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    Clinical Trial Results:
    A Phase 1b/2, Multicenter, Open-label, Basket Trial to Evaluate the Safety of Talimogene Laherparepvec Injected into Liver Tumors Alone and in Combination with Systemic Pembrolizumab in Phase 1b and to Evaluate the Efficacy and Safety of Intratumoral Talimogene Laherparepvec in Combination with Systemic Pembrolizumab to Treat Subjects with Advanced Solid Tumors in Phase 2 (MASTERKEY 318)

    Summary
    EudraCT number
    		 2014-005386-67
    Trial protocol
    		 BE   DE   AT   PL  
    Global end of trial date
    11 Jul 2023

    Results information
    Results version number
    		 v1
    This version publication date
    14 Jun 2024
    First version publication date
    14 Jun 2024
    Other versions
    		 v2 , v3

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    20140318
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Amgen Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, CA, United States,
    Public contact
    Study Director, Amgen Inc., +1 8665726436, medinfo@amgen.com
    Scientific contact
    Study Director, Amgen Inc., +1 8665726436, medinfo@amgen.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
    11 Jul 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Jul 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    In Part 1, the main objective was to evaluate, as assessed by the incidence of dose-limiting toxicities (DLTs) in participants with liver metastases (non- hepatocellular carcinoma [HCC]) & participants with primary HCC in the maximum tolerated volume (monotherapy cohorts) and maximum tolerated concentration (MTC) of intrahepatic injection of talimogene laherparepvec into liver tumors (monotherapy and combination cohorts) in combination with systemic intravenous (IV) administration of pembrolizumab (combination cohorts). In Part 2, the main objectives were to evaluate the efficacy, as assessed by objective response rate (ORR) of intratumoral injection of talimogene laherparepvec in combination with systemic IV administration of pembrolizumab, separately, for each non-HCC tumor type and primary HCC with and without viral hepatitis and to evaluate safety separately for each tumor type as assessed by incidence of treatment-emergent and treatment-related adverse events, including DLTs.
    Protection of trial subjects
    This study was conducted in accordance with International Council for Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Feb 2016
    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
    Korea, Republic of: 15
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Belgium: 9
    Country: Number of subjects enrolled
    Spain: 58
    Country: Number of subjects enrolled
    Switzerland: 18
    Country: Number of subjects enrolled
    United States: 21
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Australia: 3
    Worldwide total number of subjects
    127
    EEA total number of subjects
    70
    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)
    84
    From 65 to 84 years
    43
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 127 participants were enrolled at 22 centers in Australia, Europe, South Korea and the United States from February 2016 to July 2023. As of protocol amendment 6 (dated 26 October 2021), intrahepatic injections of talimogene laherparepvec were no longer performed.

    Pre-assignment
    Screening details
    		 Of the 190 participants screened, 127 participants were enrolled and received study treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part 1: Monotherapy Group A
    Arm description
    		 Participants with non-hepatocellular carcinoma (non-HCC) were administered talimogene laherparepvec.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Talimogene Laherparepvec
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intralesional use
    Dosage and administration details
    Initial concentration of 10^6 plaque forming unit (PFU)/mL in a volume of up to 4mL in Cohorts 1 & 2 and up to a volume of 8 mL in Cohorts 3 & 4 on Day 1 of the first 21-day cycle. The concentration in the second and subsequent 21-day cycles were 10^7 (Cohorts 1 & 4) or 10^8 PFU/mL (Cohorts 2 & 3).

    Arm title
    		 Part 1: Monotherapy Group B
    Arm description
    		 Participants with HCC were administered talimogene laherparepvec.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Talimogene Laherparepvec
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intralesional use
    Dosage and administration details
    Initial concentration of 10^6 PFU/mL in a volume of up to 4mL in Cohorts 1 & 2 and up to a volume of 8 mL in Cohorts 3 & 4 on Day 1 of the first 21-day cycle. The concentration in the second and subsequent 21-day cycles were 10^7 (Cohorts 1 & 4) or 10^8 PFU/mL (Cohorts 2 & 3).

    Arm title
    		 Part 1: Combination Therapy Group A
    Arm description
    		 Participants with non-HCC were administered talimogene laherparepvec and pembrolizumab.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg on Day 1 of each 21-day cycle.

    Investigational medicinal product name
    Talimogene Laherparepvec
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intralesional use
    Dosage and administration details
    Initial concentration of 10^6 PFU/mL in a volume of up to 4mL in Cohorts 5 & 6 on Day 1 of the first 21-day cycle. The concentration in the second and subsequent 21-day cycles were 10^7 (Cohort 5) or 10^8 PFU/mL (Cohorts 6).

    Arm title
    		 Part 1: Combination Therapy Group B
    Arm description
    		 Participants with HCC were administered talimogene laherparepvec and pembrolizumab.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg on Day 1 of each 21-day cycle.

    Investigational medicinal product name
    Talimogene Laherparepvec
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intralesional use
    Dosage and administration details
    Initial concentration of 10^6 PFU/mL in a volume of up to 4mL in Cohorts 5, 6a (participants without viral hepatitis) and 6b (participants with well controlled viral hepatitis) on Day 1 of the first 21-day cycle. The concentration in the second and subsequent 21-day cycles were 10^7 (Cohort 5) or 10^8 PFU/mL (Cohorts 6a and 6b).

    Arm title
    		 Part 2: Hormone Receptor Positive Breast Cancer (HRBC)
    Arm description
    		 Participants with HRBC were administered talimogene laherparepvec and pembrolizumab.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg on Day 1 of each 21-day cycle.

    Investigational medicinal product name
    Talimogene Laherparepvec
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intralesional use
    Dosage and administration details
    At the maximum tolerated concentration (MTC) and maximum tolerated volume (MTV) identified in Part 1 on Day 1 of each 21-day cycle.

    Arm title
    		 Part 2: Triple Negative Breast Cancer (TNBC)
    Arm description
    		 Participants with TNBC were administered talimogene laherparepvec and pembrolizumab.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Talimogene Laherparepvec
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intralesional use
    Dosage and administration details
    At the MTC and MTV identified in Part 1 on Day 1 of each 21-day cycle.

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg on Day 1 of each 21-day cycle.

    Arm title
    		 Part 2: Cutaneous Squamous Cell Carcinoma (CSCC)
    Arm description
    		 Participants with CSCC were administered talimogene laherparepvec and pembrolizumab.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg on Day 1 of each 21-day cycle.

    Investigational medicinal product name
    Talimogene Laherparepvec
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intralesional use
    Dosage and administration details
    At the MTC and MTV identified in Part 1 on Day 1 of each 21-day cycle.

    Arm title
    		 Part 2: Basal Cell Carcinoma (BCC)
    Arm description
    		 Participants with BCC were administered talimogene laherparepvec and pembrolizumab.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg on Day 1 of each 21-day cycle.

    Investigational medicinal product name
    Talimogene Laherparepvec
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intralesional use
    Dosage and administration details
    At the MTC and MTV identified in Part 1 on Day 1 of each 21-day cycle.

    Arm title
    		 Part 2: Colorectal Adenocarcinoma (CRC)
    Arm description
    		 Participants with CRC were administered talimogene laherparepvec and pembrolizumab.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg on Day 1 of each 21-day cycle.

    Investigational medicinal product name
    Talimogene Laherparepvec
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intralesional use
    Dosage and administration details
    At the MTC and MTV identified in Part 1 on Day 1 of each 21-day cycle.

    Number of subjects in period 1
    		Part 1: Monotherapy Group A Part 1: Monotherapy Group B Part 1: Combination Therapy Group A Part 1: Combination Therapy Group B Part 2: Hormone Receptor Positive Breast Cancer (HRBC) Part 2: Triple Negative Breast Cancer (TNBC) Part 2: Cutaneous Squamous Cell Carcinoma (CSCC) Part 2: Basal Cell Carcinoma (BCC) Part 2: Colorectal Adenocarcinoma (CRC)
    Started
    23
    5
    24
    22
    10
    18
    10
    5
    10
    Received Talimogene Laherparepvec
    23
    5
    24
    22
    10
    18
    10
    5
    10
    Received Pembrolizumab
    0
    0 [1]
    24
    22
    10
    18
    10
    5
    10
    Completed
    0
    1
    1
    4
    1
    1
    1
    1
    1
    Not completed
    23
    4
    23
    18
    9
    17
    9
    4
    9
         Adverse event, serious fatal
    21
    3
    22
    14
    8
    12
    5
    4
    8
         Consent withdrawn by subject
    2
    -
    1
    4
    1
    3
    4
    -
    1
         Lost to follow-up
    -
    1
    -
    -
    -
    2
    -
    -
    -
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Only participants in combination cohorts received pembrolizumab.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 1: Monotherapy Group A
    Reporting group description
    		 Participants with non-hepatocellular carcinoma (non-HCC) were administered talimogene laherparepvec.

    Reporting group title
    Part 1: Monotherapy Group B
    Reporting group description
    		 Participants with HCC were administered talimogene laherparepvec.

    Reporting group title
    Part 1: Combination Therapy Group A
    Reporting group description
    		 Participants with non-HCC were administered talimogene laherparepvec and pembrolizumab.

    Reporting group title
    Part 1: Combination Therapy Group B
    Reporting group description
    		 Participants with HCC were administered talimogene laherparepvec and pembrolizumab.

    Reporting group title
    Part 2: Hormone Receptor Positive Breast Cancer (HRBC)
    Reporting group description
    		 Participants with HRBC were administered talimogene laherparepvec and pembrolizumab.

    Reporting group title
    Part 2: Triple Negative Breast Cancer (TNBC)
    Reporting group description
    		 Participants with TNBC were administered talimogene laherparepvec and pembrolizumab.

    Reporting group title
    Part 2: Cutaneous Squamous Cell Carcinoma (CSCC)
    Reporting group description
    		 Participants with CSCC were administered talimogene laherparepvec and pembrolizumab.

    Reporting group title
    Part 2: Basal Cell Carcinoma (BCC)
    Reporting group description
    		 Participants with BCC were administered talimogene laherparepvec and pembrolizumab.

    Reporting group title
    Part 2: Colorectal Adenocarcinoma (CRC)
    Reporting group description
    		 Participants with CRC were administered talimogene laherparepvec and pembrolizumab.

