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    Clinical Trial Results:
    mRNA-transfected dendritic cell vaccination in high risk uveal melanoma patients

    Summary
    EudraCT number
    		 2008-001974-33
    Trial protocol
    		 NL  
    Global end of trial date
    01 Apr 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Jun 2020
    First version publication date
    10 Jun 2020
    Other versions
    Summary report(s)
    		 Publication Ophthalmology 2016

    Trial information

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    Trial identification
    Sponsor protocol code
    08/014
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00929019
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Radboudumc
    Sponsor organisation address
    Geert Grooteplein 26, Nijmegen, Netherlands,
    Public contact
    Prof. dr. Jolanda de Vries, Radboudumc, department of Tumor Immunology, 0031 243655750, Jolanda.deVries@radboudumc.nl
    Scientific contact
    Prof. dr. Jolanda de Vries, Radboudumc, department of Tumor Immunology, 0031 243655750, Jolanda.deVries@radboudumc.nl
    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
    01 Apr 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Apr 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Apr 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The first objective is to study the efficacy of autologous mRNA-transfected monocyte-derived DC in terms of progression free survival (PFS) in high-risk uveal melanoma patients.
    Protection of trial subjects
    Adverse events were defined as any undesirable experience occurring to a subject during a clinical trial, whether or not considered related to the investigational treatment. All adverse events (AE) occurring during the study, whether or not definitely attributable to the immunization procedure, were recorded. Any CTC-grade 4 or other serious, life-threatening or fatal adverse event occurring within 28 days of receiving the last treatment must be reported within 24 hours to the study coordinator. A serious adverse event is any untoward medical occurrence or effect that results in death; - is life threatening (at the time of the event); - requires hospitalisation or prolongation of existing inpatients’ hospitalisation; - results in persistent or significant disability or incapacity; - is a congenital anomaly or birth defect; - is a new event of the trial likely to affect the safety of the subjects, such as an unexpected outcome of an adverse reaction, lack of efficacy of the treatment of a life threatening disease, major safety finding from a newly completed animal study, etc. All SAEs will be reported to the accredited CMO that approved the protocol, according to the requirements of that CMO. Follow-up of adverse events: All adverse events will be followed until they have abated, or until a stable situation has been reached. Depending on the event, follow up may require additional tests or medical procedures as indicated, and/or referral to the general physician or a medical specialist.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 May 2008
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Scientific research
    Long term follow-up duration
    		 6 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 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)
    18
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Uvea melanoma patients with a loss of chromosome 3 (monosomy 3; high-risk uvea melanoma), with an interval since local treatment <12 months, were included in this trial.

    Pre-assignment
    Screening details
    		 Additional inclusion criteria were UM expressing the melanoma-associated antigens gp100, age 18-75 years, and WHO performance status 0 or 1. Patients with distant metastases, serious concomitant disease or a history of a second malignancy we were excluded. HLA-A*02:01-positive patients were vaccinated, negative patients served as a control group.

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

    Arms
    Arm title
    		 All included patients
    Arm description
    		 DC vaccinated patients
    Arm type
    		 Experimental

    Investigational medicinal product name
    DC vaccination
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Sterile concentrate, Concentrate for solution for injection/infusion
    Routes of administration
    Intradermal use, Intravenous use
    Dosage and administration details
    DC vaccination with DC loaded with KLH and transfected with mRNA encoding gp100 and tyrosinase will be administered three times on day 0, 14 and 28. DC will be simultaneously administered intradermally (i.d.) in the upper leg and intravenously (i.v.) 10 and 20 x 106 cells, respectively. This regime is comparable to our previous trials in melanoma patients. The reason why we choose for this vaccination strategy is that it is shown in preclinical models that it may be beneficial to combine different routes of administration: depending on the localization of the tumor, intravenous or intradermal may be preferential for visceral and non-visceral metastases, respectively. Furthermore, to date our most promising clinical data are obtained in a group of stage IV melanoma patients vaccinated i.d. and i.v..

