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    Clinical Trial Results:
    A Phase 2 Study in First Line Metastatic or Unresectable, Recurrent Head and Neck Squamous Cell Carcinoma to Evaluate Intratumoral MK-1454 in Combination with IV Pembrolizumab vs IV Pembrolizumab Monotherapy

    Summary
    EudraCT number
    		 2019-003060-42
    Trial protocol
    		 NO   ES   FR   GB  
    Global end of trial date
    30 Sep 2022

    Results information
    Results version number
    		 v2(current)
    This version publication date
    14 Dec 2023
    First version publication date
    13 Oct 2023
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    1454-002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04220866
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme LLC
    Sponsor organisation address
    126 East Lincoln Avenue,, Rahway, NJ, United States, P.O. Box 2000
    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
    30 Sep 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Sep 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Sep 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to assess the efficacy and safety of intratumoral (IT) ulevostinag PLUS pembrolizumab (MK-3475) compared to pembrolizumab alone as a first line treatment of adults with metastatic or unresectable, recurrent head and neck squamous cell carcinoma (HNSCC). The primary study hypotheses are that IT ulevostinag in combination with pembrolizumab results in a superior Objective Response Rate (ORR), per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1), compared to pembrolizumab alone: 1. In participants with a tumor that has a programmed cell death-ligand 1 (PD-L1) Combined Positive Scoring (CPS) ≥ 1, and 2. In participants with a tumor that has a PD-L1 CPS ≥ 20.
    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
    04 Mar 2022
    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
    Australia: 1
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    Israel: 4
    Country: Number of subjects enrolled
    Korea, Republic of: 1
    Country: Number of subjects enrolled
    Norway: 1
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    United States: 4
    Worldwide total number of subjects
    18
    EEA total number of subjects
    8
    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)
    10
    From 65 to 84 years
    8
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Adults with a confirmed diagnosis of metastatic or unresectable, recurrent head and neck squamous cell carcinoma (HNSCC) with a tumor programmed cell death-1 ligand 1 (PD-L1) immunohistochemistry (IHC) combined positive scoring (CPS) ≥1 and had at least 1 measurable lesion that was amenable to intratumor (IT) injection were enrolled in this study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ulevostinag + Pembrolizumab
    Arm description
    		 Participants received ulevostinag 540 ug via intratumoral (IT) injection on Day 1 of every week for two 3-week cycles (Cycles 1-2), then on Day 1 of each 3-week cycle for up 33 cycles (Cycles 3-35), for a total of 35 cycles PLUS pembrolizumab 200 mg via intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 cycles. The total duration of treatment was up to approximately 2 years.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    MK-3475 KEYTRUDA®
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received pembrolizumab 200 mg via IV infusion on Day 1 of each 3-week cycle for up to 35 cycles. The total duration of treatment is up to approximately 2 years

    Investigational medicinal product name
    Ulevostinag
    Investigational medicinal product code
    Other name
    MK-1454
    Pharmaceutical forms
    Injection
    Routes of administration
    Intratumoral use
    Dosage and administration details
    Participants received ulevostinag 540 ug via intratumoral (IT) injection on Day 1 of every week for two 3-week cycles (Cycles 1-2), then on Day 1 of each 3-week cycle for up 33 cycles (Cycles 3-35), for a total of 35 cycles

    Arm title
    		 Pembrolizumab
    Arm description
    		 Participants received pembrolizumab 200 mg via IV infusion on Day 1 of each 3-week cycle for up to 35 cycles. The total duration of treatment is up to approximately 2 years.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    MK-3475 KEYTRUDA®
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received pembrolizumab 200 mg via IV infusion on Day 1 of each 3-week cycle for up to 35 cycles. The total duration of treatment is up to approximately 2 years

    Number of subjects in period 1
    		Ulevostinag + Pembrolizumab Pembrolizumab
    Started
    8
    10
    Completed
    0
    0
    Not completed
    8
    10
         Adverse event, serious fatal
    4
    5
         Participation in the study terminated By Sponsor
    2
    4
         Consent withdrawn by subject
    -
    1
         Participation at the site terminated By Sponsor
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ulevostinag + Pembrolizumab
    Reporting group description
    		 Participants received ulevostinag 540 ug via intratumoral (IT) injection on Day 1 of every week for two 3-week cycles (Cycles 1-2), then on Day 1 of each 3-week cycle for up 33 cycles (Cycles 3-35), for a total of 35 cycles PLUS pembrolizumab 200 mg via intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 cycles. The total duration of treatment was up to approximately 2 years.

    Reporting group title
    Pembrolizumab
    Reporting group description
    		 Participants received pembrolizumab 200 mg via IV infusion on Day 1 of each 3-week cycle for up to 35 cycles. The total duration of treatment is up to approximately 2 years.