    Reporting group values
    		 Part 1: Monotherapy Group A Part 1: Monotherapy Group B Part 1: Combination Therapy Group A Part 1: Combination Therapy Group B Part 2: Hormone Receptor Positive Breast Cancer (HRBC) Part 2: Triple Negative Breast Cancer (TNBC) Part 2: Cutaneous Squamous Cell Carcinoma (CSCC) Part 2: Basal Cell Carcinoma (BCC) Part 2: Colorectal Adenocarcinoma (CRC) Total
    Number of subjects
    		 23 5 24 22 10 18 10 5 10 127
    Age Categorical
    Units:
        18 - 64 years
    		 16 3 17 10 8 15 5 4 6 84
        65 - 74 years
    		 7 2 5 8 2 2 2 1 4 33
        75 - 84 years
    		 0 0 2 4 0 1 3 0 0 10
        >= 85 years
    		 0 0 0 0 0 0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 56.8 ( 11.4 ) 61.2 ( 8.6 ) 56.7 ( 12.6 ) 64.0 ( 13.7 ) 53.4 ( 9.7 ) 52.3 ( 12.2 ) 62.6 ( 15.1 ) 57.6 ( 8.4 ) 55.7 ( 14.8 ) -
    Sex: Female, Male
    Units:
        Female
    		 11 2 10 5 10 18 3 2 4 65
        Male
    		 12 3 14 17 0 0 7 3 6 62
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 2 0 1 1 0 2 1 1 0 8
        Not Hispanic or Latino
    		 21 5 23 21 10 16 9 4 10 119
        Unknown or Not Reported
    		 0 0 0 0 0 0 0 0 0 0
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0 0 0 0 0 0
        Asian
    		 2 1 0 8 0 3 3 1 1 19
        Black or African American
    		 1 0 0 0 0 0 0 0 0 1
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0 0 0 0 0 0
        White
    		 20 4 23 14 10 15 7 4 9 106
        Other
    		 0 0 1 0 0 0 0 0 0 1

    End points

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    End points reporting groups
    Reporting group title
    Part 1: Monotherapy Group A
    Reporting group description
    		 Participants with non-hepatocellular carcinoma (non-HCC) were administered talimogene laherparepvec.

    Reporting group title
    Part 1: Monotherapy Group B
    Reporting group description
    		 Participants with HCC were administered talimogene laherparepvec.

    Reporting group title
    Part 1: Combination Therapy Group A
    Reporting group description
    		 Participants with non-HCC were administered talimogene laherparepvec and pembrolizumab.

    Reporting group title
    Part 1: Combination Therapy Group B
    Reporting group description
    		 Participants with HCC were administered talimogene laherparepvec and pembrolizumab.

    Reporting group title
    Part 2: Hormone Receptor Positive Breast Cancer (HRBC)
    Reporting group description
    		 Participants with HRBC were administered talimogene laherparepvec and pembrolizumab.

    Reporting group title
    Part 2: Triple Negative Breast Cancer (TNBC)
    Reporting group description
    		 Participants with TNBC were administered talimogene laherparepvec and pembrolizumab.

    Reporting group title
    Part 2: Cutaneous Squamous Cell Carcinoma (CSCC)
    Reporting group description
    		 Participants with CSCC were administered talimogene laherparepvec and pembrolizumab.

    Reporting group title
    Part 2: Basal Cell Carcinoma (BCC)
    Reporting group description
    		 Participants with BCC were administered talimogene laherparepvec and pembrolizumab.

    Reporting group title
    Part 2: Colorectal Adenocarcinoma (CRC)
    Reporting group description
    		 Participants with CRC were administered talimogene laherparepvec and pembrolizumab.

    Primary: Part 2 Only: Objective Response Rate (ORR) per Modified Immune-related Response Criteria Simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST)

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    End point title
    		 Part 2 Only: Objective Response Rate (ORR) per Modified Immune-related Response Criteria Simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) [1] [2]
    End point description
    ORR was defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) per modified irRC-RECIST. - CR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment no less than 4 weeks (28 days) from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. - PR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks (28 days) after first documentation. Full Analysis Set (Part 2): Included all participants in Part 2 who received at least 1 dose of talimogene laherparepvec and at least 1 dose of pembrolizumab in combination.
    End point type
    Primary
    End point timeframe
    Up to 154 weeks
    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 comparative statistical analyses were planned.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: 'ORR' is a primary endpoint for Part 2 and a secondary endpoint for Part 1.
    End point values
    		 Part 2: Hormone Receptor Positive Breast Cancer (HRBC) Part 2: Triple Negative Breast Cancer (TNBC) Part 2: Cutaneous Squamous Cell Carcinoma (CSCC) Part 2: Basal Cell Carcinoma (BCC) Part 2: Colorectal Adenocarcinoma (CRC)
    Number of subjects analysed
    10
    18
    10
    5
    10
    Units: percentage of participants
        number (confidence interval 95%)
    10.0 (0.3 to 44.5)
    16.7 (3.6 to 41.4)
    10.0 (0.3 to 44.5)
    20.0 (0.5 to 71.6)
    0.0 (0.0 to 30.8)
    No statistical analyses for this end point

    Primary: Number of Participants Who Experienced a Dose Limiting Toxicity (DLT)

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    End point title
    		 Number of Participants Who Experienced a Dose Limiting Toxicity (DLT) [3]
    End point description
    All toxicities were graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03: - Grade 1: Mild - Grade 2: Moderate - Grade 3: Severe or medically significant but not immediately life threatening - Grade 4: Life threatening consequences - Grade 5: Death related to adverse event (AE) The occurrence of specific pre-defined toxicities during the DLT evaluation period were considered a DLT if judged by the investigator to be related to talimogene laherparepvec and/or pembrolizumab. All Grade 5 toxicities, intolerable toxicities that lead to permanent discontinuation of talimogene laherparepvec and/or pembrolizumab and Grade 3 or higher AEs related to talimogene laherparepvec and/or pembrolizumab that resulted in a study treatment delay by > 2 weeks were considered DLTs. The analysis set used was the DLT analysis set.
    End point type
    Primary
    End point timeframe
    Cycle 1 and Cycle 2: Day 1 to Day 21
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No comparative statistical analyses were planned.
    End point values
    		 Part 1: Monotherapy Group A Part 1: Monotherapy Group B Part 1: Combination Therapy Group A Part 1: Combination Therapy Group B Part 2: Hormone Receptor Positive Breast Cancer (HRBC) Part 2: Triple Negative Breast Cancer (TNBC) Part 2: Cutaneous Squamous Cell Carcinoma (CSCC) Part 2: Basal Cell Carcinoma (BCC) Part 2: Colorectal Adenocarcinoma (CRC)
    Number of subjects analysed
    18
    5
    20
    19
    8
    11
    5
    4
    9
    Units: participants
    2
    0
    1
    0
    1
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Part 2 Only: Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE)

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    End point title
    		 Part 2 Only: Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) [4] [5]
    End point description
    A TEAE was defined as an event that emerged during treatment, having been absent pretreatment, or worsened relative to the pretreatment state. A treatment-related TEAE was defined as a TEAE that was suspected to be related to the study treatment. Safety Analysis Set (Part 2): Included all participants in Part 2 who have received at least 1 dose of talimogene laherparepvec or at least 1 dose of pembrolizumab.
    End point type
    Primary
    End point timeframe
    Day 1 to 30 days post-last dose of talimogene laherparepvec or pembrolizumab, whichever is later. The maximum duration of talimogene laherparepvec treatment was 102.4 weeks and pembrolizumab treatment was 109.3 weeks in Part 2.
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No comparative statistical analyses were planned.
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: 'Number of Participants Who Experienced a TEAE' is a primary endpoint for Part 2 and a secondary endpoint for Part 1.
    End point values
    		 Part 2: Hormone Receptor Positive Breast Cancer (HRBC) Part 2: Triple Negative Breast Cancer (TNBC) Part 2: Cutaneous Squamous Cell Carcinoma (CSCC) Part 2: Basal Cell Carcinoma (BCC) Part 2: Colorectal Adenocarcinoma (CRC)
    Number of subjects analysed
    10
    18
    10
    5
    10
    Units: participants
        TEAEs
    10
    17
    9
    5
    10
        Treatment-related TEAEs
    10
    12
    4
    5
    10
    No statistical analyses for this end point

    Secondary: Part 1 Only: ORR per Modified irRC-RECIST

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    End point title
    		 Part 1 Only: ORR per Modified irRC-RECIST [6]
    End point description
    ORR was defined as the percentage of participants with a best overall response of CR or PR per modified irRC-RECIST. - CR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment no less than 4 weeks (28 days) from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. - PR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks (28 days) after first documentation. Full Analysis Set (Part 1): Included all participants in Part 1 who received at least 1 dose of talimogene laherparepvec in monotherapy and combination cohorts and at least 1 dose of pembrolizumab in combination cohorts.
    End point type
    Secondary
    End point timeframe
    Up to 297 weeks
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: 'ORR' is a primary endpoint for Part 2 and a secondary endpoint for Part 1.
    End point values
    		 Part 1: Monotherapy Group A Part 1: Monotherapy Group B Part 1: Combination Therapy Group A Part 1: Combination Therapy Group B
    Number of subjects analysed
    23
    5
    24
    22
    Units: percentage of participants
        number (confidence interval 95%)
    0.0 (0.0 to 14.8)
    0.0 (0.0 to 52.2)
    8.3 (1.0 to 27.0)
    13.6 (2.9 to 34.9)
    No statistical analyses for this end point

    Secondary: Best Overall Response (BOR) per Modified irRC-RECIST

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    End point title
    		 Best Overall Response (BOR) per Modified irRC-RECIST
    End point description
    BOR was defined as the number of participants with a best visit response in following order: CR, PR, stable disease (SD), progressive disease (PD), or unevaluable (UE) per modified irRC-RECIST. - CR: Disappearance of all lesions and confirmation by assessment no less than 4 weeks (28 days) from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. - PR: Decrease in tumor burden ≥30% relative to baseline confirmed by a consecutive assessment at least 4 weeks (28 days) after first documentation. - SD: Neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. - PD: Increase in tumor burden ≥ 20 % and at least 5 mm absolute increase relative to nadir confirmation by a repeat, consecutive assessment no less than 4 weeks (28 days) from the date first documented PD. - UE: Any lesion present at baseline which was not assessed or was unable to be evaluated. Full Analysis Set
    End point type
    Secondary
    End point timeframe
    Up to 297 weeks
    End point values
    		 Part 1: Monotherapy Group A Part 1: Monotherapy Group B Part 1: Combination Therapy Group A Part 1: Combination Therapy Group B Part 2: Hormone Receptor Positive Breast Cancer (HRBC) Part 2: Triple Negative Breast Cancer (TNBC) Part 2: Cutaneous Squamous Cell Carcinoma (CSCC) Part 2: Basal Cell Carcinoma (BCC) Part 2: Colorectal Adenocarcinoma (CRC)
    Number of subjects analysed
    23
    5
    24
    22
    10
    18
    10
    5
    10
    Units: participants
        CR
    0
    0
    0
    0
    0
    2
    0
    0
    0
        PR
    0
    0
    2
    3
    1
    1
    1
    1
    0
        SD
    1
    1
    4
    6
    1
    1
    1
    2
    3
        PD
    7
    1
    10
    3
    3
    5
    2
    0
    1
        UE
    13
    3
    7
    10
    5
    6
    4
    2
    5
        Not Done
    2
    0
    1
    0
    0
    3
    2
    0
    1
    No statistical analyses for this end point

