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    Clinical Trial Results:
    A randomized phase IIa study: natural dendritic cells for immunotherapy of chemo-naive metastatic castration-resistant prostate cancer patients

    Summary
    EudraCT number
    2012-002531-29
    Trial protocol
    NL  
    Global end of trial date
    06 Mar 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    04 Jun 2020
    First version publication date
    04 Jun 2020
    Other versions
    Summary report(s)
    Westdorp et al JITC 2019

    Trial information

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    Trial identification
    Sponsor protocol code
    NaturalDCformCRPC
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02692976
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Radboudumc
    Sponsor organisation address
    Geert Grooteplein 26, Nijmegen, Netherlands,
    Public contact
    Radboudumc, Radboud University Medical Centre Nijmegen, 0031 243617600, Jolanda.deVries@radboudumc.nl
    Scientific contact
    Radboudumc, Radboud University Medical Centre Nijmegen, 0031 243617600, 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
    06 Mar 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Mar 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Mar 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To show immunologic efficacy of tumor-peptide loaded natural DC in mCRPC patients
    Protection of trial subjects
    The investigator will inform the subjects and the CCMO if anything occurs, on the basis of which it appears that the disadvantages of participation may be significantly greater than was foreseen in the research proposal. The study will be suspended pending further review by the CCMO, except insofar as suspension would jeopardize the subjects’ health. The investigator will take care that all subjects are kept informed. Adverse events are 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 occurring during the study, whether or not definitely attributable to the immunization procedure (suspected), will be recorded. Any CTCAE 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 or is life threatening (at the time of the event); - requires hospitalization or prolongation of existing inpatients’ hospitalization; - 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 serious adverse events (SAE) and suspected unexpected serious adverse reactions (SUSAR) will be reported via ToetsingOnline to the CCMO. 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
    01 Oct 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy
    Long term follow-up duration
    5 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 21
    Worldwide total number of subjects
    21
    EEA total number of subjects
    21
    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)
    7
    From 65 to 84 years
    14
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    We screened 44 chemotherapy-naive CRPC patients. Patients with rising PSA were closely monitored. Patients were screened for study eligibility as soon as patients met the criteria for CRPC. Twenty-two of the screened patients were HLA-A-*0201. One of these patients was excluded because a second primary malignancy was detected.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    mDC arm
    Arm description
    CD1c+ mDC vaccinations (2–5 × 106 cells per injection; arm A)
    Arm type
    Experimental

    Investigational medicinal product name
    Tumor antigen peptide-loaded blood-derived dendritic cell product for use in prostate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Other use
    Dosage and administration details
    Intranodal administration. CD1c+ mDC vaccinations (2–5 × 106 cells per injection; arm A)

    Arm title
    pDC arm
    Arm description
    pDC vaccinations (1–3 × 106 cells; arm B)
    Arm type
    Experimental

    Investigational medicinal product name
    Tumor antigen peptide-loaded blood-derived dendritic cell product for use in prostate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Other use
    Dosage and administration details
    Intranodal administration. pDC vaccinations (1–3 × 106 cells; arm B)

    Arm title
    combiDC
    Arm description
    combined CD1c+ mDC and pDC vaccinations (combiDC; 3–8 × 106 cells; arm C)
    Arm type
    Experimental

    Investigational medicinal product name
    Tumor antigen peptide-loaded blood-derived dendritic cell product for use in prostate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Other use
    Dosage and administration details
    Intranodal administration. Combined CD1c+ mDC and pDC vaccinations (combiDC; 3–8 × 106 cells; arm C)

    Number of subjects in period 1
    mDC arm pDC arm combiDC
    Started
    7
    7
    7
    Completed
    7
    7
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    mDC arm
    Reporting group description
    CD1c+ mDC vaccinations (2–5 × 106 cells per injection; arm A)

    Reporting group title
    pDC arm
    Reporting group description
    pDC vaccinations (1–3 × 106 cells; arm B)

    Reporting group title
    combiDC
    Reporting group description
    combined CD1c+ mDC and pDC vaccinations (combiDC; 3–8 × 106 cells; arm C)

    Reporting group values
    mDC arm pDC arm combiDC Total
    Number of subjects
    7 7 7 21
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    2 2 3 7
        From 65-84 years
    5 5 4 14
    Age continuous
    Units: years
        geometric mean (full range (min-max))
    67.9 (60 to 78) 69.4 (59 to 82) 66.3 (53 to 74) -
    Gender categorical
    Units: Subjects
        Female
    0 0 0 0
        Male
    7 7 7 21
    Baseline PSA
    Units: ug/l
        median (full range (min-max))
    10 (4.6 to 260) 6.3 (2.6 to 19) 38 (3.7 to 120) -
    Subject analysis sets

    Subject analysis set title
    Immunological response after mDC vaccinations
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Paired t-tests were performed to evaluate immunological responses before and after vaccination and independentsamples t-tests (Mann-Whitney U tests) were used to evaluate differences between groups.

    Subject analysis set title
    Immunological response after pDC vaccination
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Paired t-tests were performed to evaluate immunological responses before and after vaccination and independentsamples t-tests (Mann-Whitney U tests) were used to evaluate differences between groups.