    Reporting group values
    		 Ulevostinag + Pembrolizumab Pembrolizumab Total
    Number of subjects
    		 8 10 18
    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)
    		 3 7 10
        From 65-84 years
    		 5 3 8
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 65.3 ( 9.8 ) 59.8 ( 9.8 ) -
    Sex: Female, Male
    Units:
        Female
    		 0 1 1
        Male
    		 8 9 17
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 0 1 1
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 0 0
        White
    		 8 9 17
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 0 0
        Not Hispanic or Latino
    		 8 10 18
        Unknown or Not Reported
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Ulevostinag + Pembrolizumab
    Reporting group description
    		 Participants received ulevostinag 540 ug via intratumoral (IT) injection on Day 1 of every week for two 3-week cycles (Cycles 1-2), then on Day 1 of each 3-week cycle for up 33 cycles (Cycles 3-35), for a total of 35 cycles PLUS pembrolizumab 200 mg via intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 cycles. The total duration of treatment was up to approximately 2 years.

    Reporting group title
    Pembrolizumab
    Reporting group description
    		 Participants received pembrolizumab 200 mg via IV infusion on Day 1 of each 3-week cycle for up to 35 cycles. The total duration of treatment is up to approximately 2 years.

    Primary: Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

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    End point title
    		 Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [1]
    End point description
    ORR was defined as the percentage of participants in the analysis population who have a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. ORR was assessed by blinded independent central review (BICR), and the 95% confidence interval (CI) was based on the exact method for binomial data. The population analyzed was all randomized participants based on the treatment arm to which they were randomized.
    End point type
    Primary
    End point timeframe
    Up to 913.0 days
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical comparisons between treatment groups were neither planned nor performed for this primary endpoint.
    End point values
    		 Ulevostinag + Pembrolizumab Pembrolizumab
    Number of subjects analysed
    8
    10
    Units: Percentage of participants
        number (confidence interval 95%)
    50.0 (15.7 to 84.3)
    10.0 (0.3 to 44.5)
    No statistical analyses for this end point

    Secondary: Progression-free Survival (PFS) per RECIST 1.1

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    End point title
    		 Progression-free Survival (PFS) per RECIST 1.1
    End point description
    PFS was defined as the time from randomization to the first documented progressive disease (PD) or death from any cause, whichever occurs first. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD. PFS was assessed by BICR and was based on the product-limit (Kaplan-Meier) method for censored data. The population analyzed was all randomized participants based on the treatment arm to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Up to 913.0 days
    End point values
    		 Ulevostinag + Pembrolizumab Pembrolizumab
    Number of subjects analysed
    8 [2]
    10 [3]
    Units: Months
        median (confidence interval 95%)
    6.4 (1.0 to 99999)
    1.5 (0.5 to 99999)
    Notes
    [2] - 99999 = Upper limit not reached due to insufficient number of participants with an even
    [3] - 99999 = Upper limit not reached due to insufficient number of participants with an even
    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 is defined as the time from randomization to the date of death from any cause, and is based on the product-limit (Kaplan-Meier) method for censored data. The population analyzed was all randomized participants based on the treatment arm to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Up to 913.0 days
    End point values
    		 Ulevostinag + Pembrolizumab Pembrolizumab
    Number of subjects analysed
    8 [4]
    10 [5]
    Units: Months
        median (confidence interval 95%)
    99999 (1.0 to 99999)
    11.1 (0.8 to 99999)
    Notes
    [4] - 99999 = Median and upper limit not reached due to insufficient number of participants with an event.
    [5] - 99999 = Median and upper limit not reached due to insufficient number of participants with an event.
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) per RECIST 1.1

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    End point title
    		 Duration of Response (DOR) per RECIST 1.1
    End point description
    DOR was defined as the time from the first documented evidence of a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 until Progressive Disease (PD) or death due to any cause, whichever occurs first, in participants demonstrating a CR or PR. Per RECIST 1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD. DOR was based on the product-limit (Kaplan-Meier) method for censored data. The population analyzed was all randomized participants based on the treatment arm to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Up to 913.0 days
    End point values
    		 Ulevostinag + Pembrolizumab Pembrolizumab
    Number of subjects analysed
    8 [6]
    10 [7]
    Units: Months
        median (full range (min-max))
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Notes
    [6] - .99999 = Results not reached due to insufficient number of responding participants with relapse
    [7] - .99999 = Results not reached due to insufficient number of responding participants with relapse
    No statistical analyses for this end point

    Secondary: Number of participants discontinuing study treatment due to an AE

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    End point title
    		 Number of participants discontinuing study treatment due to an AE
    End point description
    An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The population analyzed was all randomized participants who received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 715.0 days
    End point values
    		 Ulevostinag + Pembrolizumab Pembrolizumab
    Number of subjects analysed
    8
    10
    Units: Participants
    3
    2
    No statistical analyses for this end point

    Secondary: Number of participants who experienced an Adverse Event (AE)

