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    Clinical Trial Results:
    Open Label Phase 2 Study of Tisotumab Vedotin for Patients with Platinum-Resistant Ovarian Cancer with a Safety Run-in of a Dose-Dense Regimen

    Summary
    EudraCT number
    		 2019-001219-22
    Trial protocol
    		 ES   IE   BE   DK   IT  
    Global end of trial date
    08 Feb 2022

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

    Trial information

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    Trial identification
    Sponsor protocol code
    SGNTV-002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03657043
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Seagen Inc.
    Sponsor organisation address
    21823 30th Drive S.E., Bothell, United States, 98021
    Public contact
    Chief Medical Officer, Seagen Inc., 1 8554732436, medinfo@seagen.com
    Scientific contact
    Chief Medical Officer, Seagen Inc., 1 8554732436, medinfo@seagen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    02 Nov 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Feb 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    ● (Safety run-in) Evaluate safety and tolerability of a dose-dense regimen of tisotumab vedotin ● (Part A and B) Evaluate antitumor activity of tisotumab vedotin
    Protection of trial subjects
    This study was conducted in accordance with applicable regulations/guidelines set forth by the Food and Drug Administration (FDA) in 21 CFR Parts 11, 50, 54, 56, and 312; the European Union (EU) Directive 2001/20/EC and 2005/28/EC; and with International Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines. Essential documents are retained in accordance with ICH GCP.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Mar 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 57
    Country: Number of subjects enrolled
    Spain: 23
    Country: Number of subjects enrolled
    Italy: 8
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    Ireland: 3
    Country: Number of subjects enrolled
    Denmark: 1
    Worldwide total number of subjects
    98
    EEA total number of subjects
    41
    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)
    59
    From 65 to 84 years
    38
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 98 participants were enrolled into the Safety Run-In and Part B Expansion cohorts, of which 94 received study drug. No participants were enrolled into Part A. The date of first participant enrollment was 21-Mar-2019. The date of last participant completion was 08-Feb-2022.

    Pre-assignment
    Screening details
    		 Participants were screened for eligibility prior to enrollment.

    Period 1
    Period 1 title
    All Enrolled
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Safety Run-In 0.9 mg/kg 3Q4W
    Arm description
    		 Tisotumab Vedotin 0.9 mg/kg by IV infusion on Days 1, 8, and 15 of every 4-week cycle
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tisotumab vedotin
    Investigational medicinal product code
    Other name
    TIVDAK
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Tisotumab vedotin 0.9 mg/kg as an intravenous (IV) infusion on Days 1, 8, and 15 of every 4-week treatment cycle.

    Arm title
    		 Safety Run-In 1.2 mg/kg 3Q4W
    Arm description
    		 Tisotumab Vedotin 1.2 mg/kg by IV infusion on Days 1, 8, and 15 of every 4-week cycle
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tisotumab vedotin
    Investigational medicinal product code
    Other name
    TIVDAK
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Tisotumab vedotin 1.2 mg/kg as an intravenous (IV) infusion on Days 1, 8, and 15 of every 4-week treatment cycle.

    Arm title
    		 Part B Expansion
    Arm description
    		 Tisotumab Vedotin 0.9 mg/kg by IV infusion on Days 1, 8, and 15 of every 4-week cycle
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tisotumab vedotin
    Investigational medicinal product code
    Other name
    TIVDAK
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Tisotumab vedotin 0.9 mg/kg as an intravenous (IV) infusion on Days 1, 8, and 15 of every 4-week treatment cycle.

    Number of subjects in period 1
    		Safety Run-In 0.9 mg/kg 3Q4W Safety Run-In 1.2 mg/kg 3Q4W Part B Expansion
    Started
    8
    8
    82
    Completed
    7
    8
    79
    Not completed
    1
    0
    3
         Consent withdrawn by subject
    -
    -
    1
         Adverse event, non-fatal
    -
    -
    2
         Met exclusion criteria after enrollment
    1
    -
    -
    Period 2
    Period 2 title
    All Treated
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Safety Run-In 0.9 mg/kg 3Q4W
    Arm description
    		 Tisotumab Vedotin 0.9 mg/kg by IV infusion on Days 1, 8, and 15 of every 4-week cycle
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tisotumab vedotin
    Investigational medicinal product code
    Other name
    TIVDAK
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Tisotumab vedotin 0.9 mg/kg as an intravenous (IV) infusion on Days 1, 8, and 15 of every 4-week treatment cycle.

    Arm title
    		 Safety Run-In 1.2 mg/kg 3Q4W
    Arm description
    		 Tisotumab Vedotin 1.2 mg/kg by IV infusion on Days 1, 8, and 15 of every 4-week cycle
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tisotumab vedotin
    Investigational medicinal product code
    Other name
    TIVDAK
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Tisotumab vedotin 1.2 mg/kg as an intravenous (IV) infusion on Days 1, 8, and 15 of every 4-week treatment cycle.