    Secondary: Durable Response Rate (DRR) per Modified irRC-RECIST

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    End point title
    		 Durable Response Rate (DRR) per Modified irRC-RECIST
    End point description
    DRR per modified irRC-RECIST was defined as the percentage of participants with an objective response (CR/PR) with a duration of response of at least 6 months. - CR: Disappearance of all lesions and confirmation by assessment no less than 4 weeks (28 days) from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. - PR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks (28 days) after first documentation. Full Analysis Set: Included all participants who received at least 1 dose of talimogene laherparepvec in monotherapy and combination cohorts and at least 1 dose of pembrolizumab in combination cohorts in Part 1 and Part 2.
    End point type
    Secondary
    End point timeframe
    Up to 297 weeks
    End point values
    		 Part 1: Monotherapy Group A Part 1: Monotherapy Group B Part 1: Combination Therapy Group A Part 1: Combination Therapy Group B Part 2: Hormone Receptor Positive Breast Cancer (HRBC) Part 2: Triple Negative Breast Cancer (TNBC) Part 2: Cutaneous Squamous Cell Carcinoma (CSCC) Part 2: Basal Cell Carcinoma (BCC) Part 2: Colorectal Adenocarcinoma (CRC)
    Number of subjects analysed
    23
    5
    24
    22
    10
    18
    10
    5
    10
    Units: percentage of participants
        number (confidence interval 95%)
    0.0 (0.0 to 14.8)
    0.0 (0.0 to 52.2)
    8.3 (1.0 to 27.0)
    9.1 (1.1 to 29.2)
    10.0 (0.3 to 44.5)
    11.1 (1.4 to 34.7)
    10.0 (0.3 to 44.5)
    20.0 (0.5 to 71.6)
    0.0 (0.0 to 30.8)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) per Modified irRC-RECIST

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    End point title
    		 Duration of Response (DOR) per Modified irRC-RECIST
    End point description
    DOR per modified irRC-RECIST was defined as time from date of initial response (CR/PR) that was confirmed to earlier of PD or death. Estimated using Kaplan-Meier method. - CR: Disappearance of all lesions confirmed by assessment ≥ 28 days from date first documented. Any pathological lymph nodes must have reduced in short axis to < 10 mm. - PR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by consecutive assessment at least 28 days after first documentation. - PD: Increase in tumor burden ≥ 20 % and at least 5 mm absolute increase relative to nadir confirmation by a repeat, consecutive assessment no less than 28 days from date first documented PD. Full Analysis Set: Included all participants who received at least 1 dose of talimogene laherparepvec in monotherapy and combination cohorts and at least 1 dose of pembrolizumab in combination cohorts in Part 1 and Part 2. Only participants who had a BOR of CR/PR were included. Values of 9999.9 indicate no data available.
    End point type
    Secondary
    End point timeframe
    Up to 297 weeks
    End point values
    		 Part 1: Monotherapy Group A Part 1: Monotherapy Group B Part 1: Combination Therapy Group A Part 1: Combination Therapy Group B Part 2: Hormone Receptor Positive Breast Cancer (HRBC) Part 2: Triple Negative Breast Cancer (TNBC) Part 2: Cutaneous Squamous Cell Carcinoma (CSCC) Part 2: Basal Cell Carcinoma (BCC) Part 2: Colorectal Adenocarcinoma (CRC)
    Number of subjects analysed
    0 [7]
    0 [8]
    2
    3
    1
    3
    1
    1
    0 [9]
    Units: months
        median (confidence interval 95%)
    ( to )
    ( to )
    16.8 (12.2 to 9999.9)
    8.9 (4.3 to 9999.9)
    9999.9 (9999.9 to 9999.9)
    23.1 (5.1 to 9999.9)
    9999.9 (9999.9 to 9999.9)
    9999.9 (9999.9 to 9999.9)
    ( to )
    Notes
    [7] - Only participants that had a response and subsequently had PD/death were included.
    [8] - Only participants that had a response and subsequently had PD/death were included.
    [9] - Only participants that had a response and subsequently had PD/death were included.
    No statistical analyses for this end point

    Secondary: Disease Control Rate (DCR) per Modified irRC-RECIST

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    End point title
    		 Disease Control Rate (DCR) per Modified irRC-RECIST
    End point description
    DCR per modified irRC-RECIST was defined as percentage of participants that had a BOR in 1 of the following: CR, PR or SD. - CR: Disappearance of all lesions and confirmation by assessment no less than 4 weeks (28 days) from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. - PR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks (28 days) after first documentation. - SD: Neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. Full Analysis Set: Included all participants who received at least 1 dose of talimogene laherparepvec in monotherapy and combination cohorts and at least 1 dose of pembrolizumab in combination cohorts in Part 1 and Part 2.
    End point type
    Secondary
    End point timeframe
    Up to 297 weeks
    End point values
    		 Part 1: Monotherapy Group A Part 1: Monotherapy Group B Part 1: Combination Therapy Group A Part 1: Combination Therapy Group B Part 2: Hormone Receptor Positive Breast Cancer (HRBC) Part 2: Triple Negative Breast Cancer (TNBC) Part 2: Cutaneous Squamous Cell Carcinoma (CSCC) Part 2: Basal Cell Carcinoma (BCC) Part 2: Colorectal Adenocarcinoma (CRC)
    Number of subjects analysed
    23
    5
    24
    22
    10
    18
    10
    5
    10
    Units: percentage of participants
        number (confidence interval 95%)
    4.3 (0.1 to 21.9)
    20.0 (0.5 to 71.6)
    25.0 (9.8 to 46.7)
    40.9 (20.7 to 63.6)
    20.0 (2.5 to 55.6)
    22.2 (6.4 to 47.6)
    20.0 (2.5 to 55.6)
    60.0 (14.7 to 94.7)
    30.0 (6.7 to 65.2)
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS) per Modified irRC-RECIST

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    End point title
    		 Progression Free Survival (PFS) per Modified irRC-RECIST
    End point description
    PFS was defined as the time from first dose to the date of first of confirmed PD per modified irRC-RECIST criteria, or death, whichever occurs first. PFS was estimated using the Kaplan-Meier method. Participants that did not have an event of death or disease progression were censored at the latter of their last evaluable tumor assessment date or first dose date. - PD: Increase in tumor burden ≥ 20 % and at least 5 mm absolute increase relative to nadir confirmation by a repeat, consecutive assessment no less than 4 weeks (28 days) from the date first documented PD. Full Analysis Set: Included all participants who received at least 1 dose of talimogene laherparepvec in monotherapy and combination cohorts and at least 1 dose of pembrolizumab in combination cohorts in Part 1 and Part 2. Values of 9999.9 indicate no data available.
    End point type
    Secondary
    End point timeframe
    Up to 297 weeks
    End point values
    		 Part 1: Monotherapy Group A Part 1: Monotherapy Group B Part 1: Combination Therapy Group A Part 1: Combination Therapy Group B Part 2: Hormone Receptor Positive Breast Cancer (HRBC) Part 2: Triple Negative Breast Cancer (TNBC) Part 2: Cutaneous Squamous Cell Carcinoma (CSCC) Part 2: Basal Cell Carcinoma (BCC) Part 2: Colorectal Adenocarcinoma (CRC)
    Number of subjects analysed
    23
    5
    24
    22
    10
    18
    10
    5
    10
    Units: months
        median (confidence interval 95%)
    2.3 (1.9 to 9.0)
    3.9 (1.9 to 9999.9)
    2.0 (1.9 to 6.2)
    8.1 (3.2 to 13.2)
    6.1 (1.6 to 20.5)
    2.9 (1.2 to 10.2)
    5.4 (2.2 to 9999.9)
    16.4 (5.4 to 9999.9)
    8.8 (2.4 to 12.5)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS was defined as the time from the date of first dose date to the date of death from any cause. OS time was censored at the last date the participant was known to be alive when the confirmation of death was absent or unknown, or at the date 24 months after the last participant enrolled if the last known to be alive/death date was beyond it. One month = 365.25/12 days. OS was estimated using the Kaplan-Meier method. Full Analysis Set: Included all participants who received at least 1 dose of talimogene laherparepvec in monotherapy and combination cohorts and at least 1 dose of pembrolizumab in combination cohorts in Part 1 and Part 2. Values of 9999.9 indicates no data available.
    End point type
    Secondary
    End point timeframe
    Up to 297 weeks
    End point values
    		 Part 1: Monotherapy Group A Part 1: Monotherapy Group B Part 1: Combination Therapy Group A Part 1: Combination Therapy Group B Part 2: Hormone Receptor Positive Breast Cancer (HRBC) Part 2: Triple Negative Breast Cancer (TNBC) Part 2: Cutaneous Squamous Cell Carcinoma (CSCC) Part 2: Basal Cell Carcinoma (BCC) Part 2: Colorectal Adenocarcinoma (CRC)
    Number of subjects analysed
    23
    5
    24
    22
    10
    18
    10
    5
    10
    Units: months
        median (confidence interval 95%)
    8.7 (2.7 to 17.1)
    9.1 (3.9 to 9999.9)
    7.8 (4.4 to 14.2)
    12.8 (6.8 to 29.5)
    9.1 (2.4 to 20.5)
    10.2 (2.7 to 27.2)
    9.6 (2.3 to 9999.9)
    16.4 (5.4 to 9999.9)
    11.2 (2.4 to 18.9)
    No statistical analyses for this end point

    Secondary: Part 1 Only: Number of Participants Who Experienced a TEAE

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    End point title
    		 Part 1 Only: Number of Participants Who Experienced a TEAE [10]
    End point description
    A TEAE was defined as an event that emerged during treatment, having been absent pretreatment, or worsened relative to the pretreatment state. A treatment-related TEAE was defined as a TEAE that was suspected to be related to the study treatment. Safety Analysis Set (Part 1): Included all participants in Part 1 who have received at least 1 dose of talimogene laherparepvec or at least 1 dose of pembrolizumab.
    End point type
    Secondary
    End point timeframe
    Day 1 to 30 days post-last dose of talimogene laherparepvec or pembrolizumab, whichever is later. The maximum duration of talimogene laherparepvec treatment was 34.1 weeks and pembrolizumab treatment was 98.3 weeks in Part 1.
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: 'Number of Participants Who Experienced a TEAE' is a primary endpoint for Part 2 and a secondary endpoint for Part 1.
    End point values
    		 Part 1: Monotherapy Group A Part 1: Monotherapy Group B Part 1: Combination Therapy Group A Part 1: Combination Therapy Group B
    Number of subjects analysed
    23
    5
    24
    22
    Units: participants
        TEAEs
    23
    5
    24
    21
        Treatment-related TEAEs
    23
    5
    22
    20
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Detectable Talimogene Laherparepvec Deoxyribonucleic Acid (DNA) in Blood

