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    Clinical Trial Results:
    A parallel group phase I/II marker lesion study to assess the safety, tolerability and efficacy of intravenous or intravesical pembrolizumab in intermediate risk recurrent non-muscle invasive bladder cancer

    Summary
    EudraCT number
    		 2016-002267-33
    Trial protocol
    		 GB  
    Global end of trial date
    26 Jun 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Jan 2020
    First version publication date
    01 Jan 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    OCTO-089
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03167151
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 ClinicalTrials.gov : NCT03167151
    Sponsors
    Sponsor organisation name
    University of Oxford
    Sponsor organisation address
    Joint Research Office, 1st floor, Boundary Brook House, Churchill Drive, Headington, Oxford, United Kingdom, OX3 7GB
    Public contact
    Linda Collins, Oncology Clinical Trials Office, +44 01865227162, octo-pembla@oncology.ox.ac.uk
    Scientific contact
    Linda Collins, Oncology Clinical Trials Office, +44 01865227162, octo-pembla@oncology.ox.ac.uk
    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
    24 Jul 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Mar 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Jun 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To test the safety, tolerability and side effects of a drug called pembrolizumab in patients with recurrent bladder cancer.
    Protection of trial subjects
    The trial received ethical and regulatory approval, and was run in compliance with the Medicines for Human Use (Clinical Trials) Regulations 2004, and amendments thereafter, the guidelines for Good Clinical Practice, and the applicable policies of the Sponsor, the University of Oxford. The protocol complied with all current applicable Regulatory Authority, Research Ethics Committee and Sponsor reporting requirements. Safety reporting will continue for 90 days post end of treatment.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Aug 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
    United Kingdom: 6
    Worldwide total number of subjects
    6
    EEA total number of subjects
    6
    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)
    1
    From 65 to 84 years
    4
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Initially, the plan was to recruit the 6 participants for the safety run-in phase of the study within 6 months. 9 patients, of which 6 were evaluable, were recruited at the Oxford Churchill Hospital site from 17 July 2017 until 31 Jan 2019. Due to the issues with slow recruitment, the steering committee decided to end recruitment on 31 Jan 2019

    Pre-assignment
    Screening details
    		 16 patients were assessed for eligibility, 7 of whom were excluded; 1 because they were ineligible (Hep C positive in past) and 6 declined to participate.

    Period 1
    Period 1 title
    Safety run-in phase (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not a blinded study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1
    Arm description
    		 Cohort 1 in the safety run-in phase. Day 1 starting dose 50mg intravesical pembrolizumab
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Intravesical solution
    Routes of administration
    Intravesical use
    Dosage and administration details
    Day 1 - 50mg Day 8 - 50mg Day 15 - 100mg Day 22 - 100mg Day 29 - 200mg Day 36 - 200mg

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Intravesical solution
    Routes of administration
    Intravesical use
    Dosage and administration details
    Day 1 - 50mg Day 8 - 50mg Day 15 - 100mg Day 22 - 100mg Day 29 - 200mg Day 36 - 200mg

    Arm title
    		 Cohort 2
    Arm description
    		 Cohort 2 in the safety run-in phase. Day 1 starting dose 100mg intravesical pembrolizumab
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Intravesical solution
    Routes of administration
    Intravesical use
    Dosage and administration details
    Day 1 - 100mg Day 8 - 100mg Day 15 - 200mg Day 22 - 200mg Day 29 - 200mg Day 36 - 200mg

    Arm title
    		 Cohort 3
    Arm description
    		 Cohort 3 in the safety run-in phase. Day 1 starting dose 200mg intravesical pembrolizumab
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Intravesical solution
    Routes of administration
    Intravesical use
    Dosage and administration details
    Day 1 - 200mg Day 8 - 200mg Day 15 - 200mg Day 22 - 200mg Day 29 - 200mg Day 36 - 200mg

    Number of subjects in period 1
    		Cohort 1 Cohort 2 Cohort 3
    Started
    2
    2
    2
    Completed
    2
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    		 Cohort 1 in the safety run-in phase. Day 1 starting dose 50mg intravesical pembrolizumab

    Reporting group title
    Cohort 2
    Reporting group description
    		 Cohort 2 in the safety run-in phase. Day 1 starting dose 100mg intravesical pembrolizumab

    Reporting group title
    Cohort 3
    Reporting group description
    		 Cohort 3 in the safety run-in phase. Day 1 starting dose 200mg intravesical pembrolizumab

    Reporting group values
    		 Cohort 1 Cohort 2 Cohort 3 Total
    Number of subjects
    		 2 2 2 6
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 0 1 0 1
        From 65-84 years
    		 2 1 1 4
        85 years and over
    		 0 0 1 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 73 ( 0 ) 66 ( 10.6 ) 81 ( 7.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 0 1 0 1
        Male
    		 2 1 2 5
    Race/Ethnicity
    Units: Subjects
        White British
    		 2 2 2 6
    Smoking status
    Units: Subjects
        Current
    		 0 1 0 1
        Ex-smoker
    		 2 1 1 4
        Never smoker
    		 0 0 1 1
    ECOG Performance Status
    Units: Subjects
        Performance Status 0
    		 2 2 2 6
    Site of primary tumour
    Units: Subjects
        Bladder
    		 1 2 1 4
        Left renal pelvis
    		 0 0 1 1
        Urothelial
    		 1 0 0 1
    Prior chemotherapy
    Units: Subjects
        Yes
    		 2 2 2 6
    Prior surgery
    Units: Subjects
        Yes
    		 2 2 2 6
    Subject analysis sets

    Subject analysis set title
    Safety run-in
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Population for (DLT and tolerability) safety run-in analysis: six patients received at least 5 out of 6 scheduled treatments, or withdrew early due to drug-related toxicity, and hence these six patients will contribute to the DLT and tolerability analysis.

