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    Clinical Trial Results:
    Phase I trial of stereotactic body radiotherapy with concurrent pembrolizumab in metastatic urothelial cancer.

    Summary
    EudraCT number
    		 2016-001263-37
    Trial protocol
    		 BE  
    Global end of trial date
    18 Dec 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Jun 2024
    First version publication date
    06 Jun 2024
    Other versions
    Summary report(s)
    		 Final Study Report

    Trial information

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    Trial identification
    Sponsor protocol code
    2016-001263-37
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02826564
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    UZ Ghent
    Sponsor organisation address
    C. Heymanslaan 10, Ghent, Belgium, 9000
    Public contact
    HIRUZ CTU, UZ Gent, +32 9332 05 00, hiruz.ctu@uzgent.be
    Scientific contact
    HIRUZ CTU, UZ Gent, +32 9332 05 00, hiruz.ctu@uzgent.be
    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
    12 Jun 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Apr 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Dec 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the SBRT-schedule associated with DLT in 20% of patients
    Protection of trial subjects
    : Ethics review and approval, informed consent, supportive care and routine monitoring.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jun 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 23
    Worldwide total number of subjects
    23
    EEA total number of subjects
    23
    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)
    12
    From 65 to 84 years
    11
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 30 patients were screened from 14/11/2016 and 2/1/2018. 23 patients were enrolled, 18 patients were randomized. End of trial notification was 27/12/18 (last patient last visit) and submitted to EC and CA on dd-mm-yyyy. There were 6 dropouts, 1 patient was excluded fue to CNS lesion, 5 patients died during treatment

    Pre-assignment
    Screening details
    		 Inclusion Criteria: ≥ 18 years of age Have measurable disease based on RECIST 1.1. Have had any prior treatment more than 2 weeks prior to study day 1, treatment naive patients are allowed Histologically confirmed diagnosis of urothelial carcinoma Willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion

    Pre-assignment period milestones
    Number of subjects started
    		 23
    Number of subjects completed
    		 18

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Physician decision: 1
    Reason: Number of subjects
    		 drop-out before start of treatment: 4
    Period 1
    Period 1 title
    Baseline period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Baseline Arm T1
    Arm description
    		 4 cycles of pembrolizumab with SBRT applied before the first cycle
    Arm type
    		 Experimental

    Investigational medicinal product name
    pembrolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg per day 1 of each 3 week cycle

    Investigational medicinal product name
    Radio therapy
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Radionuclide generator
    Routes of administration
    Other use
    Dosage and administration details
    8 Gy day 1, 3, 5

    Arm title
    		 Baseline Arm T2
    Arm description
    		 4 cycles of pembrolizumab with SBRT applied before the third cycle
    Arm type
    		 Experimental

    Investigational medicinal product name
    pembrolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg per day one of each 3 week cycle

    Investigational medicinal product name
    Radio therapy
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Radionuclide generator
    Routes of administration
    Other use
    Dosage and administration details
    8 Gy day 38, 40, 42

    Number of subjects in period 1 [1]
    		Baseline Arm T1 Baseline Arm T2
    Started
    9
    9
    Completed
    9
    9
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 23 patients were enrolled, 5 patients dropped out before start of treatment hereby only 18 patients were treated. See attachment Final Study Report
    Period 2
    Period 2 title
    Overall Trial
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Randomized - non controlled - open label This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or designee are not blinded to treatment. Drug identity (name, strength) is included in the label text; random code/disclosure envelopes or lists are not provided.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm T1
    Arm description
    		 4 cycles of pembrolizumab with SBRT applied before the first cycle
    Arm type
    		 Experimental

    Investigational medicinal product name
    pembrolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg per day 1 of each 3 week cycle

    Arm title
    		 Arm T2
    Arm description
    		 4 cycles of pembrolizumab with SBRT applied before the third cycle
    Arm type
    		 Experimental

    Investigational medicinal product name
    pembrolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg per day one of each 3 week cycle

    Number of subjects in period 2
    		Arm T1 Arm T2
    Started
    9
    9
    Completed
    9
    3
    Not completed
    0
    6
         Adverse event, serious fatal
    -
    5
         Consent withdrawn by subject
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline Arm T1
    Reporting group description
    		 4 cycles of pembrolizumab with SBRT applied before the first cycle

    Reporting group title
    Baseline Arm T2
    Reporting group description
    		 4 cycles of pembrolizumab with SBRT applied before the third cycle