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    End point title
    		 Percentage of Participants with Detectable Talimogene Laherparepvec Deoxyribonucleic Acid (DNA) in Blood
    End point description
    Blood samples were tested using real-time polymerase chain reaction (qPCR). Detectable DNA was defined as a positive result by qPCR analysis. Blood Evaluable Analysis Set: Included all participants who were enrolled, received at least one dose of talimogene laherparepvec, and had at least one post dose blood sample collected.
    End point type
    Secondary
    End point timeframe
    Week 1 to Week 10
    End point values
    		 Part 1: Monotherapy Group A Part 1: Monotherapy Group B Part 1: Combination Therapy Group A Part 1: Combination Therapy Group B Part 2: Hormone Receptor Positive Breast Cancer (HRBC) Part 2: Triple Negative Breast Cancer (TNBC) Part 2: Cutaneous Squamous Cell Carcinoma (CSCC) Part 2: Basal Cell Carcinoma (BCC) Part 2: Colorectal Adenocarcinoma (CRC)
    Number of subjects analysed
    23
    5
    24
    22
    10
    18
    10
    5
    10
    Units: percentage of participants
        number (confidence interval 95%)
    100.0 (85.2 to 100.0)
    100.0 (47.8 to 100.0)
    100.0 (85.8 to 100.0)
    95.5 (77.2 to 99.9)
    90.0 (55.5 to 99.7)
    88.9 (65.3 to 98.6)
    50.0 (18.7 to 81.3)
    60.0 (14.7 to 94.7)
    100.0 (69.2 to 100.0)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Detectable Talimogene Laherparepvec DNA in Urine

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    End point title
    		 Percentage of Participants with Detectable Talimogene Laherparepvec DNA in Urine
    End point description
    Urine samples were tested using qPCR. Detectable DNA was defined as a positive result by qPCR analysis. Urine Evaluable Analysis Set: Included all participants who were enrolled, received at least one dose of talimogene laherparepvec, and had at least one post dose urine sample collected.
    End point type
    Secondary
    End point timeframe
    Week 1 to Week 10
    End point values
    		 Part 1: Monotherapy Group A Part 1: Monotherapy Group B Part 1: Combination Therapy Group A Part 1: Combination Therapy Group B Part 2: Hormone Receptor Positive Breast Cancer (HRBC) Part 2: Triple Negative Breast Cancer (TNBC) Part 2: Cutaneous Squamous Cell Carcinoma (CSCC) Part 2: Basal Cell Carcinoma (BCC) Part 2: Colorectal Adenocarcinoma (CRC)
    Number of subjects analysed
    23
    5
    24
    22
    10
    18
    10
    5
    10
    Units: percentage of participants
        number (confidence interval 95%)
    34.8 (16.4 to 57.3)
    40.0 (5.3 to 85.3)
    37.5 (18.8 to 59.4)
    54.5 (32.2 to 75.6)
    10.0 (0.3 to 44.5)
    27.8 (9.7 to 53.5)
    20.0 (2.5 to 55.6)
    0.0 (0.0 to 52.2)
    30.0 (6.7 to 65.2)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Clearance of Talimogene Laherparepvec in Blood

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    End point title
    		 Percentage of Participants with Clearance of Talimogene Laherparepvec in Blood
    End point description
    Blood samples were tested using real-time qPCR. A participant was defined as having cleared talimogene laherparepvec if a negative qPCR in a sample was obtained following a prior positive test and if there were no subsequent positive test results in the same cycle. Blood Clearance Analysis Set: Included participants who were enrolled, received at least one dose of talimogene laherparepvec, and had at least 2 post dose samples, collected within the same dosing cycle. Participants must have had at least 1 positive sample and at least 1 subsequent sample at any time during the cycle. All participants included in the overall number of participants contributed analyzed data. Values of 9999.9 indicate no data available. Values of 99999.9 indicate N = 0.
    End point type
    Secondary
    End point timeframe
    Cycles 2, 3 and 4: Day 1 pre-dose. Each cycle was 21 days.
    End point values
    		 Part 1: Monotherapy Group A Part 1: Monotherapy Group B Part 1: Combination Therapy Group A Part 1: Combination Therapy Group B Part 2: Hormone Receptor Positive Breast Cancer (HRBC) Part 2: Triple Negative Breast Cancer (TNBC) Part 2: Cutaneous Squamous Cell Carcinoma (CSCC) Part 2: Basal Cell Carcinoma (BCC) Part 2: Colorectal Adenocarcinoma (CRC)
    Number of subjects analysed
    23 [11]
    5 [12]
    24 [13]
    21 [14]
    9 [15]
    16 [16]
    5 [17]
    3 [18]
    10 [19]
    Units: percentage of participants
    number (confidence interval 95%)
        Cycle 2, Day 1 Pre-dose
    73.9 (51.6 to 89.8)
    100.0 (47.8 to 100.0)
    52.2 (30.6 to 73.2)
    95.2 (76.2 to 99.9)
    85.7 (42.1 to 99.6)
    80.0 (51.9 to 95.7)
    66.7 (9.4 to 99.2)
    66.7 (9.4 to 99.2)
    60.0 (26.2 to 87.8)
        Cycle 3, Day 1 Pre-dose
    66.7 (41.0 to 86.7)
    100.0 (47.8 to 100.0)
    70.0 (45.7 to 88.1)
    100.0 (81.5 to 100.0)
    77.8 (40.0 to 97.2)
    75.0 (42.8 to 94.5)
    75.0 (19.4 to 99.4)
    100.0 (15.8 to 100.0)
    70.0 (34.8 to 93.3)
        Cycle 4, Day 1 Pre-dose
    66.7 (9.4 to 99.2)
    99999.9 (99999.9 to 99999.9)
    37.5 (8.5 to 75.5)
    99999.9 (99999.9 to 99999.9)
    99999.9 (99999.9 to 99999.9)
    99999.9 (99999.9 to 99999.9)
    99999.9 (99999.9 to 99999.9)
    99999.9 (99999.9 to 99999.9)
    100.0 (2.5 to 100.0)
    Notes
    [11] - Cycle 2 N = 23 Cycle 3 N = 18 Cycle 4 N = 3
    [12] - Cycle 2 N = 5 Cycle 3 N = 5 Cycle 4 N = 0
    [13] - Cycle 2 N = 23 Cycle 3 N = 20 Cycle 4 N = 8
    [14] - Cycle 2 N = 21 Cycle 3 N = 18 Cycle 4 N = 0
    [15] - Cycle 2 N = 7 Cycle 3 N = 9 Cycle 4 N = 0
    [16] - Cycle 2 N = 15 Cycle 3 N = 12 Cycle 4 N = 0
    [17] - Cycle 2 N = 3 Cycle 3 N = 4 Cycle 4 N = 0
    [18] - Cycle 2 N = 3 Cycle 3 N = 2 Cycle 4 N = 0
    [19] - Cycle 2 N = 10 Cycle 3 N = 10 Cycle 4 N = 1
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Clearance of Talimogene Laherparepvec in Urine

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    End point title
    		 Percentage of Participants with Clearance of Talimogene Laherparepvec in Urine
    End point description
    Urine samples were tested using qPCR. A participant was defined as having cleared talimogene laherparepvec if a negative qPCR in a sample was obtained following a prior positive test and if there were no subsequent positive test results in the same cycle. Urine Clearance Analysis Set: Included participants who were enrolled, received at least one dose of talimogene laherparepvec, and had at least 2 post dose samples, collected within the same dosing cycle. Participants must have had at least 1 positive sample and at least 1 subsequent sample at any time during the cycle. Values of 9999.9 indicate no data available. Values of 99999.9 indicate N = 0.
    End point type
    Secondary
    End point timeframe
    Cycles 2, 3 and 4: Day 1 pre-dose. Each cycle was 21 days.
    End point values
    		 Part 1: Monotherapy Group A Part 1: Monotherapy Group B Part 1: Combination Therapy Group A Part 1: Combination Therapy Group B Part 2: Hormone Receptor Positive Breast Cancer (HRBC) Part 2: Triple Negative Breast Cancer (TNBC) Part 2: Cutaneous Squamous Cell Carcinoma (CSCC) Part 2: Basal Cell Carcinoma (BCC) Part 2: Colorectal Adenocarcinoma (CRC)
    Number of subjects analysed
    8 [20]
    2 [21]
    9 [22]
    11 [23]
    1 [24]
    5 [25]
    1 [26]
    0 [27]
    3 [28]
    Units: percentage of participants
    number (confidence interval 95%)
        Cycle 2, Day 1 Pre-dose
    100.0 (29.2 to 100.0)
    100.0 (2.5 to 100.0)
    80.0 (28.4 to 99.5)
    100.0 (29.2 to 100.0)
    99999.9 (99999.9 to 99999.9)
    100.0 (29.2 to 100.0)
    0.0 (0.0 to 97.5)
    ( to )
    100.0 (15.8 to 100.0)
        Cycle 3, Day 1 Pre-dose
    100.0 (59.0 to 100.0)
    100.0 (2.5 to 100.0)
    100.0 (47.8 to 100.0)
    100.0 (69.2 to 100.0)
    100.0 (2.5 to 100.0)
    100.0 (29.2 to 100.0)
    99999.9 (99999.9 to 99999.9)
    ( to )
    100.0 (15.8 to 100.0)
        Cycle 4, Day 1 Pre-dose
    99999.9 (99999.9 to 99999.9)
    99999.9 (99999.9 to 99999.9)
    99999.9 (99999.9 to 99999.9)
    99999.9 (99999.9 to 99999.9)
    99999.9 (99999.9 to 99999.9)
    99999.9 (99999.9 to 99999.9)
    99999.9 (99999.9 to 99999.9)
    ( to )
    99999.9 (99999.9 to 99999.9)
    Notes
    [20] - Cycle 2 N = 3 Cycle 3 N = 7 Cycle 4 N = 0
    [21] - Cycle 2 N = 1 Cycle 3 N = 1 Cycle 4 N = 0
    [22] - Cycle 2 N = 5 Cycle 3 N = 5 Cycle 4 N = 0
    [23] - Cycle 2 N = 3 Cycle 3 N = 10 Cycle 4 N = 0
    [24] - Cycle 2 N = 0 Cycle 3 N = 1 Cycle 4 N = 0
    [25] - Cycle 2 N = 3 Cycle 3 N = 3 Cycle 4 N = 0
    [26] - Cycle 2 N = 1 Cycle 3 N = 1 Cycle 4 N = 0
    [27] - No participants had evaluable data.
    [28] - Cycle 2 N = 2 Cycle 3 N = 2 Cycle 4 N = 0
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Detectable Talimogene Laherparepvec DNA at the Surface of Injection Site

