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    Clinical Trial Results:
    A Phase 2, Open-Label, Single Arm Study to Evaluate the Safety and Efficacy of Pembrolizumab in Participants with Recurrent or Metastatic Cutaneous Squamous Cell Carcinoma (R/M cSCC)

    Summary
    EudraCT number
    		 2017-000594-37
    Trial protocol
    		 DE   ES   GB  
    Global end of trial date
    13 Sep 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Sep 2024
    First version publication date
    05 Sep 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MK-3475-629
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme LLC
    Sponsor organisation address
    126 East Lincoln Avenue, P.O. Box 2000, Rahway, NJ, United States, 07065
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.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
    13 Sep 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Jul 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Sep 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to evaluate the safety and efficacy of pembrolizumab (MK-3475) in adult participants with recurrent or metastatic (R/M) cutaneous Squamous Cell Carcinoma (cSCC) or locally advanced (LA) unresectable cSCC that is not amenable to surgery and/or radiation and/or systemic therapies.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Oct 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 25
    Country: Number of subjects enrolled
    Canada: 10
    Country: Number of subjects enrolled
    France: 44
    Country: Number of subjects enrolled
    Germany: 7
    Country: Number of subjects enrolled
    Israel: 16
    Country: Number of subjects enrolled
    Mexico: 11
    Country: Number of subjects enrolled
    Norway: 5
    Country: Number of subjects enrolled
    Spain: 17
    Country: Number of subjects enrolled
    United Kingdom: 7
    Country: Number of subjects enrolled
    United States: 17
    Worldwide total number of subjects
    159
    EEA total number of subjects
    73
    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)
    42
    From 65 to 84 years
    91
    85 years and over
    26

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 There were 2 cohorts in this study and each cohort received the same dose/treatment regimen. Baseline characteristics and outcome measures are presented by cohort. Adverse events were pre-specified to be reported as a single group by intervention for first and second course pembrolizumab.

    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
    		 Locally Advanced Unresectable cSCC Cohort
    Arm description
    		 Participants received pembrolizumab 200 mg via IV infusion on Day 1 of each 3-week cycle for up to 35 doses (approximately 24 months).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    KEYTRUDA® MK-3475
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg administered as IV infusion on Day 1 of every 3-week cycle

    Arm title
    		 Recurrent or Metastatic Cutaneous cSCC Cohort
    Arm description
    		 Participants received pembrolizumab 200 mg via intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 doses (approximately 24 months).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    KEYTRUDA® MK-3475
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg administered as IV infusion on Day 1 of every 3-week cycle

    Number of subjects in period 1
    		Locally Advanced Unresectable cSCC Cohort Recurrent or Metastatic Cutaneous cSCC Cohort
    Started
    54
    105
    Received Second Course of Pembrolizumab
    1
    2
    Completed
    0
    0
    Not completed
    54
    105
         Adverse event, serious fatal
    24
    70
         Sponsor's decision
    22
    27
         Physician decision
    2
    1
         Consent withdrawn by subject
    5
    4
         Lost to follow-up
    1
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Locally Advanced Unresectable cSCC Cohort
    Reporting group description
    		 Participants received pembrolizumab 200 mg via IV infusion on Day 1 of each 3-week cycle for up to 35 doses (approximately 24 months).

    Reporting group title
    Recurrent or Metastatic Cutaneous cSCC Cohort
    Reporting group description
    		 Participants received pembrolizumab 200 mg via intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 doses (approximately 24 months).

    Reporting group values
    		 Locally Advanced Unresectable cSCC Cohort Recurrent or Metastatic Cutaneous cSCC Cohort Total
    Number of subjects
    		 54 105 159
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 11 31 42
        From 65-84 years
    		 32 59 91
        85 years and over
    		 11 15 26
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 73.7 ( 12.4 ) 70.0 ( 14.3 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 15 25 40
        Male
    		 39 80 119
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 1 3 4
        Asian
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 1 1
        Black or African American
    		 1 0 1
        White
    		 40 68 108
        More than one race
    		 0 1 1
        Unknown or Not Reported
    		 12 32 44
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 2 13 15
        Not Hispanic or Latino
    		 40 57 97
        Unknown or Not Reported
    		 12 35 47

    End points

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    End points reporting groups
    Reporting group title
    Locally Advanced Unresectable cSCC Cohort
    Reporting group description
    		 Participants received pembrolizumab 200 mg via IV infusion on Day 1 of each 3-week cycle for up to 35 doses (approximately 24 months).

    Reporting group title
    Recurrent or Metastatic Cutaneous cSCC Cohort
    Reporting group description
    		 Participants received pembrolizumab 200 mg via intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 doses (approximately 24 months).