    Arm title
    		 Part B Expansion
    Arm description
    		 Tisotumab Vedotin 0.9 mg/kg by IV infusion on Days 1, 8, and 15 of every 4-week cycle
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tisotumab vedotin
    Investigational medicinal product code
    Other name
    TIVDAK
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Tisotumab vedotin 0.9 mg/kg as an intravenous (IV) infusion on Days 1, 8, and 15 of every 4-week treatment cycle.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Baseline characteristics are based on the All Treated population.
    Number of subjects in period 2 [2]
    		Safety Run-In 0.9 mg/kg 3Q4W Safety Run-In 1.2 mg/kg 3Q4W Part B Expansion
    Started
    7
    8
    79
    Completed
    0
    0
    0
    Not completed
    7
    8
    79
         Consent withdrawn by subject
    1
    1
    3
         Study Closure by Sponsor
    -
    2
    17
         Death
    6
    5
    53
         Withdrawal - declined follow-up
    -
    -
    1
         Lost to follow-up
    -
    -
    4
         Withdrawal - subsequent treatment
    -
    -
    1
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Out of 98 enrolled participants, 94 were treated and displayed here. Baseline characteristics are based on participants who received any amount of study drug.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Safety Run-In 0.9 mg/kg 3Q4W
    Reporting group description
    		 Tisotumab Vedotin 0.9 mg/kg by IV infusion on Days 1, 8, and 15 of every 4-week cycle

    Reporting group title
    Safety Run-In 1.2 mg/kg 3Q4W
    Reporting group description
    		 Tisotumab Vedotin 1.2 mg/kg by IV infusion on Days 1, 8, and 15 of every 4-week cycle

    Reporting group title
    Part B Expansion
    Reporting group description
    		 Tisotumab Vedotin 0.9 mg/kg by IV infusion on Days 1, 8, and 15 of every 4-week cycle

    Reporting group values
    		 Safety Run-In 0.9 mg/kg 3Q4W Safety Run-In 1.2 mg/kg 3Q4W Part B Expansion Total
    Number of subjects
    		 7 8 79 94
    Age categorical
    Units: Participants
        <=18 years
    		 0 0 0 0
        Between 18 and 64 years
    		 3 3 51 57
        >=65 years
    		 4 5 28 37
    Age Continuous
    Units: Years
        median (full range (min-max))
    		 69.0 (50.0 to 87.0) 67.5 (51.0 to 74.0) 60.0 (38.0 to 81.0) -
    Sex/Gender, Customized
    Units: Participants
        Female
    		 7 8 79 94
        Intersex
    		 0 0 0 0
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino/a, or of Spanish Origin
    		 0 1 9 10
        Not of Hispanic or Latino/a, or of Spanish Origin
    		 6 7 69 82
        Unknown
    		 1 0 1 2
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 0 1 3 4
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 0 1 6 7
        White
    		 6 6 69 81
        More than one race
    		 0 0 0 0
        Unknown or Not Reported
    		 1 0 1 2
    Eastern Cooperative Oncology Group (ECOG) Performance Score
    Measure Description: 0=Normal activity; 1=Symtoms but ambulatory; 2=In bed <50% of the time; 3= In bed > 50% of the time; 4=100% bedridden; 5=Dead
    Units: Subjects
        Grade 0
    		 4 5 48 57
        Grade 1
    		 3 3 31 37

    End points

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    End points reporting groups
    Reporting group title
    Safety Run-In 0.9 mg/kg 3Q4W
    Reporting group description
    		 Tisotumab Vedotin 0.9 mg/kg by IV infusion on Days 1, 8, and 15 of every 4-week cycle

    Reporting group title
    Safety Run-In 1.2 mg/kg 3Q4W
    Reporting group description
    		 Tisotumab Vedotin 1.2 mg/kg by IV infusion on Days 1, 8, and 15 of every 4-week cycle

    Reporting group title
    Part B Expansion
    Reporting group description
    		 Tisotumab Vedotin 0.9 mg/kg by IV infusion on Days 1, 8, and 15 of every 4-week cycle
    Reporting group title
    Safety Run-In 0.9 mg/kg 3Q4W
    Reporting group description
    		 Tisotumab Vedotin 0.9 mg/kg by IV infusion on Days 1, 8, and 15 of every 4-week cycle

    Reporting group title
    Safety Run-In 1.2 mg/kg 3Q4W
    Reporting group description
    		 Tisotumab Vedotin 1.2 mg/kg by IV infusion on Days 1, 8, and 15 of every 4-week cycle

    Reporting group title
    Part B Expansion
    Reporting group description
    		 Tisotumab Vedotin 0.9 mg/kg by IV infusion on Days 1, 8, and 15 of every 4-week cycle

    Subject analysis set title
    Part B Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full Analysis Set includes all participants who received any amount of study drug.

    Subject analysis set title
    Part B Safety Analysis Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Analysis Set includes all participants who received any amount of study drug.

    Subject analysis set title
    Part B PK Analysis Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    PK Analysis Set includes enrolled participants who received any amount of study drug and at least one PK parameter can be estimated.