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    End point title
    		 Percentage of Participants with Detectable Talimogene Laherparepvec DNA at the Surface of Injection Site
    End point description
    The percentage of participants with positive qPCR and subsequent positive plaque assays were evaluated from swabs of skin surface of injections. Detectable DNA was defined as a positive result by qPCR analysis. Skin Surface of Injections Evaluable Analysis Set: Included participants who were enrolled, received at least one dose of talimogene laherparepvec, and had at least one swab collected from the skin surface of injections.
    End point type
    Secondary
    End point timeframe
    Week 1 to Week 10
    End point values
    		 Part 1: Monotherapy Group A Part 1: Monotherapy Group B Part 1: Combination Therapy Group A Part 1: Combination Therapy Group B Part 2: Hormone Receptor Positive Breast Cancer (HRBC) Part 2: Triple Negative Breast Cancer (TNBC) Part 2: Cutaneous Squamous Cell Carcinoma (CSCC) Part 2: Basal Cell Carcinoma (BCC) Part 2: Colorectal Adenocarcinoma (CRC)
    Number of subjects analysed
    23
    5
    24
    22
    10
    16
    10
    4
    10
    Units: percentage of participants
        number (confidence interval 95%)
    69.6 (47.1 to 86.8)
    60.0 (14.7 to 94.7)
    79.2 (57.8 to 92.9)
    72.7 (49.8 to 89.3)
    60.0 (26.2 to 87.8)
    68.8 (41.3 to 89.0)
    80.0 (44.4 to 97.5)
    100.0 (39.8 to 100.0)
    60.0 (26.2 to 87.8)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Detectable Talimogene Laherparepvec Virus at the Surface of Injection Site

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    End point title
    		 Percentage of Participants with Detectable Talimogene Laherparepvec Virus at the Surface of Injection Site
    End point description
    The percentage of participants with detectable virus were evaluated from swabs of skin surface of injections. Detectable virus was defined as a positive result by TCID50. Skin Surface of Injections Evaluable Analysis Set: Included participants who were enrolled, received at least one dose of talimogene laherparepvec, and had at least one swab collected from the skin surface of injections. Only participants with a positive surface of injection site qPCR test were included.
    End point type
    Secondary
    End point timeframe
    Week 1 to Week 10
    End point values
    		 Part 1: Monotherapy Group A Part 1: Monotherapy Group B Part 1: Combination Therapy Group A Part 1: Combination Therapy Group B Part 2: Hormone Receptor Positive Breast Cancer (HRBC) Part 2: Triple Negative Breast Cancer (TNBC) Part 2: Cutaneous Squamous Cell Carcinoma (CSCC) Part 2: Basal Cell Carcinoma (BCC) Part 2: Colorectal Adenocarcinoma (CRC)
    Number of subjects analysed
    16
    3
    18
    16
    6
    11
    8
    4
    6
    Units: percentage of participants
        number (confidence interval 95%)
    0.0 (0.0 to 20.6)
    0.0 (0.0 to 70.8)
    0.0 (0.0 to 18.5)
    0.0 (0.0 to 20.6)
    16.7 (0.4 to 64.1)
    0.0 (0.0 to 28.5)
    12.5 (0.3 to 52.7)
    0.0 (0.0 to 60.2)
    0.0 (0.0 to 45.9)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Detectable Talimogene Laherparepvec Virus at the Exterior of the Occlusive Dressing

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    End point title
    		 Percentage of Participants with Detectable Talimogene Laherparepvec Virus at the Exterior of the Occlusive Dressing
    End point description
    The percentage of participants with detectable virus were evaluated from swabs of the exterior of the occlusive dressings. Detectable virus was defined as a positive result by TCID50. Exterior of Occlusive Dressing Evaluable Analysis Set: Included participants who were enrolled, received at least one dose of talimogene laherparepvec, and had at least one swab collected from the exterior of the occlusive dressing. Only participants with a positive exterior of the occlusive dressing qPCR test were included.
    End point type
    Secondary
    End point timeframe
    Week 1 to Week 7
    End point values
    		 Part 1: Monotherapy Group A Part 1: Monotherapy Group B Part 1: Combination Therapy Group A Part 1: Combination Therapy Group B Part 2: Hormone Receptor Positive Breast Cancer (HRBC) Part 2: Triple Negative Breast Cancer (TNBC) Part 2: Cutaneous Squamous Cell Carcinoma (CSCC) Part 2: Basal Cell Carcinoma (BCC) Part 2: Colorectal Adenocarcinoma (CRC)
    Number of subjects analysed
    7
    1
    9
    13
    6
    4
    5
    3
    1
    Units: percentage of participants
        number (confidence interval 95%)
    0.0 (0.0 to 41.0)
    0.0 (0.0 to 97.5)
    0.0 (0.0 to 33.6)
    0.0 (0.0 to 24.7)
    16.7 (0.4 to 64.1)
    0.0 (0.0 to 60.2)
    0.0 (0.0 to 52.2)
    0.0 (0.0 to 70.8)
    0.0 (0.0 to 97.5)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Detectable Talimogene Laherparepvec DNA at the Exterior of the Occlusive Dressing

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    End point title
    		 Percentage of Participants with Detectable Talimogene Laherparepvec DNA at the Exterior of the Occlusive Dressing
    End point description
    The percentage of participants with positive qPCR and subsequent positive plaque assays were evaluated from swabs of the exterior of the occlusive dressing. Detectable DNA was defined as a positive result by qPCR analysis. Exterior of Occlusive Dressing Evaluable Analysis Set: Included participants who were enrolled, received at least one dose of talimogene laherparepvec, and had at least one swab collected from the exterior of the occlusive dressing.
    End point type
    Secondary
    End point timeframe
    Week 1 to Week 7
    End point values
    		 Part 1: Monotherapy Group A Part 1: Monotherapy Group B Part 1: Combination Therapy Group A Part 1: Combination Therapy Group B Part 2: Hormone Receptor Positive Breast Cancer (HRBC) Part 2: Triple Negative Breast Cancer (TNBC) Part 2: Cutaneous Squamous Cell Carcinoma (CSCC) Part 2: Basal Cell Carcinoma (BCC) Part 2: Colorectal Adenocarcinoma (CRC)
    Number of subjects analysed
    23
    5
    23
    21
    9
    12
    9
    5
    7
    Units: percentage of participants
        number (confidence interval 95%)
    30.4 (13.2 to 52.9)
    20.0 (0.5 to 71.6)
    39.1 (19.7 to 61.5)
    61.9 (38.4 to 81.9)
    66.7 (29.9 to 92.5)
    33.3 (9.9 to 65.1)
    44.4 (13.7 to 78.8)
    60.0 (14.7 to 94.7)
    14.3 (0.4 to 57.9)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Detectable Talimogene Laherparepvec DNA at the Oral Mucosa

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    End point title
    		 Percentage of Participants with Detectable Talimogene Laherparepvec DNA at the Oral Mucosa
    End point description
    The percentage of participants with positive qPCR and subsequent positive plaque assays were evaluated from swabs of the oral mucosa. Detectable DNA was defined as a positive result by qPCR analysis. Oral Mucosa Evaluable Analysis Set: Included participants who were enrolled, received at least one dose of talimogene laherparepvec, and had at least one swab collected from the oral mucosa.
    End point type
    Secondary
    End point timeframe
    Part 1: Week 1 to Week 37. Part 2: Week 1 to Week 43
    End point values
    		 Part 1: Monotherapy Group A Part 1: Monotherapy Group B Part 1: Combination Therapy Group A Part 1: Combination Therapy Group B Part 2: Hormone Receptor Positive Breast Cancer (HRBC) Part 2: Triple Negative Breast Cancer (TNBC) Part 2: Cutaneous Squamous Cell Carcinoma (CSCC) Part 2: Basal Cell Carcinoma (BCC) Part 2: Colorectal Adenocarcinoma (CRC)
    Number of subjects analysed
    23
    5
    24
    22
    10
    16
    10
    5
    10
    Units: percentage of participants
        number (confidence interval 95%)
    0.0 (0.0 to 14.8)
    0.0 (0.0 to 52.2)
    29.2 (12.6 to 51.1)
    4.5 (0.1 to 22.8)
    0.0 (0.0 to 30.8)
    12.5 (1.6 to 38.3)
    10.0 (0.3 to 44.5)
    60.0 (14.7 to 94.7)
    10.0 (0.3 to 44.5)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Detectable Talimogene Laherparepvec Virus at the Oral Mucosa

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    End point title
    		 Percentage of Participants with Detectable Talimogene Laherparepvec Virus at the Oral Mucosa
    End point description
    The percentage of participants with detectable virus were evaluated from swabs of the oral mucosa. Detectable virus was defined as a positive result by TCID50. Oral Mucosa Evaluable Analysis Set: Included participants who were enrolled, received at least one dose of talimogene laherparepvec, and had at least one swab collected from the oral mucosa. Only participants with a positive oral mucosa qPCR test were included.
    End point type
    Secondary
    End point timeframe
    Week 1 to Week 7
    End point values
    		 Part 1: Monotherapy Group A Part 1: Monotherapy Group B Part 1: Combination Therapy Group A Part 1: Combination Therapy Group B Part 2: Hormone Receptor Positive Breast Cancer (HRBC) Part 2: Triple Negative Breast Cancer (TNBC) Part 2: Cutaneous Squamous Cell Carcinoma (CSCC) Part 2: Basal Cell Carcinoma (BCC) Part 2: Colorectal Adenocarcinoma (CRC)
    Number of subjects analysed
    0 [29]
    0 [30]
    7
    2
    1
    2
    2
    3
    1
    Units: percentage of participants
        number (confidence interval 95%)
    ( to )
    ( to )
    0.0 (0.0 to 41.0)
    0.0 (0.0 to 84.2)
    0.0 (0.0 to 97.5)
    0.0 (0.0 to 84.2)
    0.0 (0.0 to 84.2)
    0.0 (0.0 to 70.8)
    0.0 (0.0 to 97.5)
    Notes
    [29] - No participants had a positive qPCR result.
    [30] - No participants had a positive qPCR result.
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Detectable Talimogene Laherparepvec DNA in Lesions Suspected to be Herpetic in Origin