    Primary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR) [1]
    End point description
    ORR was defined as the percentage of participants who have best response of Complete Response (CR: Disappearance of all target lesions) or Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). ORR per RECIST 1.1 as assessed by blinded independent central review (BICR) is presented. The analysis population consisted of all participants who received ≥1 dose of study treatment.
    End point type
    Primary
    End point timeframe
    Up to approximately 32 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No between-group statistical analyses were performed for this endpoint.
    End point values
    		 Locally Advanced Unresectable cSCC Cohort Recurrent or Metastatic Cutaneous cSCC Cohort
    Number of subjects analysed
    54
    105
    Units: Percentage of participants
        number (confidence interval 95%)
    51.9 (37.8 to 65.7)
    35.2 (26.2 to 45.2)
    No statistical analyses for this end point

    Secondary: Disease Control Rate (DCR)

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    End point title
    		 Disease Control Rate (DCR)
    End point description
    DCR is defined as the percentage of participants who have a CR or PR or Stable Disease (SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease). The DCR per RECIST 1.1 as assessed by BICR is presented. The analysis population consisted of all participants who received ≥1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 56 months
    End point values
    		 Locally Advanced Unresectable cSCC Cohort Recurrent or Metastatic Cutaneous cSCC Cohort
    Number of subjects analysed
    54
    105
    Units: Percentage of participants
        number (confidence interval 95%)
    64.8 (50.6 to 77.3)
    52.4 (42.4 to 62.2)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR)

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    End point title
    		 Duration of Response (DOR)
    End point description
    For participants who demonstrated a confirmed CR or PR per RECIST 1.1, DOR was defined as the time from first documented evidence of a CR or PR until progressive disease (PD) or death. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions as well as an absolute increase of at least a 5 mm in the sum of diameters. The appearance of one or more new lesions was also considered PD. The DOR per RECIST 1.1 as assessed by BICR is presented for all participants who experienced a confirmed CR or PR. The analysis population consisted of all participants who received ≥1 dose of study treatment and had confirmed complete response or partial response.
    End point type
    Secondary
    End point timeframe
    Up to approximately 56 months
    End point values
    		 Locally Advanced Unresectable cSCC Cohort Recurrent or Metastatic Cutaneous cSCC Cohort
    Number of subjects analysed
    28
    37
    Units: Months
        median (full range (min-max))
    2.7 (1.1 to 12.3)
    1.6 (1.2 to 24.7)
    No statistical analyses for this end point

    Secondary: Progression-free Survival (PFS)

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    End point title
    		 Progression-free Survival (PFS)
    End point description
    PFS was defined as the time from first dose of study treatment to the first documented PD or death due to any cause, whichever occurred first. PFS per RECIST 1.1 as assessed by BICR is presented. The analysis population consisted of all participants who received ≥1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 56 months
    End point values
    		 Locally Advanced Unresectable cSCC Cohort Recurrent or Metastatic Cutaneous cSCC Cohort
    Number of subjects analysed
    54
    105
    Units: Months
        median (confidence interval 95%)
    14.4 (5.5 to 43.6)
    5.7 (3.1 to 8.5)
    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 first dose of study treatment to death due to any cause. The OS for all participants is presented. The analysis population consisted of all participants who received ≥1 dose of study treatment. A value of 9999 indicates that median and upper limit were not reached at time of data cut-off due to insufficient number of participants with an event.
    End point type
    Secondary
    End point timeframe
    Up to approximately 56 months
    End point values
    		 Locally Advanced Unresectable cSCC Cohort Recurrent or Metastatic Cutaneous cSCC Cohort
    Number of subjects analysed
    54
    105
    Units: Months
        median (confidence interval 95%)
    9999 (33.3 to 9999)
    23.8 (13.4 to 30.9)
    No statistical analyses for this end point

    Secondary: Number of Participants Who Experienced One or More Adverse Events (AEs)

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    End point title
    		 Number of Participants Who Experienced One or More Adverse Events (AEs)
    End point description
    An AE is defined as any unfavorable and unintended sign, symptom, or disease (new or worsening) temporally associated with the use of study therapy, regardless of whether or not a causal relationship with the study therapy. The number of participants who experienced an AE is presented. The analysis population consisted of all participants who received ≥1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 56 months
    End point values
    		 Locally Advanced Unresectable cSCC Cohort Recurrent or Metastatic Cutaneous cSCC Cohort
    Number of subjects analysed
    54
    105
    Units: Participants
    51
    102
    No statistical analyses for this end point

