered a pharmaceutical product and which did not necessarily have a causal relationship with the product. An AE can therefore be any unfavorable or unintended sign, symptom or disease temporally associated with the use of the pharmaceutical product whether or not considered related to the pharmaceutical product. This included any occurrence that was new, an exacerbation of an existing disease (a worsening of the character, frequency or severity of a known condition) or abnormal results of diagnostic procedures, including clinically significant laboratory test abnormalities. The ES population was analyzed in this endpoint.
    End point type
    Secondary
    End point timeframe
    Approximately 61 months (From the date of first observation to the last observation)
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    50
    29
    20
    Units: Subjects
    49
    29
    20
    No statistical analyses for this end point

    Secondary: Median PFS

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    End point title
    		 Median PFS
    End point description
    The PFS was defined as the time from start of treatment until the date of radiological disease progression (the date on which the confirmed progression was initially observed) or the date of death (whichever was earlier). Kaplan-Meier technique was used for calculation. The EE population was analyzed in this endpoint.
    End point type
    Secondary
    End point timeframe
    Approximately 61 months (From the date of first observation to the last observation)
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    44
    27
    19
    Units: Months
        median (confidence interval 95%)
    8.2 (4.1 to 12.4)
    6.0 (2.2 to 8.3)
    6.0 (2.2 to 14.8)
    No statistical analyses for this end point

    Secondary: Elimination Half Life (T1/2) of Bemcentinib at Cycle 1 Day 1

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    End point title
    		 Elimination Half Life (T1/2) of Bemcentinib at Cycle 1 Day 1
    End point description
    The T1/2 was reported. The PK datasets were analyzed.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0h) at Cycle Day 1 and 2 (24h post dose for Day 1), and 2, 4, 6, and 8h post dose at Cycle 1 Day 1
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    50
    29
    20
    Units: Hours
        arithmetic mean (standard deviation)
    109 ( 202 )
    102 ( 661 )
    172 ( 206 )
    No statistical analyses for this end point

    Secondary: T1/2 of Bemcentinib at Cycle 1 Day 3

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    End point title
    		 T1/2 of Bemcentinib at Cycle 1 Day 3
    End point description
    The T1/2 was reported. The PK datasets were analyzed.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0h) at Cycle 1 Day 3 and 4 (24h post dose for Day 3), and 2, 4, 6, and 8h post dose at Cycle 1 Day 3
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    47
    29
    20
    Units: Hours
        arithmetic mean (standard deviation)
    142 ( 137 )
    221 ( 353 )
    103 ( 164 )
    No statistical analyses for this end point

    Secondary: T1/2 of Bemcentinib at Steady State

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    End point title
    		 T1/2 of Bemcentinib at Steady State
    End point description
    The T1/2 was reported. The PK datasets were analyzed.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0h) at Cycle 1 Day 1, 2 (24h post dose for Day 1), 3, and 4 (24h post-dose for Day 3), and 2, 4, 6, and 8h post dose at Cycle 1 Day 1 and 3
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    50
    29
    20
    Units: Hours
        arithmetic mean (standard deviation)
    181 ( 263 )
    192 ( 195 )
    135 ( 89.9 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Approximately 61 months (From the date of first observation to the last observation).
    Adverse event reporting additional description
    All treatment emergent serious adverse events (SAEs) and Non-SAEs were reported.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Cohort B
    Reporting group description
    		 This arm included subjects who had a maximum of one prior line of an anti-PD-(L)1 therapy (monotherapy). During the course of study all subjects received at least one dose of bemcentinib and pembrolizumab.

    Reporting group title
    Cohort C
    Reporting group description
    		 This arm included subjects who had a maximum of one prior line of therapy with an anti-PD-(L)1 therapy in combination with a platinum-containing chemotherapy. During the course of study all subjects received at least one dose of bemcentinib and pembrolizumab.

    Reporting group title
    Cohort A
    Reporting group description
    		 This arm included subjects who had a maximum of one prior line of platinum-containing chemotherapy and had not received prior immunotherapy of any kind. During the course of the study all subjects received at least one dose of bemcentinib and pembrolizumab.