    Number of subjects in period 1
    		All included patients
    Started
    23
    Completed
    18
    Not completed
    5
         Lack of efficacy
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 23 23
    Age categorical
    Inclusion criteria included human leukocyte antigen (HLA)-A*02:01 positivity, interval since local treatment <12 months, and age 18 to 75 years.
    Units: Subjects
        Adults (18-64 years)
    		 18 18
        From 65-84 years
    		 5 5
    Age continuous
    Units: years
        geometric mean (full range (min-max))
    		 56 (31 to 69) -
    Gender categorical
    Units: Subjects
        Female
    		 11 11
        Male
    		 12 12
    T stage
    T stage of uvea melanoma.
    Units: Subjects
        T stage
    		 23 23
    Tumor size
    Mean tumor size
    Units: mm
        geometric mean (full range (min-max))
    		 14 (7 to 23) -
    Subject analysis sets

    Subject analysis set title
    Tumor-specific T cells in skin biopsies
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Descriptive statistics of the immunological response and patient survival data will include means, standard deviations and medians for both groups. Survival of patients will be presented as Kaplan-Meier plots.

    Subject analysis set title
    No tumor-specific T cells in skin biopsies
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Number of patients without induction of tumor-specific T cells in skin biopsies upon dendritic cell vaccination.

    Subject analysis sets values
    		 Tumor-specific T cells in skin biopsies No tumor-specific T cells in skin biopsies
    Number of subjects
    17
    6
    Age categorical
    Inclusion criteria included human leukocyte antigen (HLA)-A*02:01 positivity, interval since local treatment <12 months, and age 18 to 75 years.
    Units: Subjects
        Adults (18-64 years)
        From 65-84 years
    Age continuous
    Units: years
        geometric mean (full range (min-max))
    Gender categorical
    Units: Subjects
        Female
        Male
    T stage
    T stage of uvea melanoma.
    Units: Subjects
        T stage
    23
    Tumor size
    Mean tumor size
    Units: mm
        geometric mean (full range (min-max))
    14 (7 to 23)

    End points

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    End points reporting groups
    Reporting group title
    All included patients
    Reporting group description
    		 DC vaccinated patients

    Subject analysis set title
    Tumor-specific T cells in skin biopsies
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Descriptive statistics of the immunological response and patient survival data will include means, standard deviations and medians for both groups. Survival of patients will be presented as Kaplan-Meier plots.

    Subject analysis set title
    No tumor-specific T cells in skin biopsies
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Number of patients without induction of tumor-specific T cells in skin biopsies upon dendritic cell vaccination.

    Primary: Tumor-specific T cells in the skin tests

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    End point title
    		 Tumor-specific T cells in the skin tests
    End point description
    End point type
    Primary
    End point timeframe
    After a cycle of DC vaccinations skin tests were performed after each vaccination cycle, and the presence and functionality of tumor-specific T cells induced by DC vaccination were analyzed
    End point values
    		 All included patients Tumor-specific T cells in skin biopsies No tumor-specific T cells in skin biopsies
    Number of subjects analysed
    23
    17
    6
    Units: yes or no
        Tumor-specific T cells in the skin tests
    17
    17
    6
    Statistical analysis title
    		 Description of tumor-specific T cells in biopsies
    Statistical analysis description
    Percentage of tumor-specific T cells in biopsies upon dendritic cell vaccination. Tumor-specific T cells in the skin tests were present in 17 patients (74%), demonstrating the effectiveness of these type of vaccines.
    Comparison groups
    All included patients v Tumor-specific T cells in skin biopsies v No tumor-specific T cells in skin biopsies
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 < 0.05 [2]
    Method
    		 Not applicable
    Parameter type
    		 Not applicable
    Confidence interval
    Notes
    [1] - Not applicable.
    [2] - Not applicable.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events (AE) occurring during the study, whether or not definitely attributable to the immunization procedure, will be recorded. All adverse events will be followed until they have abated, or until a stable situation has been reached.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    3.0
    Reporting groups
    Reporting group title
    Flu-like symptoms
    Reporting group description
    		 -

    Serious adverse events
    		 Flu-like symptoms
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 23 (0.00%)
         number of deaths (all causes)
    12
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Flu-like symptoms
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 23 (91.30%)
    General disorders and administration site conditions
    Flu-like symptoms
         subjects affected / exposed
    21 / 23 (91.30%)
         occurrences all number
    21
    Erythema at injection site
         subjects affected / exposed
    20 / 23 (86.96%)
         occurrences all number
    20

    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
    25 Jun 2015
    Because of low accrual rates, mainly caused by the rarity of the tumor, older age at diagnosis, HLA restriction, and the increase of eye-conserving treatments interfering with the availability of tumor material for genetic testing, the trial was stopped prematurely. Still, 23 patients received at least 1 cycle of adjuvant DC vaccination and were considered evaluable.
    -

    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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