    Subject analysis set title
    Part B CA-125 Evaluable Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The CA-125 evaluable analysis set includes participants who have an elevated baseline CA-125 value of ≥2 x ULN (upper limit of normal) within 2 weeks prior to the first dose of study drug.

    Subject analysis set title
    Part B Full Analysis Set - Subjects with Confirmed CR or PR
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subset of the Full Analysis Set includes all participants who received any amount of study drug and had a confirmed CR or PR.

    Primary: Number of Participants with Dose-Limiting Toxicities (DLTs) (Safety Run-In Only)

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    End point title
    		 Number of Participants with Dose-Limiting Toxicities (DLTs) (Safety Run-In Only) [1]
    End point description
    Incidence of dose-limiting toxicity (DLT) was evaluated in participants enrolled in the Safety Run-In, who were followed for protocol-defined DLT events up to 28 days after the first dose of tisotumab vedotin.
    End point type
    Primary
    End point timeframe
    Up to 0.9 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The planned analysis was to evaluate the incidence of DLTs, which was observed to occur in 1/8 participants, as reported here.
    End point values
    		 Safety Run-In 0.9 mg/kg 3Q4W Safety Run-In 1.2 mg/kg 3Q4W
    Number of subjects analysed
    7
    8
    Units: Participants
    0
    1
    No statistical analyses for this end point

    Primary: Confirmed Objective Response rate (ORR) (Part B)

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    End point title
    		 Confirmed Objective Response rate (ORR) (Part B) [2]
    End point description
    Proportion of participants who achieve a confirmed complete response (CR) or partial response (PR) according to RECIST v1.1 as assessed by the investigator
    End point type
    Primary
    End point timeframe
    Up to 9.7 months
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The ORR for Part B with 95% confidence interval provided for the end point is the statistical analysis.
    End point values
    		 Part B Full Analysis Set
    Number of subjects analysed
    79
    Units: Percentage of Participants
        number (confidence interval 95%)
    9.0 (3.6 to 17.4)
    No statistical analyses for this end point

    Secondary: Number of Participants with Adverse Events (AEs) (Part B)

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    End point title
    		 Number of Participants with Adverse Events (AEs) (Part B)
    End point description
    An AE is any untoward medical occurrence in a patient or clinical investigational participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. Treatment emergent AEs (TEAEs) are defined as events that are new or worsened on or after receiving the first dose of study treatment and up through 30 days after the last dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to 23.0 months
    End point values
    		 Part B Safety Analysis Set
    Number of subjects analysed
    79
    Units: Participants
        Any TEAE
    79
        Treatment-related TEAE
    67
        Treatment-related Grade 3-4 TEAE
    14
        Treatment-related Grade 5 TEAE
    0
        Max severity of TEAE - Grade 1
    7
        Max severity of TEAE - Grade 2
    35
        Max severity of TEAE - Grade 3
    32
        Max severity of TEAE - Grade 4
    3
        Max severity of TEAE - Grade 5
    2
        Any treatment-emergent serious AE (SAE)
    28
        Treatment-related SAE
    6
    No statistical analyses for this end point

    Secondary: Confirmed and unconfirmed ORR (Part B)

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    End point title
    		 Confirmed and unconfirmed ORR (Part B)
    End point description
    Proportion of participants who achieve a CR or PR according to RECIST v1.1 as assessed by the investigator
    End point type
    Secondary
    End point timeframe
    Up to 9.7 months
    End point values
    		 Part B Expansion Part B Full Analysis Set
    Number of subjects analysed
    79
    79
    Units: Percentage of Participants
        number (confidence interval 95%)
    18.0 (10.0 to 27.9)
    18.0 (10.0 to 27.9)
    No statistical analyses for this end point

    Secondary: Cancer Antigen 125 (CA-125) response rate according to Gynecologic Cancer Intergroup (GCIG) criteria (Part B)

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    End point title
    		 Cancer Antigen 125 (CA-125) response rate according to Gynecologic Cancer Intergroup (GCIG) criteria (Part B)
    End point description
    Proportion of participants who have at least a 50% reduction in CA-125 value from baseline
    End point type
    Secondary
    End point timeframe
    Up to 10.1 months
    End point values
    		 Part B CA-125 Evaluable Set
    Number of subjects analysed
    51
    Units: Percentage of Participants
        number (confidence interval 95%)
    12.0 (4.4 to 23.9)
    No statistical analyses for this end point

    Secondary: Overall response according to the Gynecological Cancer Intergroup (GCIG) combined RECIST and CA-125 criteria (Part B)

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    End point title
    		 Overall response according to the Gynecological Cancer Intergroup (GCIG) combined RECIST and CA-125 criteria (Part B)
    End point description
    Proportion of participants whose best response is a CR or PR according to the GCIG combined RECIST and CA-125 criteria
    End point type
    Secondary
    End point timeframe
    Up to 10.1 months
    End point values
    		 Part B Full Analysis Set
    Number of subjects analysed
    79
    Units: Percentage of Participants
        number (confidence interval 95%)
    11.0 (5.3 to 20.5)
    No statistical analyses for this end point