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    End point title
    		 Number of participants who experienced an Adverse Event (AE)
    End point description
    An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The population analyzed was all randomized participants who received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to 913.0 days
    End point values
    		 Ulevostinag + Pembrolizumab Pembrolizumab
    Number of subjects analysed
    8
    10
    Units: Participants
    8
    10
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events (AEs): from first treatment up to 913.0 days. All Cause Mortality (ACM): from randomization up to 913.0 days.:
    Adverse event reporting additional description
    The ACM population consisted of all randomized participants. The AE population consisted of all randomized participants who received at least1 dose of study treatment. Per protocol the following AE preferred terms not related to the drug were excluded: Neoplasm progression, Malignant neoplasm progression and Disease progression.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Pembrolizumab
    Reporting group description
    		 Participants received pembrolizumab 200 mg via IV infusion on Day 1 of each 3-week cycle for up to 35 cycles. The total duration of treatment is up to approximately 2 years

    Reporting group title
    Ulevostinag + Pembrolizumab
    Reporting group description
    		 Participants received ulevostinag 540 ug via intratumoral (IT) injection on Day 1 of every week for two 3-week cycles (Cycles 1-2), then on Day 1 of each 3-week cycle for up 33 cycles (Cycles 3-35), for a total of 35 cycles PLUS pembrolizumab 200 mg via intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 cycles. The total duration of treatment was up to approximately 2 years.

    Serious adverse events
    		 Pembrolizumab Ulevostinag + Pembrolizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 10 (40.00%)
    5 / 8 (62.50%)
         number of deaths (all causes)
    5
    4
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour haemorrhage
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (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
    Wound haemorrhage
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injection related reaction
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Pericarditis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery aneurysm
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         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
    Pyrexia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injection site ulcer
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         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
    Pleuritic pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis aspiration
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Infections and infestations
    Sepsis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         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 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Pembrolizumab Ulevostinag + Pembrolizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 10 (90.00%)
    8 / 8 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm swelling
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Skin neoplasm bleeding
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Tumour inflammation
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    2
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    0
    5
    Axillary pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Asthenia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    1
    Fatigue
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 8 (12.50%)
         occurrences all number
    2
    1
    Injection site swelling
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    2
    Injection site reaction
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Injection site pain
         subjects affected / exposed
    0 / 10 (0.00%)
    4 / 8 (50.00%)
         occurrences all number
    0
    6
    Injection site necrosis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Injection site erythema
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    2
    Influenza like illness
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Pyrexia
         subjects affected / exposed
    0 / 10 (0.00%)
    4 / 8 (50.00%)
         occurrences all number
    0
    10
    Swelling face
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    2
    Swelling
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Productive cough
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Nasal cavity mass
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Epistaxis
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    0
    2
    Dyspnoea
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    1
    Cough
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Depression
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Insomnia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    1
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Blood creatinine increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Liver function test abnormal
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Tri-iodothyronine free increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Stoma site discharge
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Vascular pseudoaneurysm
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Congenital, familial and genetic disorders
    Tracheo-oesophageal fistula
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Nervous system disorders
    Anosmia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Dizziness
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Dysgeusia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Speech disorder
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Lymphadenitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Leukopenia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Anaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    1
    Lymphopenia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Hyperacusis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    2
    Dry mouth
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Constipation
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Diarrhoea
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    2
    Vomiting
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    0
    4
    Palatal disorder
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Oral pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 8 (37.50%)
         occurrences all number
    0
    3
    Impaired gastric emptying
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Dysphagia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    3 / 10 (30.00%)
    0 / 8 (0.00%)
         occurrences all number
    3
    0
    Dry skin
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Drug eruption
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Dermatitis acneiform
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Skin burning sensation
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Sensitive skin
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Rash
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    1
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Proteinuria
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Acute kidney injury
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    1
    Haematuria
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Bone pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Neck pain
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    1
    Infections and infestations
    Bacterial disease carrier
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Bacteriuria
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    COVID-19
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    1
    Candida infection
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Cellulitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Hepatitis C
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Pneumonia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    2
    Urinary tract infection
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Tongue fungal infection
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Soft tissue infection
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Sinusitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Relapsing fever
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Pyuria
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 8 (37.50%)
         occurrences all number
    1
    3
    Dehydration
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Hypercalcaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    Hyperkalaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Hyperphosphataemia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Hypokalaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Hyponatraemia
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    Hypophosphataemia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Sep 2020
    Amendment 1:To address Health Authority requests, including to provide rationale for minimum creatinine clearance in the eligibility criteria, to add clarification for PD-L1 testing to the protocol, to clarify ongoing safety monitoring during the conduct of the clinical trial, and to provide additional clarifications.
    16 Aug 2021
    Amendment 2: To update the dose modification and toxicity management guidelines for irAEs associated with pembrolizumab.

    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
    For support, Contact us.
    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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