    Serious adverse events
    		 Cohort B Cohort C Cohort A
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 29 (37.93%)
    9 / 20 (45.00%)
    29 / 50 (58.00%)
         number of deaths (all causes)
    2
    0
    4
         number of deaths resulting from adverse events
    0
    0
    0
    Vascular disorders
    Embolism
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 20 (5.00%)
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pneumonitis
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 20 (5.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    3 / 50 (6.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    8 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    3 / 50 (6.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial flutter
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Neuromyelitis optica spectrum disorder
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paralysis recurrent laryngeal nerve
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Obstructive pancreatitis
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Faecalith
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Immune-mediated hepatitis
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    3 / 50 (6.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertransaminasaemia
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 20 (10.00%)
    5 / 50 (10.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    Respiratory tract infection
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Septic shock
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Urinary tract infection
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Type 1 diabetes mellitus
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Cohort B Cohort C Cohort A
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    29 / 29 (100.00%)
    20 / 20 (100.00%)
    47 / 50 (94.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour associated fever
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Cancer pain
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    2
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    1
    3
    Deep vein thrombosis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    1
    0
    2
    Varicose vein
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Hypotension
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Peripheral artery occlusion
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    General disorders and administration site conditions
    Mucosal inflammation
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    2
    0
    2
    Chest pain
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Asthenia
         subjects affected / exposed
    9 / 29 (31.03%)
    2 / 20 (10.00%)
    18 / 50 (36.00%)
         occurrences all number
    23
    3
    41
    Chest discomfort
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Feeling of body temperature change
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Fatigue
         subjects affected / exposed
    8 / 29 (27.59%)
    7 / 20 (35.00%)
    8 / 50 (16.00%)
         occurrences all number
    10
    9
    13
    Device related thrombosis
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Chills
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    5 / 50 (10.00%)
         occurrences all number
    0
    1
    5
    Oedema peripheral
         subjects affected / exposed
    4 / 29 (13.79%)
    1 / 20 (5.00%)
    3 / 50 (6.00%)
         occurrences all number
    4
    1
    4
    Pain
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    1
    Peripheral swelling
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 20 (10.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    2
    0
    Pyrexia
         subjects affected / exposed
    6 / 29 (20.69%)
    4 / 20 (20.00%)
    7 / 50 (14.00%)
         occurrences all number
    6
    4
    8
    Suprapubic pain
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Swelling face
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Temperature regulation disorder
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Influenza like illness
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 20 (0.00%)
    6 / 50 (12.00%)
         occurrences all number
    2
    0
    8
    Malaise
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Illness
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Hunger
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    General physical health deterioration
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 20 (5.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    1
    0
    Oedema
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Breast pain
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Erectile dysfunction
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    7 / 29 (24.14%)
    3 / 20 (15.00%)
    12 / 50 (24.00%)
         occurrences all number
    7
    4
    13
    Bronchospasm
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Dysphonia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    1
    0
    2
    Pleuritic pain
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Dyspnoea
         subjects affected / exposed
    8 / 29 (27.59%)
    4 / 20 (20.00%)
    7 / 50 (14.00%)
         occurrences all number
    11
    4
    11
    Rhinorrhoea
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Epistaxis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    0
    1
    Haemoptysis
         subjects affected / exposed
    2 / 29 (6.90%)
    3 / 20 (15.00%)
    4 / 50 (8.00%)
         occurrences all number
    2
    3
    4
    Hiccups
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Pleural effusion
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Pneumothorax
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Respiratory failure
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    1
    Respiratory tract congestion
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Rhinalgia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Dyspnoea exertional
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    1
    2
    Sputum discoloured
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Wheezing
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    1
    2
    Productive cough
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    1
    0
    2
    Tachypnoea
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Psychiatric disorders
    Persistent depressive disorder
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Anxiety
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    1
    0
    3
    Confusional state
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Delirium
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Depressed mood
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Depression
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    1
    2
    Insomnia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    5 / 50 (10.00%)
         occurrences all number
    1
    0
    5
    Adjustment disorder
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 20 (5.00%)
    2 / 50 (4.00%)
         occurrences all number
    1
    3
    3
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    8 / 29 (27.59%)
    4 / 20 (20.00%)
    17 / 50 (34.00%)
         occurrences all number
    18
    9
    38
    Amylase increased
         subjects affected / exposed
    2 / 29 (6.90%)
    4 / 20 (20.00%)
    4 / 50 (8.00%)
         occurrences all number
    3
    11
    9
    Aspartate aminotransferase increased
         subjects affected / exposed
    7 / 29 (24.14%)
    7 / 20 (35.00%)
    15 / 50 (30.00%)
         occurrences all number
    16
    13
    36
    Blood alkaline phosphatase increased
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 20 (10.00%)
    6 / 50 (12.00%)
         occurrences all number
    2
    3
    8
    Blood cholesterol increased
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 20 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    3