    Secondary: Duration of response (DOR) (Part B)

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    End point title
    		 Duration of response (DOR) (Part B)
    End point description
    Time from the first documentation of objective response (CR or PR that is subsequently confirmed) to the first documentation of PD or death due to any cause, whichever comes first
    End point type
    Secondary
    End point timeframe
    Up to 8.3 months
    End point values
    		 Part B Full Analysis Set - Subjects with Confirmed CR or PR
    Number of subjects analysed
    7 [3]
    Units: Months
        median (confidence interval 95%)
    4.21 (3.02 to 999)
    Notes
    [3] - 999 = Not Available
    No statistical analyses for this end point

    Secondary: Disease control rate (DCR) (Part B)

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    End point title
    		 Disease control rate (DCR) (Part B)
    End point description
    Proportion of participants who achieved a confirmed Complete Response(CR) or Partial Response (PR) per RECIST v1.1 as assessed by the investigator, or meet the Stable Disease (SD) criteria at least once after start of study treatment at a minimum interval of 12 weeks.
    End point type
    Secondary
    End point timeframe
    Up to 3.0 months
    End point values
    		 Part B Full Analysis Set
    Number of subjects analysed
    79
    Units: Percentage of Participants
        number (confidence interval 95%)
    54.4 (42.8 to 65.7)
    No statistical analyses for this end point

    Secondary: Time to response (TTR) (Part B)

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    End point title
    		 Time to response (TTR) (Part B)
    End point description
    Time from the start of study treatment to the first documentation of objective response (CR or PR that is subsequently confirmed)
    End point type
    Secondary
    End point timeframe
    Up to 23.0 months
    End point values
    		 Part B Full Analysis Set - Subjects with Confirmed CR or PR
    Number of subjects analysed
    7
    Units: Months
        median (full range (min-max))
    1.4 (1.0 to 3.0)
    No statistical analyses for this end point

    Secondary: Progression-free survival (PFS) (Part B)

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    End point title
    		 Progression-free survival (PFS) (Part B)
    End point description
    Time from the start of study treatment to the first documentation of PD or death due to any cause, whichever comes first
    End point type
    Secondary
    End point timeframe
    Up to 9.7 months
    End point values
    		 Part B Full Analysis Set
    Number of subjects analysed
    79
    Units: Months
        median (confidence interval 95%)
    2.73 (1.64 to 2.99)
    No statistical analyses for this end point

    Secondary: Overall survival (OS) (Part B)

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    End point title
    		 Overall survival (OS) (Part B)
    End point description
    Time from the start of study treatment to date of death due to any cause
    End point type
    Secondary
    End point timeframe
    Up to 23.0 months
    End point values
    		 Part B Full Analysis Set
    Number of subjects analysed
    79
    Units: Months
        median (confidence interval 95%)
    10.68 (7.75 to 12.81)
    No statistical analyses for this end point

    Secondary: Pharmacokinetic (PK) parameter: Antibody-Drug Conjugate (ADC) Maximum concentration (Cmax) (Part B)

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    End point title
    		 Pharmacokinetic (PK) parameter: Antibody-Drug Conjugate (ADC) Maximum concentration (Cmax) (Part B)
    End point description
    ADC Cmax was derived from the PK blood samples collected.
    End point type
    Secondary
    End point timeframe
    Samples for PK endpoints were collected at Cycle 1 Day 1 (predose, end of infusion, 1 hr, and 5 hr), Day 3, Day 8 (predose), Day 15 (predose, end of infusion, 1 hr, and 5 hr), Day 17, Day 22, and Cycle 2 Day 1 (predose). Approximately 4 weeks per cycle.
    End point values
    		 Part B PK Analysis Set
    Number of subjects analysed
    77
    Units: µg/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1, Dose 1
    20.582 ( 26.963 )
        Cycle 1, Dose 3
    21.817 ( 26.823 )
    No statistical analyses for this end point

    Secondary: PK parameter: ADC Time of Cmax (Tmax) (Part B)

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    End point title
    		 PK parameter: ADC Time of Cmax (Tmax) (Part B)
    End point description
    ADC Tmax was derived from the PK blood samples collected.
    End point type
    Secondary
    End point timeframe
    Samples for PK endpoints were collected at Cycle 1 Day 1 (predose, end of infusion, 1 hr, and 5 hr), Day 3, Day 8 (predose), Day 15 (predose, end of infusion, 1 hr, and 5 hr), Day 17, Day 22, and Cycle 2 Day 1 (predose). Approximately 4 weeks per cycle.
    End point values
    		 Part B PK Analysis Set
    Number of subjects analysed
    77
    Units: Days
    geometric mean (geometric coefficient of variation)
        Cycle 1, Dose 1
    0.041 ( 53.112 )
        Cycle 1, Dose 3
    0.041 ( 78.407 )
    No statistical analyses for this end point

    Secondary: PK parameter: ADC Area Under Concentration-Time Curve (AUC) (Part B)