    Reporting group values
    		 Baseline Arm T1 Baseline Arm T2 Total
    Number of subjects
    		 9 9 18
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 58 (54 to 75) 71 (50 to 84) -
    Gender categorical
    Units: Subjects
        Female
    		 1 1 2
        Male
    		 8 8 16
    ECOG performance-status score
    Units: Subjects
        score 0
    		 4 6 10
        score 1
    		 5 3 8
    Previous systemic treatments
    Units: Subjects
        value: 0
    		 2 3 5
        value: 1
    		 4 5 9
        value: 2
    		 1 1 2
        value: 3
    		 2 0 2
    Modified proportion score of PD-L1 ≥1%
    Units: Subjects
        PD-L1 ≥1%: yes
    		 3 6 9
        PD-L1 ≥1%: no
    		 6 3 9
    Modified proportion score of PD-L1 ≥10%
    Units: Subjects
        PD-L1 ≥10% : yes
    		 2 5 7
        PD-L1 ≥10% : no
    		 7 4 11
    Modified proportion score of PD-L1 ≥95%
    Units: Subjects
        PD-L1 ≥95%: yes
    		 1 2 3
        PD-L1 ≥95%: no
    		 8 7 15
    Visceral disease
    Units: Subjects
        yes
    		 5 6 11
        no
    		 4 3 7
    Liver metastases
    Units: Subjects
        yes
    		 2 1 3
        no
    		 7 8 15
    Hemoglobin concentration <10g/dL
    Units: Subjects
        <10g/dL
    		 0 1 1
        >10g/dL
    		 9 8 17

    End points

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    End points reporting groups
    Reporting group title
    Baseline Arm T1
    Reporting group description
    		 4 cycles of pembrolizumab with SBRT applied before the first cycle

    Reporting group title
    Baseline Arm T2
    Reporting group description
    		 4 cycles of pembrolizumab with SBRT applied before the third cycle
    Reporting group title
    Arm T1
    Reporting group description
    		 4 cycles of pembrolizumab with SBRT applied before the first cycle

    Reporting group title
    Arm T2
    Reporting group description
    		 4 cycles of pembrolizumab with SBRT applied before the third cycle

    Primary: Dose limiting toxicity between start of SBRT and 12 weeks after completion of SBRT

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    End point title
    		 Dose limiting toxicity between start of SBRT and 12 weeks after completion of SBRT [1]
    End point description
    End point type
    Primary
    End point timeframe
    dosing cycle dependent
    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: DLT was assessed using the Common Terminology Criteria for Adverse Events. No DLTs occured. No statistical analysis available. See attachment Final Study Report
    End point values
    		 Arm T1 Arm T2
    Number of subjects analysed
    9
    9
    Units: number of patients
        AE grade 1-2
    6
    9
        AE grade 3
    0
    1
        AE grade 4-5
    0
    0
        DLT
    0
    0
    No statistical analyses for this end point

    Secondary: determination of local control of the irradiated metastases

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    End point title
    		 determination of local control of the irradiated metastases
    End point description
    local response of the irradiated lesion
    End point type
    Secondary
    End point timeframe
    N/A
    End point values
    		 Arm T1 Arm T2
    Number of subjects analysed
    9
    9
    Units: type of response
        complete response
    2
    4
        partial response
    1
    0
        stable disease
    4
    4
        progressive disease
    1
    1
    No statistical analyses for this end point

    Secondary: assessment of progression-free survival

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    End point title
    		 assessment of progression-free survival
    End point description
    End point type
    Secondary
    End point timeframe
    time from inclusion to documented disease prograssion according to irRC or death from any cause
    End point values
    		 Arm T1 Arm T2
    Number of subjects analysed
    9
    9
    Units: months
        median (full range (min-max))
    3.3 (0 to 18)
    3.5 (0 to 18)
    No statistical analyses for this end point

    Secondary: assesment response of the combination treatment in non-irradiated metastases (evaluated as per RECIST v1.1)

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    End point title
    		 assesment response of the combination treatment in non-irradiated metastases (evaluated as per RECIST v1.1)
    End point description
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Arm T1 Arm T2
    Number of subjects analysed
    9
    9
    Units: number
    0
    4
    No statistical analyses for this end point

    Post-hoc: assessment of overall survival

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    End point title
    		 assessment of overall survival
    End point description
    End point type
    Post-hoc
    End point timeframe
    12 weeks
    End point values
    		 Arm T1 Arm T2
    Number of subjects analysed
    9
    9
    Units: months
        median (full range (min-max))
    4.5 (0 to 18)
    12.1 (0 to 18)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Adverse events will be reported between the first dose administration of trial medication and the last trial related activity.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23
    Reporting groups
    Reporting group title
    Arm T1
    Reporting group description
    		 -

    Reporting group title
    Arm T2
    Reporting group description
    		 -

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: See attachment Final Study Report
    Serious adverse events
    		 Arm T1 Arm T2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 9 (44.44%)
    2 / 9 (22.22%)
         number of deaths (all causes)
    2
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Immune system disorders
    Auto-immune adrenalinitis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         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
    Dyspnoea
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         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
    Lower back pain
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    fever
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm T1 Arm T2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Aug 2016
    amendment 1: Use of liquid formulation of the IMP pembroluzimab in stead of the powder for solution for infusion formulation
    31 Jan 2017
    Amendment 2: Protocol adjustment to conform to recent scientific findings
    26 Apr 2017
    Amendment 3: Inclusion of phase II trial information in the protocol. Addition of recent findings concerning rare side effects of the IMP pembrolizumab to the ICF as provided by the manufacturer.
    20 Jun 2017
    Amendment 4: Adjustment to the number of participant from 20 to 25 patients to account for potential drop-outs.
    23 Oct 2017
    Amendment 5: Adjustments to EudraCT form sections D2.3 and D.9

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30665814
    http://www.ncbi.nlm.nih.gov/pubmed/28662677
    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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