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    End point title
    		 Percentage of Participants with Detectable Talimogene Laherparepvec DNA in Lesions Suspected to be Herpetic in Origin
    End point description
    The percentage of participants with positive qPCR were evaluated in any swab of a lesion suspected to be herpetic in origin. Detectable DNA was defined as a positive result by qPCR analysis. Participants returned to the clinic within 3 days of the occurrence of reportable lesion suspected to be herpetic in origin such as cold sores or vesicles. The lesion was evaluated by the Investigator and swabbed if herpes simplex virus (HSV) infection was suspected. Reactive Swab Analysis Set: Included participants who were enrolled, received at least one dose of talimogene laherparepvec, and had at least one swab sample collected from lesions that were suspected to be herpetic in origin.
    End point type
    Secondary
    End point timeframe
    Day 1 to 30 days post-last dose of talimogene laherparepvec. The maximum duration of talimogene laherparepvec treatment was 102.4 weeks and pembrolizumab treatment was 109.3 weeks.
    End point values
    		 Part 1: Monotherapy Group A Part 1: Monotherapy Group B Part 1: Combination Therapy Group A Part 1: Combination Therapy Group B Part 2: Hormone Receptor Positive Breast Cancer (HRBC) Part 2: Triple Negative Breast Cancer (TNBC) Part 2: Cutaneous Squamous Cell Carcinoma (CSCC) Part 2: Basal Cell Carcinoma (BCC) Part 2: Colorectal Adenocarcinoma (CRC)
    Number of subjects analysed
    2
    0 [31]
    0 [32]
    1
    0 [33]
    0 [34]
    0 [35]
    0 [36]
    0 [37]
    Units: percentage of participants
        number (confidence interval 95%)
    0.0 (0.0 to 84.2)
    ( to )
    ( to )
    100.0 (2.5 to 100.0)
    ( to )
    ( to )
    ( to )
    ( to )
    ( to )
    Notes
    [31] - No participants had lesions suspected to be herpetic in origin.
    [32] - No participants had lesions suspected to be herpetic in origin.
    [33] - No participants had lesions suspected to be herpetic in origin.
    [34] - No participants had lesions suspected to be herpetic in origin.
    [35] - No participants had lesions suspected to be herpetic in origin.
    [36] - No participants had lesions suspected to be herpetic in origin.
    [37] - No participants had lesions suspected to be herpetic in origin.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose date to the earlier of 90 days for treatment-emergent SAEs or 30 days for other (non-serious) TEAEs after the last dose date (talimogene laherparepvec or pembrolizumab, whichever is later) or the participants initiated new therapy.
    Adverse event reporting additional description
    Median [min, max] duration of exposure was 6.1 [0.1, 33.1] weeks in Part 1 monotherapy cohorts, 9.2 [0.1, 98.3] weeks in Part 1 combination cohorts and 6.1 [0.1, 109.3] weeks in Part 2.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Part 1: Monotherapy Group A
    Reporting group description
    		 Participants with non-hepatocellular carcinoma (non-HCC) were administered talimogene laherparepvec by intralesional injection at an initial concentration of 10^6 plaque forming unit (PFU)/mL in a volume of up to 4mL in Cohorts 1 & 2 and up to a volume of 8 mL in Cohorts 3 & 4 on Day 1 of the first 21-day cycle. The concentration of talimogene laherparepvec doses in the second and subsequent 21-day cycles were 10^7 (Cohorts 1 & 4) or 10^8 PFU/mL (Cohorts 2 & 3)

    Reporting group title
    Part 1: Combination Therapy Group A
    Reporting group description
    		 Participants with non-hepatocellular carcinoma (non-HCC) were administered talimogene laherparepvec by intralesional injection at an initial concentration of 10^6 plaque forming unit (PFU)/mL in a volume of up to 4mL in Cohorts 5 & 6 on Day 1 of the first 21-day cycle. The concentration of talimogene laherparepvec doses in the second and subsequent 21-day cycles were 10^7 (Cohort 5) or 10^8 PFU/mL (Cohorts 6). Participants were also administered 200 mg of pembrolizumab on Day 1 of each 21-day cycle as an intravenous infusion.

    Reporting group title
    Part 1: Combination Therapy Group B
    Reporting group description
    		 Participants with hepatocellular carcinoma (HCC) were administered talimogene laherparepvec by intralesional injection at an initial concentration of 10^6 plaque forming unit (PFU)/mL in a volume of up to 4mL in Cohorts 5, 6a (participants without viral hepatitis) and 6b (participants with well controlled viral hepatitis) on Day 1 of the first 21-day cycle. The concentration of talimogene laherparepvec doses in the second and subsequent 21-day cycles were 10^7 (Cohort 5) or 10^8 PFU/mL (Cohorts 6a and 6b). Participants were also administered 200 mg of pembrolizumab on Day 1 of each 21-day cycle as an intravenous infusion.

    Reporting group title
    Part 1: Monotherapy Group B
    Reporting group description
    		 Participants with hepatocellular carcinoma (HCC) were administered talimogene laherparepvec by intralesional injection at an initial concentration of 10^6 plaque forming unit (PFU)/mL in a volume of up to 4mL in Cohorts 1 & 2 and up to a volume of 8 mL in Cohorts 3 & 4 on Day 1 of the first 21-day cycle. The concentration of talimogene laherparepvec doses in the second and subsequent 21-day cycles were 10^7 (Cohorts 1 & 4) or 10^8 PFU/mL (Cohorts 2 & 3).

    Reporting group title
    Part 2: Hormone Receptor Positive Breast Cancer (HRBC)
    Reporting group description
    		 Participants with HRBC were administered talimogene laherparepvec by intralesional injection at the maximum tolerated concentration (MTC) and maximum tolerated volume (MTV) identified in Part 1 on Day 1 of each 21-day cycle. Participants were also administered 200 mg of pembrolizumab on Day 1 of each 21-day cycle as an intravenous infusion.

    Reporting group title
    Part 2: Triple Negative Breast Cancer (TNBC)
    Reporting group description
    		 Participants with TNBC were administered talimogene laherparepvec by intralesional injection at the MTC and MTV identified in Part 1 on Day 1 of each 21-day cycle. Participants were also administered 200 mg of pembrolizumab on Day 1 of each 21-day cycle as an intravenous infusion.

    Reporting group title
    Part 2: Cutaneous Squamous Cell Carcinoma (CSCC)
    Reporting group description
    		 Participants with CSCC were administered talimogene laherparepvec by intralesional injection at the MTC and MTV identified in Part 1 on Day 1 of each 21-day cycle. Participants were also administered 200 mg of pembrolizumab on Day 1 of each 21-day cycle as an intravenous infusion.

    Reporting group title
    Part 2: Basal Cell Carcinoma (BCC)
    Reporting group description
    		 Participants with BCC were administered talimogene laherparepvec by intralesional injection at the MTC and MTV identified in Part 1 on Day 1 of each 21-day cycle. Participants were also administered 200 mg of pembrolizumab on Day 1 of each 21-day cycle as an intravenous infusion.

    Reporting group title
    Part 2: Colorectal Adenocarcinoma (CRC)
    Reporting group description
    		 Participants with CRC were administered talimogene laherparepvec by intralesional injection at the MTC and MTV identified in Part 1 on Day 1 of each 21-day cycle. Participants were also administered 200 mg of pembrolizumab on Day 1 of each 21-day cycle as an intravenous infusion.

