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    Clinical Trial Results:
    A Phase 3 Randomized, Open-Label Clinical Study to Evaluate the Efficacy and Safety of Pembrolizumab plus Epacadostat, Pembrolizumab Monotherapy, and the EXTREME Regimen as First-line Treatment for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (KEYNOTE-669/ECHO-304)

    Summary
    EudraCT number
    		 2017-002311-34
    Trial protocol
    		 BE   ES   NL   GB   PL   FR  
    Global end of trial date
    10 Aug 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Dec 2021
    First version publication date
    04 Dec 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    KEYNOTE-672/ECHO-307
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Incyte
    Sponsor organisation address
    1801 Augustine Cutoff drive, Wilmington, United States, 19803
    Public contact
    Study Director, Incyte Corporation, +1 8554633463, medinfo@incyte.com
    Scientific contact
    Study Director, Incyte Corporation, +1 8554633463, medinfo@incyte.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
    10 Aug 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Aug 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study was to evaluate the efficacy and safety of pembrolizumab + epacadostat vs pembrolizumab + placebo in participants with cisplatin-ineligible urothelial carcinoma.
    Protection of trial subjects
    This study was conducted in conformance with applicable country or local requirements regarding ethical committee review, informed consent, and other statutes or regulations regarding the protection of the rights and welfare of human participants in biomedical research.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Dec 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: 4
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Canada: 5
    Country: Number of subjects enrolled
    Spain: 8
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    Israel: 11
    Country: Number of subjects enrolled
    Italy: 3
    Country: Number of subjects enrolled
    Japan: 1
    Country: Number of subjects enrolled
    Korea, Republic of: 11
    Country: Number of subjects enrolled
    Netherlands: 12
    Country: Number of subjects enrolled
    Poland: 4
    Country: Number of subjects enrolled
    Russian Federation: 10
    Country: Number of subjects enrolled
    Taiwan: 5
    Country: Number of subjects enrolled
    Ukraine: 9
    Country: Number of subjects enrolled
    United States: 2
    Worldwide total number of subjects
    93
    EEA total number of subjects
    35
    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)
    18
    From 65 to 84 years
    66
    85 years and over
    9

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 47 centers in 15 countries.

    Pre-assignment
    Screening details
    		 This study was conducted at 95 centers in 16 countries. Study enrollment was discontinued early and final efficacy was reported at the time of enrollment discontinuation. Only safety data was collected from ongoing participants until the study completion.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pembrolizumab 200 mg + Epacadostat 100 mg BID
    Arm description
    		 Pembrolizumab administered intravenously every 3 weeks. Epacadostat administered orally twice daily.
    Arm type
    		 Experimental

    Investigational medicinal product name
    epacadostat
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral Twice a day

    Investigational medicinal product name
    pembrolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV every 3 weeks

    Arm title
    		 Pembrolizumab 200 mg + Placebo BID
    Arm description
    		 Pembrolizumab administered intravenously every 3 weeks. Matching placebo administered orally twice daily.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    pembrolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV every 3 weeks

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral Twice a day

    Number of subjects in period 1
    		Pembrolizumab 200 mg + Epacadostat 100 mg BID Pembrolizumab 200 mg + Placebo BID
    Started
    44
    49
    Intention-to-Treat (ITT)
    44
    49
    All Participants as Treated (APaT)
    43
    49
    Completed
    25
    22
    Not completed
    19
    27
         Adverse event, serious fatal
    17
    18
         Physician decision
    1
    9
         Consent withdrawn by subject
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pembrolizumab 200 mg + Epacadostat 100 mg BID
    Reporting group description
    		 Pembrolizumab administered intravenously every 3 weeks. Epacadostat administered orally twice daily.

    Reporting group title
    Pembrolizumab 200 mg + Placebo BID
    Reporting group description
    		 Pembrolizumab administered intravenously every 3 weeks. Matching placebo administered orally twice daily.

    Reporting group values
    		 Pembrolizumab 200 mg + Epacadostat 100 mg BID Pembrolizumab 200 mg + Placebo BID Total
    Number of subjects
    		 44 49 93
    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)
    		 9 9 18
        From 65-84 years
    		 29 37 66
        85 years and over
    		 6 3 9
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 73.3 ± 9.5 72.4 ± 8.9 -
    Sex: Female, Male
    Units:
        Female
    		 11 11 22
        Male
    		 33 38 71
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 2 0 2
        Not Hispanic or Latino
    		 35 42 77
        Unknown or Not Reported
    		 7 7 14
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 9 8 17
        White
    		 33 37 70
        Missing
    		 2 4 6
    Metastasis Status at Screening
    Units: Subjects
        Metastatic
    		 38 45 83
        Advanced/Unresectable
    		 6 4 10

    End points

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    End points reporting groups
    Reporting group title
    Pembrolizumab 200 mg + Epacadostat 100 mg BID
    Reporting group description
    		 Pembrolizumab administered intravenously every 3 weeks. Epacadostat administered orally twice daily.