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    End point title
    		 PK parameter: ADC Area Under Concentration-Time Curve (AUC) (Part B)
    End point description
    ADC AUC was derived from the PK blood samples collected.
    End point type
    Secondary
    End point timeframe
    Samples for PK endpoints were collected at Cycle 1 Day 1 (predose, end of infusion, 1 hr, and 5 hr), Day 3, Day 8 (predose), Day 15 (predose, end of infusion, 1 hr, and 5 hr), Day 17, Day 22, and Cycle 2 Day 1 (predose). Approximately 4 weeks per cycle.
    End point values
    		 Part B PK Analysis Set
    Number of subjects analysed
    77
    Units: µg/mL*day
    geometric mean (geometric coefficient of variation)
        Cycle 1, Dose 1 - AUC 7 Days-ADC
    25.198 ( 25.335 )
        Cycle 1, Dose 3 - AUC 7 Days-ADC
    30.159 ( 32.261 )
        Cycle 1, Dose 3 - AUC 14 Days-ADC
    31.716 ( 31.632 )
    No statistical analyses for this end point

    Secondary: PK parameter: Free Monomethyl Auristatin E (MMAE) Cmax (Part B)

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    End point title
    		 PK parameter: Free Monomethyl Auristatin E (MMAE) Cmax (Part B)
    End point description
    MMAE Cmax was derived from the PK blood samples collected.
    End point type
    Secondary
    End point timeframe
    Samples for PK endpoints were collected at Cycle 1 Day 1 (predose, end of infusion, 1 hr, and 5 hr), Day 3, Day 8 (predose), Day 15 (predose, end of infusion, 1 hr, and 5 hr), Day 17, Day 22, and Cycle 2 Day 1 (predose). Approximately 4 weeks per cycle.
    End point values
    		 Part B PK Analysis Set
    Number of subjects analysed
    77
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1, Dose 1
    1.778 ( 66.636 )
        Cycle 1, Dose 3
    2.552 ( 52.442 )
    No statistical analyses for this end point

    Secondary: PK parameter: MMAE Tmax (Part B)

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    End point title
    		 PK parameter: MMAE Tmax (Part B)
    End point description
    MMAE Tmax was derived from the PK blood samples collected.
    End point type
    Secondary
    End point timeframe
    Samples for PK endpoints were collected at Cycle 1 Day 1 (predose, end of infusion, 1 hr, and 5 hr), Day 3, Day 8 (predose), Day 15 (predose, end of infusion, 1 hr, and 5 hr), Day 17, Day 22, and Cycle 2 Day 1 (predose). Approximately 4 weeks per cycle.
    End point values
    		 Part B PK Analysis Set
    Number of subjects analysed
    77
    Units: Days
    geometric mean (geometric coefficient of variation)
        Cycle 1, Dose 1
    2.061 ( 26.838 )
        Cycle 1, Dose 3
    2.101 ( 28.820 )
    No statistical analyses for this end point

    Secondary: PK parameter: MMAE AUC (Part B)

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    End point title
    		 PK parameter: MMAE AUC (Part B)
    End point description
    MMAE AUC was derived from the PK blood samples collected.
    End point type
    Secondary
    End point timeframe
    Samples for PK endpoints were collected at Cycle 1 Day 1 (predose, end of infusion, 1 hr, and 5 hr), Day 3, Day 8 (predose), Day 15 (predose, end of infusion, 1 hr, and 5 hr), Day 17, Day 22, and Cycle 2 Day 1 (predose). Approximately 4 weeks per cycle.
    End point values
    		 Part B PK Analysis Set
    Number of subjects analysed
    77
    Units: ng/mL*day
    geometric mean (geometric coefficient of variation)
        Cycle 1, Dose 1 - AUC Last-MMAE
    8.709 ( 63.747 )
        Cycle 1, Dose 3 - AUC Last-MMAE
    16.578 ( 52.121 )
    No statistical analyses for this end point

    Secondary: PK parameter: MMAE Trough Concentration (Ctrough) (Part B)

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    End point title
    		 PK parameter: MMAE Trough Concentration (Ctrough) (Part B)
    End point description
    MMAE Ctrough was derived from the PK blood samples collected.
    End point type
    Secondary
    End point timeframe
    Samples for PK endpoints were collected at Cycle 1 Day 1 (predose, end of infusion, 1 hr, and 5 hr), Day 3, Day 8 (predose), Day 15 (predose, end of infusion, 1 hr, and 5 hr), Day 17, Day 22, and Cycle 2 Day 1 (predose). Approximately 4 weeks per cycle.
    End point values
    		 Part B PK Analysis Set
    Number of subjects analysed
    77
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1, Dose 3
    0.230 ( 82.638 )
    No statistical analyses for this end point

    Secondary: PK parameter: Total Antibody (TAb) Cmax (Part B)