    Secondary: Number of Participants Who Discontinued Study Treatment Due to AE

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    End point title
    		 Number of Participants Who Discontinued Study Treatment Due to AE
    End point description
    An AE is defined as any unfavorable and unintended sign, symptom, or disease (new or worsening) temporally associated with the use of study therapy, regardless of whether or not a causal relationship with the study therapy. The number of participants who discontinued study treatment due to an AE is presented. The analysis population consisted of all participants who received ≥1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 56 months
    End point values
    		 Locally Advanced Unresectable cSCC Cohort Recurrent or Metastatic Cutaneous cSCC Cohort
    Number of subjects analysed
    54
    105
    Units: Participants
    11
    20
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 56 months
    Adverse event reporting additional description
    All participants who received ≥1 dose of study treatment are included. AEs were pre-specified to be reported as a single group by intervention for first course and second course. Per protocol, disease progression was not considered an AE unless considered related to study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    R/M Cutaneous and LA Unresectable cSCC Second Course
    Reporting group description
    		 Eligible participants who stopped the initial course of pembrolizumab but progressed after discontinuation may have been able to initiate a second course of pembrolizumab for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion.

    Reporting group title
    R/M Cutaneous and LA Unresectable cSCC First Course
    Reporting group description
    		 Participants received pembrolizumab 200 mg via intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 doses (approximately 24 months).