    Serious adverse events
    		 Part 1: Monotherapy Group A Part 1: Combination Therapy Group A Part 1: Combination Therapy Group B Part 1: Monotherapy Group B Part 2: Hormone Receptor Positive Breast Cancer (HRBC) Part 2: Triple Negative Breast Cancer (TNBC) Part 2: Cutaneous Squamous Cell Carcinoma (CSCC) Part 2: Basal Cell Carcinoma (BCC) Part 2: Colorectal Adenocarcinoma (CRC)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 23 (43.48%)
    10 / 24 (41.67%)
    11 / 22 (50.00%)
    2 / 5 (40.00%)
    4 / 10 (40.00%)
    7 / 18 (38.89%)
    5 / 10 (50.00%)
    3 / 5 (60.00%)
    3 / 10 (30.00%)
         number of deaths (all causes)
    21
    22
    14
    3
    8
    13
    5
    4
    8
         number of deaths resulting from adverse events
    0
    0
    3
    0
    0
    3
    0
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    1 / 10 (10.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to lung
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Liver carcinoma ruptured
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer metastatic
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    2 / 10 (20.00%)
    1 / 18 (5.56%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 23 (13.04%)
    4 / 24 (16.67%)
    1 / 22 (4.55%)
    1 / 5 (20.00%)
    2 / 10 (20.00%)
    2 / 18 (11.11%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    2 / 3
    5 / 5
    0 / 1
    1 / 1
    4 / 4
    4 / 5
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Cytokine release syndrome
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    2 / 18 (11.11%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procalcitonin increased
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hernial eventration
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic haemorrhage
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis cholestatic
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Glomerulonephritis proliferative
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Soft tissue haemorrhage
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Haemophilus infection
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pseudomonal skin infection
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Part 1: Monotherapy Group A Part 1: Combination Therapy Group A Part 1: Combination Therapy Group B Part 1: Monotherapy Group B Part 2: Hormone Receptor Positive Breast Cancer (HRBC) Part 2: Triple Negative Breast Cancer (TNBC) Part 2: Cutaneous Squamous Cell Carcinoma (CSCC) Part 2: Basal Cell Carcinoma (BCC) Part 2: Colorectal Adenocarcinoma (CRC)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 23 (100.00%)
    24 / 24 (100.00%)
    21 / 22 (95.45%)
    5 / 5 (100.00%)
    10 / 10 (100.00%)
    15 / 18 (83.33%)
    8 / 10 (80.00%)
    5 / 5 (100.00%)
    10 / 10 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Tumour pain
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    1 / 18 (5.56%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    0
    0
    0
    Tumour ulceration
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 24 (4.17%)
    1 / 22 (4.55%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    3
    1
    2
    0
    1
    0
    0
    0
    0
    Hypotension
         subjects affected / exposed
    1 / 23 (4.35%)
    6 / 24 (25.00%)
    2 / 22 (9.09%)
    1 / 5 (20.00%)
    1 / 10 (10.00%)
    2 / 18 (11.11%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    13
    2
    1
    5
    2
    1
    0
    0
    Lymphoedema
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    1
    0
    0
    Surgical and medical procedures
    Mass excision
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 23 (4.35%)
    5 / 24 (20.83%)
    2 / 22 (9.09%)
    2 / 5 (40.00%)
    3 / 10 (30.00%)
    5 / 18 (27.78%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    1
    9
    3
    2
    3
    7
    0
    0
    2
    Application site pain
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
    2 / 22 (9.09%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    2
    0
    2
    0
    0
    0
    0
    0
    1
    Axillary pain
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    0
    Catheter site pain
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Chest pain
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    0
    0
    Chills
         subjects affected / exposed
    4 / 23 (17.39%)
    13 / 24 (54.17%)
    8 / 22 (36.36%)
    1 / 5 (20.00%)
    8 / 10 (80.00%)
    0 / 18 (0.00%)
    2 / 10 (20.00%)
    0 / 5 (0.00%)
    3 / 10 (30.00%)
         occurrences all number
    9
    20
    21
    3
    15
    0
    4
    0
    5
    Facial pain
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Injection site pain
         subjects affected / exposed
    2 / 23 (8.70%)
    3 / 24 (12.50%)
    4 / 22 (18.18%)
    0 / 5 (0.00%)
    2 / 10 (20.00%)
    1 / 18 (5.56%)
    2 / 10 (20.00%)
    0 / 5 (0.00%)
    4 / 10 (40.00%)
         occurrences all number
    2
    5
    5
    0
    2
    1
    2
    0
    6
    Influenza like illness
         subjects affected / exposed
    2 / 23 (8.70%)
    2 / 24 (8.33%)
    3 / 22 (13.64%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    1 / 18 (5.56%)
    2 / 10 (20.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
         occurrences all number
    3
    7
    12
    0
    2
    3
    3
    2
    0
    Injection site erythema
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Injection site haematoma
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    1 / 18 (5.56%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    1
    0
    0
    0
    Injection site haemorrhage
         subjects affected / exposed
    1 / 23 (4.35%)
    2 / 24 (8.33%)
    1 / 22 (4.55%)
    2 / 5 (40.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    3
    8
    2
    0
    0
    0
    0
    0
    Fatigue
         subjects affected / exposed
    11 / 23 (47.83%)
    8 / 24 (33.33%)
    4 / 22 (18.18%)
    1 / 5 (20.00%)
    3 / 10 (30.00%)
    1 / 18 (5.56%)
    1 / 10 (10.00%)
    2 / 5 (40.00%)
    5 / 10 (50.00%)
         occurrences all number
    19
    14
    5
    1
    5
    1
    1
    4
    5
    Injection site paraesthesia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Injection site ulcer
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Malaise
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Oedema
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Pain
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
    2 / 22 (9.09%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    3
    1
    0
    0
    0
    0
    1
    Pyrexia
         subjects affected / exposed
    18 / 23 (78.26%)
    22 / 24 (91.67%)
    17 / 22 (77.27%)
    4 / 5 (80.00%)
    9 / 10 (90.00%)
    8 / 18 (44.44%)
    3 / 10 (30.00%)
    1 / 5 (20.00%)
    9 / 10 (90.00%)
         occurrences all number
    41
    73
    64
    11
    24
    19
    4
    3
    18
    Oedema peripheral
         subjects affected / exposed
    0 / 23 (0.00%)
    3 / 24 (12.50%)
    2 / 22 (9.09%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    4
    2
    0
    1
    0
    0
    1
    0
    Peripheral swelling
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Immune system disorders
    Contrast media allergy
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Immune-mediated adverse reaction
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 23 (0.00%)
    3 / 24 (12.50%)
    1 / 22 (4.55%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    4
    1
    0
    0
    0
    0
    0
    1
    Dysphonia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    0
    0
    Nasal congestion
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Pleural effusion
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    2 / 10 (20.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    2
    0
    0
    1
    0
    Pulmonary embolism
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Hyperventilation
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Epistaxis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Dyspnoea
         subjects affected / exposed
    3 / 23 (13.04%)
    2 / 24 (8.33%)
    1 / 22 (4.55%)
    3 / 5 (60.00%)
    3 / 10 (30.00%)
    2 / 18 (11.11%)
    1 / 10 (10.00%)
    1 / 5 (20.00%)
    1 / 10 (10.00%)
         occurrences all number
    7
    2
    1
    3
    5
    3
    1
    1
    1
    Psychiatric disorders
    Restlessness
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Insomnia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    0
    1
    Confusional state
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 24 (8.33%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    0
    0
    1
    0
    Anxiety
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 24 (8.33%)
    1 / 22 (4.55%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    2
    1
    0
    1
    0
    0
    1
    0
    Investigations
    Blood creatinine abnormal
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 23 (17.39%)
    3 / 24 (12.50%)
    0 / 22 (0.00%)
    1 / 5 (20.00%)
    3 / 10 (30.00%)
    1 / 18 (5.56%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    6
    3
    0
    1
    5
    1
    0
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 23 (4.35%)
    6 / 24 (25.00%)
    2 / 22 (9.09%)
    0 / 5 (0.00%)
    2 / 10 (20.00%)
    1 / 18 (5.56%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    5
    9
    2
    0
    5
    1
    0
    0
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    4 / 23 (17.39%)
    3 / 24 (12.50%)
    0 / 22 (0.00%)
    1 / 5 (20.00%)
    3 / 10 (30.00%)
    2 / 18 (11.11%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    5
    4
    0
    2
    6
    2
    0
    0
    1
    Blood bilirubin increased
         subjects affected / exposed
    1 / 23 (4.35%)
    3 / 24 (12.50%)
    3 / 22 (13.64%)
    0 / 5 (0.00%)
    2 / 10 (20.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    3
    7
    0
    4
    0
    0
    0
    0
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    1
    Blood creatinine increased
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    0
    1
    0
    0
    0
    0
    0
    Blood potassium decreased
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    1
    0
    0
    0
    C-reactive protein increased
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    0
    1
    CD4 lymphocyte percentage decreased
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Lymphocyte count abnormal
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Ejection fraction decreased
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Fibrin D dimer increased
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    2 / 10 (20.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    2
    1
    0
    0
    2
    0
    0
    0
    1
    Haemoglobin decreased
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Creatinine renal clearance increased
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    0
    Lymphocyte count decreased
         subjects affected / exposed
    1 / 23 (4.35%)
    2 / 24 (8.33%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    3 / 10 (30.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    8
    0
    0
    10
    0
    0
    0
    1
    Neutrophil count decreased
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    2 / 10 (20.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    10
    0
    0
    0
    0
    Platelet count decreased
         subjects affected / exposed
    3 / 23 (13.04%)
    1 / 24 (4.17%)
    3 / 22 (13.64%)
    1 / 5 (20.00%)
    2 / 10 (20.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    3
    1
    6
    3
    4
    0
    0
    0
    0
    Serum ferritin decreased
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Serum ferritin increased
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Thyroxine free decreased
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Transaminases increased
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    1
    Weight decreased
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 24 (8.33%)
    2 / 22 (9.09%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    2
    3
    0
    0
    0
    0
    0
    0
    Weight increased
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 24 (8.33%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    3
    0
    0
    1
    0
    0
    0
    0
    White blood cell count decreased
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    2 / 10 (20.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    12
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    2 / 10 (20.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    2
    0
    0
    1
    0
    2
    0
    0
    Infusion related reaction
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 24 (4.17%)
    3 / 22 (13.64%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    3
    0
    0
    1
    1
    0
    1
    Injection related reaction
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Post procedural diarrhoea
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Procedural pain
         subjects affected / exposed
    2 / 23 (8.70%)
    2 / 24 (8.33%)
    0 / 22 (0.00%)
    2 / 5 (40.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    5
    4
    0
    5
    0
    1
    0
    0
    0
    Wound haemorrhage
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Immunisation reaction
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    2 / 10 (20.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    0
    0
    0
    Cardiac disorders
    Pericardial effusion
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Angina pectoris
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Sinus tachycardia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    2 / 10 (20.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    2
    0
    0
    0
    0
    Tachycardia
         subjects affected / exposed
    3 / 23 (13.04%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    2 / 5 (40.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    4
    2
    0
    2
    0
    0
    0
    0
    0
    Nervous system disorders
    Hypergeusia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Headache
         subjects affected / exposed
    6 / 23 (26.09%)
    6 / 24 (25.00%)
    2 / 22 (9.09%)
    2 / 5 (40.00%)
    4 / 10 (40.00%)
    1 / 18 (5.56%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    8
    10
    2
    6
    4
    1
    0
    0
    0
    Facial paralysis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Dysgeusia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Dizziness
         subjects affected / exposed
    2 / 23 (8.70%)
    2 / 24 (8.33%)
    2 / 22 (9.09%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    1 / 18 (5.56%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    3
    2
    3
    0
    1
    1
    0
    0
    2
    Lethargy
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    0
    0
    Neurotoxicity
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Presyncope
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Sciatica
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    7 / 23 (30.43%)
    6 / 24 (25.00%)
    3 / 22 (13.64%)
    0 / 5 (0.00%)
    2 / 10 (20.00%)
    3 / 18 (16.67%)
    1 / 10 (10.00%)
    2 / 5 (40.00%)
    2 / 10 (20.00%)
         occurrences all number
    10
    7
    3
    0
    3
    8
    3
    3
    2
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    1
    0
    0
    Neutropenia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    0
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Eye disorders
    Conjunctival haemorrhage
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    0 / 23 (0.00%)
    4 / 24 (16.67%)