    0
    3
    Blood creatine increased
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Blood creatinine increased
         subjects affected / exposed
    11 / 29 (37.93%)
    8 / 20 (40.00%)
    11 / 50 (22.00%)
         occurrences all number
    23
    14
    34
    Blood folate decreased
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Blood iron decreased
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Weight decreased
         subjects affected / exposed
    2 / 29 (6.90%)
    3 / 20 (15.00%)
    3 / 50 (6.00%)
         occurrences all number
    2
    4
    4
    Computerised tomogram abnormal
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Cortisol decreased
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Eastern Cooperative Oncology Group performance status worsened
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Ejection fraction decreased
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Electrocardiogram abnormal
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Electrocardiogram QT prolonged
         subjects affected / exposed
    8 / 29 (27.59%)
    4 / 20 (20.00%)
    7 / 50 (14.00%)
         occurrences all number
    11
    5
    9
    Lipase increased
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 20 (10.00%)
    0 / 50 (0.00%)
         occurrences all number
    2
    10
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    0
    8
    Platelet count decreased
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 20 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    2
    0
    2
    Neutrophil count decreased
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    1
    0
    3
    Urine bilirubin increased
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Blood thyroid stimulating hormone decreased
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 20 (0.00%)
    5 / 50 (10.00%)
         occurrences all number
    3
    0
    9
    White blood cell count decreased
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    0
    3
    Injury, poisoning and procedural complications
    Overdose
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    0
    2
    Fall
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 20 (5.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    1
    Clavicle fracture
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Upper limb fracture
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    1
    2
    Radiation skin injury
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Rib fracture
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Tooth fracture
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Atrial fibrillation
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    1
    Sinus tachycardia
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    0
    2
    Pericardial effusion
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    1
    Bundle branch block right
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Tachycardia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Dizziness
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    1
    0
    2
    Monoparesis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Burning sensation
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Dysgeusia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Headache
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 20 (5.00%)
    3 / 50 (6.00%)
         occurrences all number
    1
    1
    3
    Hemiparesis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    0
    Hypersomnia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Lethargy
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Memory impairment
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Vocal cord paralysis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Neurotoxicity
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Paraesthesia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    1
    0
    2
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Presyncope
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Somnolence
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Syncope
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 29 (17.24%)
    4 / 20 (20.00%)
    12 / 50 (24.00%)
         occurrences all number
    7
    5
    19
    Lymph node pain
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    3
    0
    0
    Coagulopathy
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Microcytic anaemia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Neutropenia
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    3
    Thrombocytopenia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    1
    0
    2
    Lymphopenia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    4
    Ear and labyrinth disorders
    Ear haemorrhage
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Vertigo
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Tinnitus
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    1
    Ear pain
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Photopsia
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Eyelid ptosis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Conjunctivitis allergic
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Dry eye
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 20 (5.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    1
    Gingival bleeding
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Abdominal pain lower
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 20 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    2
    0
    4
    Abdominal distension
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Dysphagia
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Dyspepsia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    1
    3
    Dry mouth
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Diarrhoea
         subjects affected / exposed
    12 / 29 (41.38%)
    8 / 20 (40.00%)
    21 / 50 (42.00%)
         occurrences all number
    20
    12
    31
    Constipation
         subjects affected / exposed
    6 / 29 (20.69%)
    1 / 20 (5.00%)
    7 / 50 (14.00%)
         occurrences all number
    6
    1
    11
    Colitis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    2
    0
    1
    Cheilitis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Ascites
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    0
    1
    Lip oedema
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Inguinal hernia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Abdominal pain
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 20 (10.00%)
    0 / 50 (0.00%)
         occurrences all number
    2
    2
    0
    Pancreatitis
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Odynophagia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Nausea
         subjects affected / exposed
    7 / 29 (24.14%)
    5 / 20 (25.00%)
    12 / 50 (24.00%)
         occurrences all number
    9
    7
    18
    Stomatitis
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 20 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    2
    0
    2
    Toothache
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Vomiting
         subjects affected / exposed
    6 / 29 (20.69%)
    4 / 20 (20.00%)
    8 / 50 (16.00%)
         occurrences all number
    7
    7
    10
    Poor dental condition
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Regurgitation
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    4
    Hypertransaminasaemia
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 20 (5.00%)
    7 / 50 (14.00%)
         occurrences all number
    3
    1
    14
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    4 / 29 (13.79%)
    3 / 20 (15.00%)
    7 / 50 (14.00%)
         occurrences all number
    4
    4
    9
    Rash pruritic
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    2
    0
    Decubitus ulcer
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    0
    1