    Subject analysis sets values
    		 Safety run-in
    Number of subjects
    6
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    1
        From 65-84 years
    4
        85 years and over
    1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    ( )
    Gender categorical
    Units: Subjects
        Female
        Male
    Race/Ethnicity
    Units: Subjects
        White British
    Smoking status
    Units: Subjects
        Current
        Ex-smoker
        Never smoker
    ECOG Performance Status
    Units: Subjects
        Performance Status 0
    6
    Site of primary tumour
    Units: Subjects
        Bladder
        Left renal pelvis
        Urothelial
    Prior chemotherapy
    Units: Subjects
        Yes
    Prior surgery
    Units: Subjects
        Yes

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    		 Cohort 1 in the safety run-in phase. Day 1 starting dose 50mg intravesical pembrolizumab

    Reporting group title
    Cohort 2
    Reporting group description
    		 Cohort 2 in the safety run-in phase. Day 1 starting dose 100mg intravesical pembrolizumab

    Reporting group title
    Cohort 3
    Reporting group description
    		 Cohort 3 in the safety run-in phase. Day 1 starting dose 200mg intravesical pembrolizumab

    Subject analysis set title
    Safety run-in
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Population for (DLT and tolerability) safety run-in analysis: six patients received at least 5 out of 6 scheduled treatments, or withdrew early due to drug-related toxicity, and hence these six patients will contribute to the DLT and tolerability analysis.

    Primary: The Incidence and Severity of Adverse Events to Assess the Safety, Tolerability and Toxicities of Intravesical Pembrolizumab After TURBT in Patients With Intermediate Risk NMIBC

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    End point title
    		 The Incidence and Severity of Adverse Events to Assess the Safety, Tolerability and Toxicities of Intravesical Pembrolizumab After TURBT in Patients With Intermediate Risk NMIBC [1]
    End point description
    Patients will be assessed for dose limiting toxicities (DLT) as well as for overall tolerability of the treatment. A DLT is defined as a clinically significant, drug related, grade 4 haematological or > grade 3 non-haematological toxicity occurring within 7 days of administration of the first treatment at a given dose for that patient. If more than 1 patient experiences a DLT at a certain dose, this dose will be declared non-tolerated and further escalation will cease. No DLTs were seen in any of the three cohorts, and based on this, we can confirm the safety and tolerability of the highest pembrolizumab dose (200mg).
    End point type
    Primary
    End point timeframe
    Patients were assessed for dose limiting toxicity (DLTs) occurring within 7 days of administration of the first treatment at a given dose for that patient.
    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: The study was only a safety run-in study, so no statistical analyses were carried out.
    End point values
    		 Cohort 1 Cohort 2 Cohort 3
    Number of subjects analysed
    2
    2
    2
    Units: Dose Limiting Toxicities (DLTs)
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event monitoring starts on the day of the TURBT procedure (Day -14) until 90 days post treatment, or 30 days following administration of the last dose of study medication if the subject initiates a new anticancer therapy.
    Adverse event reporting additional description
    The Investigator will monitor each patient for clinical and laboratory evidence of adverse events on a routine basis throughout the study
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 NCI-CTCAE
    Dictionary version
    4.03
    Reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    		 -

    Reporting group title
    Cohort 2
    Reporting group description
    		 -

    Reporting group title
    Cohort 3
    Reporting group description
    		 -

    Serious adverse events
    		 Cohort 1 Cohort 2 Cohort 3
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Infections and infestations
    Urosepsis
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Cohort 1 Cohort 2 Cohort 3
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 2 (100.00%)
    1 / 2 (50.00%)
    2 / 2 (100.00%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Rigors
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    Fatigue
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 2 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    1
    0
    1
    Fever
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 2 (50.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Itching
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    1
    Rash
    Additional description: Rash over bilateral shins
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    1
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    1
    Urgency-Frequeny Syndrome
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    3
    Dysuria
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 2 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    1
    0
    1
    Infections and infestations
    Cystitis
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    Urinary tract infection
         subjects affected / exposed
    2 / 2 (100.00%)
    0 / 2 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    2
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    24 Jun 2019
    The temporary halt was requested by the Chief Investigator. The safety cohort completed LPLV on 26Mar2019 and the decision was taken to close the study at this stage (as per protocol). However, the funder was keen to evaluate whether or not it would be possible to complete the expansion cohort of the study. The temporary halt allowed time to consider the feasibility of completeing the expansion cohort. However, it was determined that this was not feasible and the study was closed 26Jun2019.
    -

    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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