    1 / 22 (4.55%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    5
    1
    1
    0
    0
    0
    0
    1
    Abdominal discomfort
         subjects affected / exposed
    2 / 23 (8.70%)
    3 / 24 (12.50%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    5
    0
    0
    0
    0
    0
    5
    0
    Abdominal distension
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    2
    0
    1
    0
    0
    0
    Abdominal pain
         subjects affected / exposed
    7 / 23 (30.43%)
    6 / 24 (25.00%)
    8 / 22 (36.36%)
    2 / 5 (40.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    10
    6
    12
    3
    0
    0
    0
    0
    1
    Abdominal pain upper
         subjects affected / exposed
    4 / 23 (17.39%)
    6 / 24 (25.00%)
    1 / 22 (4.55%)
    2 / 5 (40.00%)
    3 / 10 (30.00%)
    0 / 18 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    4
    7
    1
    2
    3
    0
    1
    0
    1
    Abnormal faeces
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Constipation
         subjects affected / exposed
    5 / 23 (21.74%)
    4 / 24 (16.67%)
    1 / 22 (4.55%)
    0 / 5 (0.00%)
    3 / 10 (30.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    2 / 5 (40.00%)
    1 / 10 (10.00%)
         occurrences all number
    5
    5
    1
    0
    3
    0
    0
    3
    1
    Diarrhoea
         subjects affected / exposed
    4 / 23 (17.39%)
    5 / 24 (20.83%)
    2 / 22 (9.09%)
    0 / 5 (0.00%)
    4 / 10 (40.00%)
    0 / 18 (0.00%)
    1 / 10 (10.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
         occurrences all number
    4
    8
    3
    0
    4
    0
    1
    7
    0
    Dry mouth
         subjects affected / exposed
    1 / 23 (4.35%)
    2 / 24 (8.33%)
    1 / 22 (4.55%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    2
    1
    0
    1
    0
    0
    0
    0
    Dysphagia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Gastritis
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    1
    0
    0
    0
    0
    0
    0
    Melaena
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    6 / 23 (26.09%)
    14 / 24 (58.33%)
    4 / 22 (18.18%)
    2 / 5 (40.00%)
    7 / 10 (70.00%)
    3 / 18 (16.67%)
    2 / 10 (20.00%)
    1 / 5 (20.00%)
    4 / 10 (40.00%)
         occurrences all number
    9
    21
    7
    4
    13
    4
    2
    1
    4
    Vomiting
         subjects affected / exposed
    5 / 23 (21.74%)
    8 / 24 (33.33%)
    5 / 22 (22.73%)
    2 / 5 (40.00%)
    5 / 10 (50.00%)
    3 / 18 (16.67%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    8
    9
    6
    4
    15
    3
    1
    0
    2
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Hepatobiliary disorders
    Portal vein stenosis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Hepatomegaly
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Liver tenderness
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Hypertransaminasaemia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Erythema
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    0
    0
    Eczema
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Night sweats
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    1
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 23 (0.00%)
    6 / 24 (25.00%)
    6 / 22 (27.27%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    2 / 18 (11.11%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    11
    8
    1
    0
    2
    0
    0
    0
    Psoriasis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    0
    Rash
         subjects affected / exposed
    2 / 23 (8.70%)
    4 / 24 (16.67%)
    2 / 22 (9.09%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    1 / 18 (5.56%)
    3 / 10 (30.00%)
    2 / 5 (40.00%)
    1 / 10 (10.00%)
         occurrences all number
    2
    4
    4
    0
    1
    1
    6
    5
    1
    Rash macular
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Rash maculo-papular
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    4
    0
    0
    1
    0
    0
    3
    0
    Skin lesion
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    0
    0
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Dysuria
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    1
    0
    Chromaturia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    2 / 22 (9.09%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    2
    0
    1
    0
    0
    0
    0
    Hypothyroidism
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
    2 / 22 (9.09%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    2 / 18 (11.11%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    2
    2
    0
    0
    2
    2
    0
    0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    0
    Muscular weakness
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    2
    0
    0
    0
    0
    Limb discomfort
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Fistula
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Back pain
         subjects affected / exposed
    4 / 23 (17.39%)
    5 / 24 (20.83%)
    1 / 22 (4.55%)
    1 / 5 (20.00%)
    1 / 10 (10.00%)
    1 / 18 (5.56%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    4
    8
    1
    1
    1
    4
    0
    0
    1
    Arthritis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Arthralgia
         subjects affected / exposed
    1 / 23 (4.35%)
    2 / 24 (8.33%)
    4 / 22 (18.18%)
    0 / 5 (0.00%)
    3 / 10 (30.00%)
    2 / 18 (11.11%)
    1 / 10 (10.00%)
    1 / 5 (20.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    2
    9
    0
    5
    6
    1
    4
    1
    Myalgia
         subjects affected / exposed
    4 / 23 (17.39%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    2 / 10 (20.00%)
    1 / 18 (5.56%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    1 / 10 (10.00%)
         occurrences all number
    4
    1
    0
    0
    4
    3
    0
    4
    1
    Pain in extremity
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    1
    Osteoporosis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Neck pain
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    1
    Cellulitis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Diverticulitis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Oral candidiasis
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 24 (8.33%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    0
    1
    0
    0
    Oral herpes
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    0
    0
    1
    0
    0
    0
    0
    Soft tissue infection
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    1 / 10 (10.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    3
    1
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 23 (4.35%)
    2 / 24 (8.33%)
    2 / 22 (9.09%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    1 / 18 (5.56%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    3 / 10 (30.00%)
         occurrences all number
    1
    2
    2
    0
    2
    1
    0
    0
    3
    Herpes simplex viraemia
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 24 (8.33%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    0
    0
    Campylobacter infection
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Vaginal infection
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    6 / 23 (26.09%)
    5 / 24 (20.83%)
    2 / 22 (9.09%)
    0 / 5 (0.00%)
    3 / 10 (30.00%)
    1 / 18 (5.56%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    3 / 10 (30.00%)
         occurrences all number
    7
    6
    4
    0
    3
    1
    0
    1
    3
    Hypomagnesaemia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    0
    0
    Hypokalaemia
         subjects affected / exposed
    3 / 23 (13.04%)
    1 / 24 (4.17%)
    1 / 22 (4.55%)
    0 / 5 (0.00%)
    2 / 10 (20.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    11
    1
    2
    0
    2
    0
    0
    0
    0
    Hypoglycaemia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    0
    0
    Hypocalcaemia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    0
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 24 (4.17%)
    1 / 22 (4.55%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    1 / 10 (10.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    1
    0
    0
    0
    1
    2
    0
    Hypercalcaemia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 24 (8.33%)
    1 / 22 (4.55%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    3
    5
    0
    0
    0
    0
    0
    0
    Dehydration
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    2 / 10 (20.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    0
    Folate deficiency
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Gout
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Hyperkalaemia
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 24 (4.17%)
    1 / 22 (4.55%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    1 / 10 (10.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    2
    2
    0
    0
    0
    2
    1
    0
    Type 1 diabetes mellitus
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Polydipsia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Hypophosphataemia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Hyponatraemia
         subjects affected / exposed
    1 / 23 (4.35%)
    2 / 24 (8.33%)
    0 / 22 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    2
    0
    0
    0
    0
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Apr 2016
    The following updates were made: • The criteria for grade 3 or higher non-hematologic laboratory values that define DLT were changed so that those that persist for > 1 week which were deemed not clinically important by both the investigator and sponsor did not trigger a DLT. Any grade 3 or higher non-hematologic laboratory value was still be considered a DLT if medical intervention was required or if it led to hospitalization. • Treatment could continue for grade 3 or higher non-hematologic laboratory values that persisted for > 1 week and were deemed not clinically important by both the investigator and sponsor so that participants could continue study treatment in spite of persistently elevated non-hematologic laboratory values with no clinical significance and long half-lives such as gamma-glutamyl transferase (GGT). • Added hepatitis D viral ribonucleic acid (RNA) as another acceptable method of testing as some institutions did not use hepatitis D serology testing. • The irRC-RECIST criteria definition was edited to make it more consistent with the conventional RECIST criteria and irRC simulating RECIST by Nishino et al. • Clarified certain laboratory tests and timing of study procedures. • Administration and editorial corrections. • Updated adverse event and disease related event language to clarify definitions and reporting periods. • Specified time points for liver tumor biopsies
    18 Oct 2017
    The following updates were made: • Added a collaborator drug, pembrolizumab, from Merck. • Aligned with more recent protocol template text. • Editorial changes (ie, typographic, grammatical, and formatting errors) and abbreviation corrections were made throughout the protocol in accordance with Amgen Inc. Style Guide.
    21 Oct 2019
    The following updates were made: • Updated study title. • Allowed intratumoral injection of talimogene laherparepvec into cutaneous, subcutaneous, and liver lesions and involved lymph nodes in Part 2 of the study. • Clarified that liver injection was not a requirement or priority in Part 2. • Expanded allowable injectable disease. • Changed the tumor types in Part 2. • Created additional BC cohort. • Created additional HCC cohort. • Allowed for well controlled viral hepatitis and allowed antiviral therapy in new cohort 6B for HCC in Part 1 and Arm VI in Part 2 of the study. • Updated study scheme. • Updated eligibility criteria. • Shortened 23 hour observation window to 6 hours in Part 2. • Added collection of PATCH 1 (PTCH) mutation status in BCC cohort if available. • Added collection of breast cancer type 1 (BRCA1) and 2 mutation status in BC cohort if available. • Added optional liver ultrasound to schedule of assessments. • Removed 24 hour and 48 hour timepoints in Week 1 and Week 4 from Part 2 schedule of assessments. • Removed assessments for anti pembrolizumab antibodies, and pembrolizumab pharmacokinetics (PK) in Part 2. • Removed blood, urine and swab collection at 24 and 48 hours in Part 2. • Allowed continuation of talimogene laherparepvec after Cycle 12 in Part 2. • Clarified maximum number of cycles. • Allowed resumption of talimogene laherparepvec at progression • Allowed up to 8 mL of talimogene laherparepvec to be used in Part 2 if 8 mL was shown safe in either Group A or B in Part 1. • Added clinical tumor assessments in Part 2. • Created a separate schedule of assessment table for Part 2. • Revised list of laboratory analytes. • Added language regarding events of clinical interest. • Added disease related events (DRE) language. • Removed language on self-evident corrections. • Updated HCC data in background and rationale sections. • Updated CTCAE version. • Updated references. • Administrative and editorial changes.
    30 Jun 2020
    The following updates were made: • Removed the 6 hour observation period and associated assessments for Part 2 participants not receiving intrahepatic injections. • Only included Part 2 enrolled participants as part of the efficacy futility analyses. • Combined arms VI and VII. • Made updates to collection time points of cytokines and qPCR. • Decreased sample size from 244 to 206. • Clarified inclusion criterion for triple negative breast cancer participants (inclusion criterion 114). • Updated administrative edits.
    02 Jul 2021
    The following updates were made: • Fixed the minor discrepancies and inconsistencies within the protocol. • Clarified medical monitor approval requirements for continuing talimogene in Part 1 and Part 2. • Updated exclusion criteria 207 to separate pneumonitis into standalone criteria 238. • Updated exclusion criteria 207 to separate pneumonitis into standalone criteria 238. • Removed the exclusion of prior checkpoint inhibitors for BCC patients to reflect the approval of cemiplimab in this population. • Updated Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated With Pembrolizumab. • Updated an exception considered to continue treatment beyond progression. • updated the requirement to report fatal DREs as SAEs. • Clarified the interim safety analysis language in Part 2. • Updated SAE reporting forms. • Updated pregnancy and lactation notification forms. • Clarified primary and final analyses clinical study report (CSR) plans. • Aligned the protocol with current protocol template and safety reporting language. • Typographic, formatting and editorial changes were made.
    26 Oct 2021
    The protocol was amended to stop study-related hepatic biopsies and hepatic injections of talimogene laherparepvec based on the overall safety assessment of the hepatic hemorrhage signal following two serious adverse events of hepatic haemorrhage that resulted in death in the study. While the full safety assessment results did not suggest an increased risk of hepatic haemorrhage with talimogene laherparepvec as a medication, there was a potential risk of hepatic haemorrhage with the transcutaneous intrahepatic route of administration of talimogene laherparepvec and hepatic biopsies. As a result, the protocol is amended to remove these procedures from study conduct. Additionally, the final enrollment numbers were updated in the protocol as enrollment had stopped for this study.

    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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