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    End point title
    		 PK parameter: Total Antibody (TAb) Cmax (Part B)
    End point description
    TAb Cmax was derived from the PK blood samples collected.
    End point type
    Secondary
    End point timeframe
    Samples for PK endpoints were collected at Cycle 1 Day 1 (predose, end of infusion, 1 hr, and 5 hr), Day 3, Day 8 (predose), Day 15 (predose, end of infusion, 1 hr, and 5 hr), Day 17, Day 22, and Cycle 2 Day 1 (predose). Approximately 4 weeks per cycle.
    End point values
    		 Part B PK Analysis Set
    Number of subjects analysed
    77
    Units: µg/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1, Dose 1
    18.418 ( 28.631 )
        Cycle 1, Dose 3
    19.955 ( 28.405 )
    No statistical analyses for this end point

    Secondary: PK parameter: TAb Tmax (Part B)

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    End point title
    		 PK parameter: TAb Tmax (Part B)
    End point description
    TAb Tmax was derived from the PK blood samples collected.
    End point type
    Secondary
    End point timeframe
    Samples for PK endpoints were collected at Cycle 1 Day 1 (predose, end of infusion, 1 hr, and 5 hr), Day 3, Day 8 (predose), Day 15 (predose, end of infusion, 1 hr, and 5 hr), Day 17, Day 22, and Cycle 2 Day 1 (predose). Approximately 4 weeks per cycle.
    End point values
    		 Part B PK Analysis Set
    Number of subjects analysed
    77
    Units: Days
    geometric mean (geometric coefficient of variation)
        Cycle 1, Dose 1
    0.041 ( 67.072 )
        Cycle 1, Dose 3
    0.043 ( 67.795 )
    No statistical analyses for this end point

    Secondary: PK parameter: TAb Area Under Concentration-Time Curve (AUC) (Part B)

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    End point title
    		 PK parameter: TAb Area Under Concentration-Time Curve (AUC) (Part B)
    End point description
    TAb AUC was derived from the PK blood samples collected.
    End point type
    Secondary
    End point timeframe
    Samples for PK endpoints were collected at Cycle 1 Day 1 (predose, end of infusion, 1 hr, and 5 hr), Day 3, Day 8 (predose), Day 15 (predose, end of infusion, 1 hr, and 5 hr), Day 17, Day 22, and Cycle 2 Day 1 (predose). Approximately 4 weeks per cycle.
    End point values
    		 Part B PK Analysis Set
    Number of subjects analysed
    77
    Units: µg/mL*day
    geometric mean (geometric coefficient of variation)
        Cycle 1, Dose 1 - AUC 7 Days-TAb
    35.535 ( 24.950 )
        Cycle 1, Dose 3 - AUC 7 Days-TAb
    39.371 ( 29.218 )
        Cycle 1, Dose 3 - AUC 14 Days-TAb
    42.240 ( 29.206 )
    No statistical analyses for this end point

    Secondary: Incidence of antitherapeutic antibodies (ATA) (Part B)

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    End point title
    		 Incidence of antitherapeutic antibodies (ATA) (Part B)
    End point description
    The proportion of participants who develop ATA at any time during the study. A positive baseline ATA result is considered positive post-baseline if the post-baseline ATA titer result is at least four times higher than the baseline result.
    End point type
    Secondary
    End point timeframe
    Up to 6.9 months
    End point values
    		 Part B Safety Analysis Set
    Number of subjects analysed
    71 [4]
    Units: Participants
    number (not applicable)
        Baseline Negative - Negative post-baseline
    65
        Baseline Negative - Positive post-baseline
    3
        Baseline Positive - Negative post-baseline
    3
        Baseline Positive - Positive post-baseline
    0
    Notes
    [4] - Participants in the Safety Analysis Set with a baseline and at least one post-baseline ATA sample.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Non-serious AEs were followed up to 10.5 months. Serious AEs and All-Cause Mortality were followed up to 31.6 months.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    PartBExpansion
    Reporting group description
    		 Tisotumab Vedotin 0.9 mg/kg by IV infusion on Days 1, 8, and 15 of every 4-week cycle

    Reporting group title
    SafetyRun-In(1.2mg/kg3Q4W)
    Reporting group description
    		 Tisotumab Vedotin 1.2 mg/kg by IV infusion on Days 1, 8, and 15 of every 4-week cycle

    Reporting group title
    SafetyRun-In(0.9mg/kg3Q4W)
    Reporting group description
    		 Tisotumab Vedotin 0.9 mg/kg by IV infusion on Days 1, 8, and 15 of every 4-week cycle