    Reporting group title
    Pembrolizumab 200 mg + Placebo BID
    Reporting group description
    		 Pembrolizumab administered intravenously every 3 weeks. Matching placebo administered orally twice daily.

    Primary: Objective response rate (ORR) with pembrolizumab + epacadostat versus pembrolizumab + placebo

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    End point title
    		 Objective response rate (ORR) with pembrolizumab + epacadostat versus pembrolizumab + placebo [1]
    End point description
    ORR was defined as the percentage of participants who had a confirmed complete response (CR) or partial response (PR) per RECIST v1.1 by investigator determination. Responses are based on Investigator assessments per RECIST 1.1 without confirmation using all scans up to the cutoff date.
    End point type
    Primary
    End point timeframe
    Week 9
    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 statistical analysis for this endpoint.
    End point values
    		 Pembrolizumab 200 mg + Epacadostat 100 mg BID Pembrolizumab 200 mg + Placebo BID
    Number of subjects analysed
    44
    49
    Units: percentage of participants
        number (confidence interval 95%)
    31.8 (22.46 to 55.24)
    24.5 (15.33 to 43.67)
    No statistical analyses for this end point

    Secondary: Safety and Tolerability of Pembrolizumab + Epacadostat Versus Pembrolizumab + Placebo as Measured by Number of Participants Experiencing Adverse Events (AEs)

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    End point title
    		 Safety and Tolerability of Pembrolizumab + Epacadostat Versus Pembrolizumab + Placebo as Measured by Number of Participants Experiencing Adverse Events (AEs)
    End point description
    AE is defined as any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment.
    End point type
    Secondary
    End point timeframe
    up to approximately 25 months
    End point values
    		 Pembrolizumab 200 mg + Epacadostat 100 mg BID Pembrolizumab 200 mg + Placebo BID
    Number of subjects analysed
    43
    49
    Units: Number of Participants
    43
    47
    No statistical analyses for this end point

    Secondary: Safety and Tolerability of Pembrolizumab + Epacadostat Versus Pembrolizumab + Placebo as Measured by Number of Participants Discontinuing Study Treatment Due to AE

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    End point title
    		 Safety and Tolerability of Pembrolizumab + Epacadostat Versus Pembrolizumab + Placebo as Measured by Number of Participants Discontinuing Study Treatment Due to AE
    End point description
    AE is defined as any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment.
    End point type
    Secondary
    End point timeframe
    up to approximately 25 months
    End point values
    		 Pembrolizumab 200 mg + Epacadostat 100 mg BID Pembrolizumab 200 mg + Placebo BID
    Number of subjects analysed
    43
    49
    Units: Number of participants
    11
    15
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    up to approximately 25 months
    Adverse event reporting additional description
    AE additional description
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16
    Reporting groups
    Reporting group title
    Pembrolizumab 200 mg + Epacadostat 100 mg BID
    Reporting group description
    		 Pembrolizumab administered intravenously every 3 weeks. Epacadostat administered orally twice daily.

    Reporting group title
    Total
    Reporting group description
    		 Total

    Reporting group title
    Pembrolizumab 200 mg + Placebo BID
    Reporting group description
    		 Pembrolizumab administered intravenously every 3 weeks. Matching placebo administered orally twice daily.