    Dermatitis acneiform
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    0
    5
    Dry skin
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    1
    0
    2
    Hyperhidrosis
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    1
    Hyperkeratosis
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Lichen sclerosus
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Night sweats
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Rash
         subjects affected / exposed
    3 / 29 (10.34%)
    2 / 20 (10.00%)
    4 / 50 (8.00%)
         occurrences all number
    3
    2
    6
    Rash erythematous
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    3
    1
    Rash macular
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 20 (10.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    3
    0
    Rash maculo-papular
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 20 (10.00%)
    4 / 50 (8.00%)
         occurrences all number
    3
    2
    7
    Skin exfoliation
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Erythema
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Skin mass
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Pollakiuria
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Polyuria
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Proteinuria
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    2
    Renal colic
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Haematuria
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Renal impairment
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Urinary retention
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    2
    Urinary tract disorder
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Urinary incontinence
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 20 (5.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    1
    0
    Renal failure
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 20 (5.00%)
    2 / 50 (4.00%)
         occurrences all number
    1
    1
    4
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Hypothyroidism
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Diabetes insipidus
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Adrenal insufficiency
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 29 (10.34%)
    4 / 20 (20.00%)
    7 / 50 (14.00%)
         occurrences all number
    3
    5
    14
    Arthritis
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    6
    Back pain
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 20 (10.00%)
    7 / 50 (14.00%)
         occurrences all number
    0
    2
    9
    Bone pain
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    1
    0
    3
    Flank pain
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Pain in extremity
         subjects affected / exposed
    1 / 29 (3.45%)
    3 / 20 (15.00%)
    2 / 50 (4.00%)
         occurrences all number
    1
    4
    2
    Greater trochanteric pain syndrome
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Joint swelling
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 20 (5.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    1
    0
    Muscle spasms
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    0
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 20 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    2
    0
    3
    Musculoskeletal pain
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    0
    1
    Myalgia
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 20 (0.00%)
    4 / 50 (8.00%)
         occurrences all number
    2
    0
    4
    Neck pain
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    0
    1
    Spondylolisthesis
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Tendonitis
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Oral herpes zoster
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 20 (10.00%)
    2 / 50 (4.00%)
         occurrences all number
    1
    2
    2
    Lower respiratory tract infection
         subjects affected / exposed
    5 / 29 (17.24%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    6
    0
    2
    Gastroenteritis
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Impetigo
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Cellulitis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Candida infection
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Oesophageal candidiasis
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Oral candidiasis
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    1
    2
    Fungal infection
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Urinary tract infection
         subjects affected / exposed
    3 / 29 (10.34%)
    3 / 20 (15.00%)
    1 / 50 (2.00%)
         occurrences all number
    3
    4
    3
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 20 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    2
    0
    2
    Fungal skin infection
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Tooth abscess
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Skin candida
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Sinusitis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Rhinitis
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Respiratory tract infection
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 20 (10.00%)
    2 / 50 (4.00%)
         occurrences all number
    3
    2
    2
    Rash pustular
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Pneumonia
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    4
    0
    1
    Pharyngitis
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Otitis media
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Toxic shock syndrome
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Tonsillitis
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    1
    0
    2
    Decreased appetite
         subjects affected / exposed
    9 / 29 (31.03%)
    5 / 20 (25.00%)
    16 / 50 (32.00%)
         occurrences all number
    10
    6
    23
    Hyperglycaemia
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 20 (0.00%)
    5 / 50 (10.00%)
         occurrences all number
    3
    0
    9
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Hypocalcaemia
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 20 (0.00%)
    4 / 50 (8.00%)
         occurrences all number
    2
    0
    5
    Hypomagnesaemia
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 20 (10.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    2
    1
    Hyponatraemia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    2
    0
    4
    Hypophosphataemia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 20 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Iron deficiency
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 20 (5.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 20 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Aug 2018
    Amendment 5.0: Consolidation of country specific protocols to create a global protocol.
    04 Dec 2018
    Amendment 6.0: Addition of Cohort B.
    29 Apr 2019
    Amendment 7.0: Revised Cohort B eligibility criteria to enroll patients who have been stable for at least 12 weeks or have had a confirmed partial response or complete response with subsequent progression.
    07 Oct 2019
    Amendment 8.0: Addition of Cohort C.
    09 Apr 2020
    Amendment 9.0: Revised Cohort B eligibility criteria to allow a maximum of one prior therapy.
    07 Oct 2020
    Amendment 10.0: Bemcentinib dose modifications harmonized with pembrolizumab. Time period for toxicity resolution amended.
    26 Jan 2022
    Amendment 11.0: Update to align with pembrolizumab standard text (including additional exclusion criteria) and introduce median overall survival (mOS) as a secondary endpoint.

    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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    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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