    Serious adverse events
    		 PartBExpansion SafetyRun-In(1.2mg/kg3Q4W) SafetyRun-In(0.9mg/kg3Q4W)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    28 / 79 (35.44%)
    4 / 8 (50.00%)
    2 / 7 (28.57%)
         number of deaths (all causes)
    53
    5
    6
         number of deaths resulting from adverse events
    2
    2
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour haemorrhage
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 8 (12.50%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Performance status decreased
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         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
    Acute respiratory failure
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    2 / 79 (2.53%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pleural effusion
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    4 / 79 (5.06%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    2 / 79 (2.53%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Psychiatric disorders
    Confusional state
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (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
    Angina pectoris
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Peripheral sensory neuropathy
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    2 / 79 (2.53%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    3 / 79 (3.80%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    2 / 79 (2.53%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascites
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    1 / 79 (1.27%)
    3 / 8 (37.50%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enteritis
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    5 / 79 (6.33%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    2 / 79 (2.53%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    3 / 79 (3.80%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    2 / 79 (2.53%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatomegaly
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jaundice cholestatic
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematuria
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (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
    Urinary tract obstruction
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    2 / 79 (2.53%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         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
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 PartBExpansion SafetyRun-In(1.2mg/kg3Q4W) SafetyRun-In(0.9mg/kg3Q4W)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    77 / 79 (97.47%)
    8 / 8 (100.00%)
    7 / 7 (100.00%)
    Vascular disorders
    Hot flush
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    1 / 79 (1.27%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    1
    0
    General disorders and administration site conditions
    Asthenia
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    19 / 79 (24.05%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    23
    0
    0
    Fatigue
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    25 / 79 (31.65%)
    4 / 8 (50.00%)
    2 / 7 (28.57%)
         occurrences all number
    27
    4
    2
    Malaise
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    2 / 79 (2.53%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    2
    2
    0
    Oedema peripheral
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    4 / 79 (5.06%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    4
    0
    1
    Pyrexia
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    5 / 79 (6.33%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    5
    1
    0
    Reproductive system and breast disorders
    Vaginal haemorrhage
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    5 / 79 (6.33%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    6
    0
    0
    Vulvovaginal pain
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    6 / 79 (7.59%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    7
    0
    1
    Dysphonia
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 8 (12.50%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    1
    Dyspnoea
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    9 / 79 (11.39%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    9
    0
    0
    Epistaxis
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    36 / 79 (45.57%)
    3 / 8 (37.50%)
    4 / 7 (57.14%)
         occurrences all number
    46
    4
    4
    Hiccups
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Nasal congestion
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    9 / 79 (11.39%)
    3 / 8 (37.50%)
    1 / 7 (14.29%)
         occurrences all number
    9
    3
    1
    Pharyngeal inflammation
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Upper-airway cough syndrome
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    2 / 79 (2.53%)
    0 / 8 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    2
    0
    2
    Productive cough
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Psychiatric disorders
    Depression
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    3 / 79 (3.80%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    3
    0
    1
    Insomnia
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    3 / 79 (3.80%)
    1 / 8 (12.50%)
    1 / 7 (14.29%)
         occurrences all number
    3
    1
    1
    Investigations
    Alanine aminotransferase increased
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    5 / 79 (6.33%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    5
    0
    0
    Aspartate aminotransferase increased
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    6 / 79 (7.59%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    6
    0
    0
    International normalised ratio increased
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    5 / 79 (6.33%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    7
    0
    0
    Weight decreased
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    5 / 79 (6.33%)
    1 / 8 (12.50%)
    1 / 7 (14.29%)
         occurrences all number
    5
    1
    1
    Injury, poisoning and procedural complications
    Corneal abrasion
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    0
    2
    Incision site impaired healing
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Cognitive disorder
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Dizziness
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    4 / 79 (5.06%)
    1 / 8 (12.50%)
    1 / 7 (14.29%)
         occurrences all number
    4
    1
    1
    Headache
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    5 / 79 (6.33%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    5
    0
    0
    Paraesthesia
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    2 / 79 (2.53%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    2
    1
    0
    Peripheral sensory neuropathy
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    18 / 79 (22.78%)
    2 / 8 (25.00%)
    3 / 7 (42.86%)
         occurrences all number
    20
    3
    3
    Restless legs syndrome
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 8 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    1
    0
    2
    Blood and lymphatic system disorders
    Anaemia
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    23 / 79 (29.11%)
    0 / 8 (0.00%)
    4 / 7 (57.14%)
         occurrences all number
    33
    0
    6
    Eye disorders
    Blepharitis
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    7 / 79 (8.86%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    9
    0
    1
    Cataract nuclear
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    1 / 79 (1.27%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    2
    0
    Conjunctival haemorrhage
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    0
    1
    Conjunctival ulcer
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Conjunctivitis allergic
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Dacryostenosis acquired
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Dry eye
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    12 / 79 (15.19%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    14
    1
    0
    Ectropion
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Entropion
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    2 / 79 (2.53%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    2
    0
    1
    Eye discharge
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    5 / 79 (6.33%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    8