    Serious adverse events
    		 Pembrolizumab 200 mg + Epacadostat 100 mg BID Total Pembrolizumab 200 mg + Placebo BID
    Total subjects affected by serious adverse events
         subjects affected / exposed
    23 / 43 (53.49%)
    46 / 92 (50.00%)
    23 / 49 (46.94%)
         number of deaths (all causes)
    17
    36
    19
         number of deaths resulting from adverse events
    10
    16
    6
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 92 (1.09%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 92 (1.09%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    8 / 43 (18.60%)
    13 / 92 (14.13%)
    5 / 49 (10.20%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 14
    0 / 5
         deaths causally related to treatment / all
    0 / 7
    0 / 10
    0 / 3
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 92 (1.09%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 43 (2.33%)
    2 / 92 (2.17%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    Fatigue
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 92 (1.09%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 92 (1.09%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 92 (1.09%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Interstitial lung disease
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 92 (1.09%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 92 (1.09%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 92 (1.09%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Product issues
    Device occlusion
         subjects affected / exposed
    2 / 43 (4.65%)
    2 / 92 (2.17%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 92 (1.09%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal stoma complication
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 92 (1.09%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 92 (1.09%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract stoma complication
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 92 (1.09%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Huntington's disease
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 92 (1.09%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 92 (1.09%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 92 (1.09%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 92 (1.09%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 92 (1.09%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 92 (1.09%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 92 (1.09%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 92 (1.09%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 92 (1.09%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatitis
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 92 (1.09%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis cholestatic
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 92 (1.09%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 92 (1.09%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 43 (0.00%)
    2 / 92 (2.17%)
    2 / 49 (4.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Autoimmune nephritis
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 92 (1.09%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Calculus bladder
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 92 (1.09%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    0 / 43 (0.00%)
    3 / 92 (3.26%)
    3 / 49 (6.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    2 / 43 (4.65%)
    2 / 92 (2.17%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephropathy toxic
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 92 (1.09%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 43 (2.33%)
    2 / 92 (2.17%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 92 (1.09%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Endocrine disorders
    Hypophysitis
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 92 (1.09%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pathological fracture
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 92 (1.09%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Encephalitis
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 92 (1.09%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterococcal bacteraemia
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 92 (1.09%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 92 (1.09%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 92 (1.09%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymph gland infection
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 92 (1.09%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 92 (1.09%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 92 (1.09%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 43 (6.98%)
    9 / 92 (9.78%)
    6 / 49 (12.24%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 13
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    2 / 43 (4.65%)
    3 / 92 (3.26%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    1 / 43 (2.33%)
    2 / 92 (2.17%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Pembrolizumab 200 mg + Epacadostat 100 mg BID Total Pembrolizumab 200 mg + Placebo BID
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    42 / 43 (97.67%)
    89 / 92 (96.74%)
    47 / 49 (95.92%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 43 (9.30%)
    9 / 92 (9.78%)
    5 / 49 (10.20%)
         occurrences all number
    4
    11
    7
    Amylase increased
         subjects affected / exposed
    4 / 43 (9.30%)
    8 / 92 (8.70%)
    4 / 49 (8.16%)
         occurrences all number
    8
    12
    4
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 43 (9.30%)
    9 / 92 (9.78%)
    5 / 49 (10.20%)
         occurrences all number
    4
    10
    6
    Blood alkaline phosphatase increased
         subjects affected / exposed
    2 / 43 (4.65%)
    7 / 92 (7.61%)
    5 / 49 (10.20%)
         occurrences all number
    2
    7
    5
    Blood creatinine increased
         subjects affected / exposed
    5 / 43 (11.63%)
    8 / 92 (8.70%)
    3 / 49 (6.12%)
         occurrences all number
    6
    12
    6
    Creatinine renal clearance decreased
         subjects affected / exposed
    3 / 43 (6.98%)
    3 / 92 (3.26%)
    0 / 49 (0.00%)