    Serious adverse events
    		 R/M Cutaneous and LA Unresectable cSCC Second Course R/M Cutaneous and LA Unresectable cSCC First Course
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 3 (66.67%)
    87 / 159 (54.72%)
         number of deaths (all causes)
    1
    97
         number of deaths resulting from adverse events
    0
    20
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuroendocrine carcinoma of the skin
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Neoplasm recurrence
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lentigo maligna
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected neoplasm
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 159 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Basal cell carcinoma
         subjects affected / exposed
    0 / 3 (0.00%)
    9 / 159 (5.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 19
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    B-cell lymphoma
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 159 (1.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Tumour pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Giant cell arteritis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Superior vena cava occlusion
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pyrexia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 159 (1.26%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 159 (1.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dyspnoea
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Investigations
    Transaminases increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound complication
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Radiation necrosis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoradionecrosis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 159 (1.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 159 (1.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 159 (1.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 159 (1.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dementia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cranial nerve disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Cerebrospinal fluid leakage
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 159 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemolytic anaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain lower
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal wall haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 159 (1.26%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Constipation
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer perforation
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 159 (1.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hypertransaminasaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 159 (1.26%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune hepatitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Photosensitivity reaction
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune nephritis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prerenal failure
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Lymphocytic hypophysitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adrenal insufficiency
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Groin pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess neck
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia
         subjects affected / exposed
    0 / 3 (0.00%)
    5 / 159 (3.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Otitis externa
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Infestation
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis salmonella
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungal skin infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermo-hypodermitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Scrotal cellulitis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 3 (33.33%)
    4 / 159 (2.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Septic shock
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 159 (1.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Soft tissue infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 159 (1.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophagia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 R/M Cutaneous and LA Unresectable cSCC Second Course R/M Cutaneous and LA Unresectable cSCC First Course
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 3 (66.67%)
    139 / 159 (87.42%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 3 (33.33%)
    6 / 159 (3.77%)
         occurrences all number
    1
    6
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 3 (33.33%)
    35 / 159 (22.01%)
         occurrences all number
    1
    44
    Chest pain
         subjects affected / exposed
    0 / 3 (0.00%)
    8 / 159 (5.03%)
         occurrences all number
    0
    8
    Fatigue
         subjects affected / exposed
    0 / 3 (0.00%)
    35 / 159 (22.01%)
         occurrences all number
    0
    39
    Oedema peripheral
         subjects affected / exposed
    0 / 3 (0.00%)
    17 / 159 (10.69%)
         occurrences all number
    0
    21
    Pyrexia
         subjects affected / exposed
    0 / 3 (0.00%)
    14 / 159 (8.81%)
         occurrences all number
    0
    17
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 3 (0.00%)
    13 / 159 (8.18%)
         occurrences all number
    0
    13
    Cough
         subjects affected / exposed
    0 / 3 (0.00%)
    19 / 159 (11.95%)
         occurrences all number
    0
    23
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 3 (0.00%)
    10 / 159 (6.29%)
         occurrences all number
    0
    10
    Investigations
    Weight decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    18 / 159 (11.32%)
         occurrences all number
    0
    19
    Protein total decreased
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 159 (0.63%)
         occurrences all number
    3
    7
    Blood urea increased
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 159 (1.26%)
         occurrences all number
    2
    2
    Blood phosphorus decreased
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 159 (1.26%)
         occurrences all number
    1
    2
    Blood creatinine increased
         subjects affected / exposed
    0 / 3 (0.00%)
    8 / 159 (5.03%)
         occurrences all number
    0
    8
    Blood bilirubin increased
         subjects affected / exposed
    1 / 3 (33.33%)
    3 / 159 (1.89%)
         occurrences all number
    1
    4
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 3 (0.00%)
    11 / 159 (6.92%)
         occurrences all number
    0
    13
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 3 (0.00%)
    11 / 159 (6.92%)
         occurrences all number
    0
    12
    Headache
         subjects affected / exposed
    0 / 3 (0.00%)
    18 / 159 (11.32%)
         occurrences all number
    0
    20
    Paraesthesia
         subjects affected / exposed
    1 / 3 (33.33%)
    6 / 159 (3.77%)
         occurrences all number
    1
    6
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    18 / 159 (11.32%)
         occurrences all number
    0
    26
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    0 / 3 (0.00%)
    16 / 159 (10.06%)
         occurrences all number
    0
    22
    Nausea
         subjects affected / exposed
    0 / 3 (0.00%)
    23 / 159 (14.47%)
         occurrences all number
    0
    29
    Diarrhoea
         subjects affected / exposed
    1 / 3 (33.33%)
    31 / 159 (19.50%)
         occurrences all number
    1
    38
    Constipation
         subjects affected / exposed
    0 / 3 (0.00%)
    40 / 159 (25.16%)
         occurrences all number
    0
    47
    Abdominal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    13 / 159 (8.18%)
         occurrences all number
    0
    14
    Skin and subcutaneous tissue disorders
    Skin lesion
         subjects affected / exposed
    0 / 3 (0.00%)
    10 / 159 (6.29%)
         occurrences all number
    0
    19
    Rash
         subjects affected / exposed
    0 / 3 (0.00%)
    25 / 159 (15.72%)
         occurrences all number
    0
    34
    Dry skin
         subjects affected / exposed
    0 / 3 (0.00%)
    11 / 159 (6.92%)
         occurrences all number
    0
    11
    Actinic keratosis
         subjects affected / exposed
    0 / 3 (0.00%)
    9 / 159 (5.66%)
         occurrences all number
    0
    15
    Pruritus
         subjects affected / exposed
    0 / 3 (0.00%)
    39 / 159 (24.53%)
         occurrences all number
    0
    45
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 3 (0.00%)
    14 / 159 (8.81%)
         occurrences all number
    0
    16
    Musculoskeletal and connective tissue disorders
    Neck pain
         subjects affected / exposed
    0 / 3 (0.00%)
    8 / 159 (5.03%)
         occurrences all number
    0
    8
    Muscle spasms
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 159 (1.26%)
         occurrences all number
    1
    2
    Back pain
         subjects affected / exposed
    0 / 3 (0.00%)
    14 / 159 (8.81%)
         occurrences all number
    0
    15
    Arthralgia
         subjects affected / exposed
    0 / 3 (0.00%)
    22 / 159 (13.84%)
         occurrences all number
    0
    26
    Pain in extremity
         subjects affected / exposed
    0 / 3 (0.00%)
    26 / 159 (16.35%)
         occurrences all number
    0
    29
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 3 (0.00%)
    8 / 159 (5.03%)
         occurrences all number
    0
    8
    Urinary tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    8 / 159 (5.03%)
         occurrences all number
    0
    10
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 3 (0.00%)
    25 / 159 (15.72%)
         occurrences all number
    0
    27
    Hyponatraemia
         subjects affected / exposed
    1 / 3 (33.33%)
    4 / 159 (2.52%)
         occurrences all number
    1
    7
    Hypocalcaemia
         subjects affected / exposed
    1 / 3 (33.33%)
    4 / 159 (2.52%)
         occurrences all number
    2
    4
    Hyperchloraemia
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 159 (0.63%)
         occurrences all number
    2
    1
    Hypercalcaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    8 / 159 (5.03%)
         occurrences all number
    0
    10

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Apr 2018
    Amendment 01: Primary reason for amendment was to add inclusion of first-line participants.
    28 Sep 2018
    Amendment 03: Primary reason for amendment was to add a cohort.
    06 Jul 2021
    Amendment 04: Primary reason for amendment was to incorporate revisions the dose modification and toxicity management guidelines.
    29 Mar 2023
    Amendment 06: Primary reason for amendment was to add language to allow participants to continue in a pembrolizumab extension 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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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