    0
    0
    Eye pain
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    1 / 79 (1.27%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    1
    0
    Keratitis
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    4 / 79 (5.06%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    9
    0
    0
    Lacrimation increased
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    7 / 79 (8.86%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    8
    0
    0
    Punctate keratitis
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    2 / 79 (2.53%)
    2 / 8 (25.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    2
    0
    Symblepharon
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    4 / 79 (5.06%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    4
    1
    0
    Vision blurred
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    9 / 79 (11.39%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    10
    0
    1
    Gastrointestinal disorders
    Abdominal distension
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    8 / 79 (10.13%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    9
    1
    0
    Abdominal pain
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    22 / 79 (27.85%)
    3 / 8 (37.50%)
    0 / 7 (0.00%)
         occurrences all number
    27
    3
    0
    Abdominal pain upper
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    6 / 79 (7.59%)
    1 / 8 (12.50%)
    1 / 7 (14.29%)
         occurrences all number
    7
    1
    2
    Constipation
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    17 / 79 (21.52%)
    3 / 8 (37.50%)
    2 / 7 (28.57%)
         occurrences all number
    20
    4
    2
    Diarrhoea
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    18 / 79 (22.78%)
    2 / 8 (25.00%)
    4 / 7 (57.14%)
         occurrences all number
    25
    2
    4
    Gastrooesophageal reflux disease
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    3 / 79 (3.80%)
    1 / 8 (12.50%)
    1 / 7 (14.29%)
         occurrences all number
    3
    1
    1
    Nausea
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    30 / 79 (37.97%)
    2 / 8 (25.00%)
    2 / 7 (28.57%)
         occurrences all number
    37
    2
    2
    Stomatitis
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    2 / 79 (2.53%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    2
    0
    1
    Vomiting
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    15 / 79 (18.99%)
    1 / 8 (12.50%)
    1 / 7 (14.29%)
         occurrences all number
    19
    1
    2
    Hepatobiliary disorders
    Hypertransaminasaemia
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    6 / 79 (7.59%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    16
    1
    0
    Skin and subcutaneous tissue disorders
    Alopecia
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    10 / 79 (12.66%)
    2 / 8 (25.00%)
    1 / 7 (14.29%)
         occurrences all number
    10
    2
    1
    Dermatitis
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Dermatitis contact
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Dry skin
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Pruritus
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    4 / 79 (5.06%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    4
    0
    0
    Rash erythematous
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Urticaria
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    1 / 79 (1.27%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    1
    0
    Rash maculo-papular
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    0
    1
    Renal and urinary disorders
    Acute kidney injury
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    0
    1
    Dysuria
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    0
    1
    Haematuria
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    4 / 79 (5.06%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    6
    0
    0
    Endocrine disorders
    Inappropriate antidiuretic hormone secretion
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    7 / 79 (8.86%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    7
    0
    0
    Back pain
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    7 / 79 (8.86%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    7
    0
    0
    Limb discomfort
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Muscle spasms
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    2 / 79 (2.53%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    2
    0
    1
    Musculoskeletal chest pain
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    0
    1
    Myalgia
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    8 / 79 (10.13%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    9
    0
    0
    Pain in extremity
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    4 / 79 (5.06%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    5
    0
    1
    Infections and infestations
    Acute sinusitis
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Conjunctivitis
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    25 / 79 (31.65%)
    1 / 8 (12.50%)
    2 / 7 (28.57%)
         occurrences all number
    33
    1
    3
    Conjunctivitis viral
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    0
    1
    Device related infection
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Gingivitis
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Pneumonia
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    1 / 79 (1.27%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    1
    0
    Pustule
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Sinusitis
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    5 / 79 (6.33%)
    2 / 8 (25.00%)
    2 / 7 (28.57%)
         occurrences all number
    6
    2
    2
    Tooth infection
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Urinary tract infection
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    5 / 79 (6.33%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    5
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    25 / 79 (31.65%)
    1 / 8 (12.50%)
    1 / 7 (14.29%)
         occurrences all number
    29
    1
    1
    Hyperglycaemia
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    4 / 79 (5.06%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    4
    0
    0
    Dehydration
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    8 / 79 (10.13%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    8
    1
    0
    Hypoalbuminaemia
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    6 / 79 (7.59%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    7
    0
    0
    Hyperuricaemia
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    5 / 79 (6.33%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    5
    0
    0
    Hypocalcaemia
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    5 / 79 (6.33%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    5
    0
    0
    Hypokalaemia
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    14 / 79 (17.72%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    17
    0
    2
    Hypomagnesaemia
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    10 / 79 (12.66%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    13
    0
    1
    Hyponatraemia
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    8 / 79 (10.13%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    9
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Oct 2018
    Removed required on-treatment ophthalmological exam. Updated exclusion criteria from “peripheral neuropathy > Grade 1” to “peripheral neuropathy ≥ Grade 2.” Changes to required ocular premedication and preventive eye therapy. Additional administrative changes and clarifications.
    02 May 2019
    Revised bevacizumab exposure criteria for safety run-in participants. Revise eGFR inclusion criteria. Remove 3 month PFS and 12 month OS timepoints. Additional corrections, administrative changes, and clarifications.
    17 Oct 2019
    Part B cohort added and number of planned participants updated to reflect added participants in Part B. 1.2 mg/kg dose escalation added to safety run-in. Additional corrections, administrative changes, and clarifications.
    24 Aug 2020
    Changed Part B to enroll approximately 80 participants. Updated exclusion criteria to permit anticoagulation and antiplatelet therapies. Updated inclusion criteria for prior treatments. Addition of interim analysis. Additional administrative changes and clarifications.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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