         occurrences all number
    3
    3
    0
    Lipase increased
         subjects affected / exposed
    4 / 43 (9.30%)
    8 / 92 (8.70%)
    4 / 49 (8.16%)
         occurrences all number
    4
    8
    4
    Weight decreased
         subjects affected / exposed
    3 / 43 (6.98%)
    7 / 92 (7.61%)
    4 / 49 (8.16%)
         occurrences all number
    3
    7
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    14 / 43 (32.56%)
    23 / 92 (25.00%)
    9 / 49 (18.37%)
         occurrences all number
    14
    26
    12
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    9 / 43 (20.93%)
    19 / 92 (20.65%)
    10 / 49 (20.41%)
         occurrences all number
    9
    19
    10
    Fatigue
         subjects affected / exposed
    6 / 43 (13.95%)
    14 / 92 (15.22%)
    8 / 49 (16.33%)
         occurrences all number
    7
    16
    9
    Oedema peripheral
         subjects affected / exposed
    3 / 43 (6.98%)
    10 / 92 (10.87%)
    7 / 49 (14.29%)
         occurrences all number
    4
    14
    10
    Pyrexia
         subjects affected / exposed
    5 / 43 (11.63%)
    11 / 92 (11.96%)
    6 / 49 (12.24%)
         occurrences all number
    6
    14
    8
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 43 (4.65%)
    8 / 92 (8.70%)
    6 / 49 (12.24%)
         occurrences all number
    2
    8
    6
    Constipation
         subjects affected / exposed
    7 / 43 (16.28%)
    14 / 92 (15.22%)
    7 / 49 (14.29%)
         occurrences all number
    10
    17
    7
    Diarrhoea
         subjects affected / exposed
    10 / 43 (23.26%)
    17 / 92 (18.48%)
    7 / 49 (14.29%)
         occurrences all number
    14
    23
    9
    Dry mouth
         subjects affected / exposed
    0 / 43 (0.00%)
    4 / 92 (4.35%)
    4 / 49 (8.16%)
         occurrences all number
    0
    4
    4
    Nausea
         subjects affected / exposed
    6 / 43 (13.95%)
    12 / 92 (13.04%)
    6 / 49 (12.24%)
         occurrences all number
    9
    15
    6
    Vomiting
         subjects affected / exposed
    4 / 43 (9.30%)
    11 / 92 (11.96%)
    7 / 49 (14.29%)
         occurrences all number
    4
    13
    9
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 43 (9.30%)
    9 / 92 (9.78%)
    5 / 49 (10.20%)
         occurrences all number
    4
    10
    6
    Dyspnoea
         subjects affected / exposed
    5 / 43 (11.63%)
    8 / 92 (8.70%)
    3 / 49 (6.12%)
         occurrences all number
    5
    8
    3
    Pneumonitis
         subjects affected / exposed
    4 / 43 (9.30%)
    4 / 92 (4.35%)
    0 / 49 (0.00%)
         occurrences all number
    4
    4
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    10 / 43 (23.26%)
    16 / 92 (17.39%)
    6 / 49 (12.24%)
         occurrences all number
    13
    20
    7
    Rash
         subjects affected / exposed
    10 / 43 (23.26%)
    24 / 92 (26.09%)
    14 / 49 (28.57%)
         occurrences all number
    12
    26
    14
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    3 / 43 (6.98%)
    6 / 92 (6.52%)
    3 / 49 (6.12%)
         occurrences all number
    3
    6
    3
    Haematuria
         subjects affected / exposed
    4 / 43 (9.30%)
    11 / 92 (11.96%)
    7 / 49 (14.29%)
         occurrences all number
    5
    14
    9
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    3 / 43 (6.98%)
    5 / 92 (5.43%)
    2 / 49 (4.08%)
         occurrences all number
    3
    5
    2
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    3 / 43 (6.98%)
    7 / 92 (7.61%)
    4 / 49 (8.16%)
         occurrences all number
    3
    7
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 43 (6.98%)
    6 / 92 (6.52%)
    3 / 49 (6.12%)
         occurrences all number
    3
    8
    5
    Back pain
         subjects affected / exposed
    7 / 43 (16.28%)
    15 / 92 (16.30%)
    8 / 49 (16.33%)
         occurrences all number
    7
    16
    9
    Flank pain
         subjects affected / exposed
    1 / 43 (2.33%)
    4 / 92 (4.35%)
    3 / 49 (6.12%)
         occurrences all number
    1
    4
    3
    Musculoskeletal pain
         subjects affected / exposed
    1 / 43 (2.33%)
    4 / 92 (4.35%)
    3 / 49 (6.12%)
         occurrences all number
    1
    4
    3
    Pain in extremity
         subjects affected / exposed
    2 / 43 (4.65%)
    5 / 92 (5.43%)
    3 / 49 (6.12%)
         occurrences all number
    2
    5
    3
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    0 / 43 (0.00%)
    4 / 92 (4.35%)
    4 / 49 (8.16%)
         occurrences all number
    0
    4
    4
    Pneumonia
         subjects affected / exposed
    3 / 43 (6.98%)
    5 / 92 (5.43%)
    2 / 49 (4.08%)
         occurrences all number
    3
    5
    2
    Urinary tract infection
         subjects affected / exposed
    5 / 43 (11.63%)
    16 / 92 (17.39%)
    11 / 49 (22.45%)
         occurrences all number
    5
    19
    14
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    5 / 43 (11.63%)
    13 / 92 (14.13%)
    8 / 49 (16.33%)
         occurrences all number
    7
    15
    8
    Hyperkalaemia
         subjects affected / exposed
    3 / 43 (6.98%)
    7 / 92 (7.61%)
    4 / 49 (8.16%)
         occurrences all number
    3
    9
    6
    Hyperuricaemia
         subjects affected / exposed
    3 / 43 (6.98%)
    3 / 92 (3.26%)
    0 / 49 (0.00%)
         occurrences all number
    7
    7
    0
    Hypoalbuminaemia
         subjects affected / exposed
    5 / 43 (11.63%)
    7 / 92 (7.61%)
    2 / 49 (4.08%)
         occurrences all number
    5
    7
    2
    Hypocalcaemia
         subjects affected / exposed
    4 / 43 (9.30%)
    5 / 92 (5.43%)
    1 / 49 (2.04%)
         occurrences all number
    6
    7
    1
    Hypokalaemia
         subjects affected / exposed
    0 / 43 (0.00%)
    3 / 92 (3.26%)
    3 / 49 (6.12%)
         occurrences all number
    0
    4
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Jun 2018
    Enrollment was permanently stopped on 02May2018 as a strategic decision. For participants who are considered to be obtaining ongoing clinical benefit, continued study treatment will be at the discretion of the investigator after a discussion with the participant of the results from KEYNOTE-252/ECHO-301 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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