    Subject analysis set title
    Immunological response after combiDC vaccination
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Paired t-tests were performed to evaluate immunological responses before and after vaccination and independentsamples t-tests (Mann-Whitney U tests) were used to evaluate differences between groups.

    Subject analysis sets values
    Immunological response after mDC vaccinations Immunological response after pDC vaccination Immunological response after combiDC vaccination
    Number of subjects
    7
    7
    7
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    7
        From 65-84 years
    14
    Age continuous
    Units: years
        geometric mean (full range (min-max))
    67.9 (53 to 82)
    Gender categorical
    Units: Subjects
        Female
    0
        Male
    21
    Baseline PSA
    Units: ug/l
        median (full range (min-max))
    10 (2.6 to 260)

    End points

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    End points reporting groups
    Reporting group title
    mDC arm
    Reporting group description
    CD1c+ mDC vaccinations (2–5 × 106 cells per injection; arm A)

    Reporting group title
    pDC arm
    Reporting group description
    pDC vaccinations (1–3 × 106 cells; arm B)

    Reporting group title
    combiDC
    Reporting group description
    combined CD1c+ mDC and pDC vaccinations (combiDC; 3–8 × 106 cells; arm C)

    Subject analysis set title
    Immunological response after mDC vaccinations
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Paired t-tests were performed to evaluate immunological responses before and after vaccination and independentsamples t-tests (Mann-Whitney U tests) were used to evaluate differences between groups.

    Subject analysis set title
    Immunological response after pDC vaccination
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Paired t-tests were performed to evaluate immunological responses before and after vaccination and independentsamples t-tests (Mann-Whitney U tests) were used to evaluate differences between groups.

    Subject analysis set title
    Immunological response after combiDC vaccination
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Paired t-tests were performed to evaluate immunological responses before and after vaccination and independentsamples t-tests (Mann-Whitney U tests) were used to evaluate differences between groups.

    Primary: Tetramer/dextramer-positive (dm+) and IFN-γ-producing (IFN-γ+) antigen specific T cells

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    End point title
    Tetramer/dextramer-positive (dm+) and IFN-γ-producing (IFN-γ+) antigen specific T cells
    End point description
    Both tetramer/dextramer-positive (dm+) and IFN-γ-producing (IFN-γ+) antigen specific T cells were detected more frequently in skin biopsies of patients with radiological non-progressive disease (5/13 patients; 38%) compared to patients with progressive disease (0/8 patients; 0%). In these patients with vaccination enhanced dm+ and IFN-γ+ antigen-specific T cells median rPFS was 18.8 months (n = 5) vs. 5.1 months (n = 16) in patients without IFN-γ-producing antigen-specific T cells (p = 0.02).
    End point type
    Primary
    End point timeframe
    Primary endpoint was the immunological response after DC vaccination, which was monitored in peripheral blood and in T cell cultures of biopsies of post-treatment delayed-type hypersensitivity-skin tests.
    End point values
    mDC arm pDC arm combiDC Immunological response after mDC vaccinations Immunological response after pDC vaccination Immunological response after combiDC vaccination
    Number of subjects analysed
    7
    7
    7
    7
    7
    7
    Units: radiological profression-free survival
    median (full range (min-max))
        rPFS (dm+ and IFN-γ+)
    23.6 (12.0 to 24.3)
    18.8 (18.8 to 18.8)
    12.0 (12.0 to 12.0)
    23.6 (12.0 to 24.3)
    18.8 (18.8 to 18.8)
    12.0 (12.0 to 12.0)
        rPFS (dm- or IFN-γ-)
    3.4 (3.4 to 24.8)
    8.6 (3.4 to 23.9)
    4.0 (3.2 to 9.7)
    3.4 (3.4 to 24.8)
    8.6 (3.4 to 23.9)
    4.0 (3.2 to 9.7)
    Statistical analysis title
    Paired t-tests and independent-samples t-tests
    Statistical analysis description
    Paired t-tests were performed to evaluate immunological responses before and after vaccination and independent-samples t-tests (Mann-Whitney U tests) were used to evaluate group differences. Statistical significance: defined as p < 0.05 (two-tailed significance level). Time-to-event data were evaluated using the Kaplan-Meier method. Statistical significance was evaluated using the two-sided log-rank test; defined as p < 0.05. Differences between treatment arms were evaluated using one-way ANOVA.
    Comparison groups
    Immunological response after mDC vaccinations v Immunological response after pDC vaccination v Immunological response after combiDC vaccination
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.05
    Method
    Wilcoxon (Mann-Whitney)
    Parameter type
    Median difference (final values)
    Confidence interval
         sides
    2-sided
         lower limit
    -
         upper limit
    -

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    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
    4.0
    Reporting groups
    Reporting group title
    Any toxicity
    Reporting group description
    -

    Reporting group title
    Flu-like symptoms
    Reporting group description
    Flu-like symptoms include fever, fatigue, chills, body aches, malaise, loss of appetite and headache.

    Serious adverse events
    Any toxicity Flu-like symptoms
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 21 (0.00%)
         number of deaths (all causes)
    8
    8
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Ruptured type A acute aortic dissection
    Additional description: Patient (pDC-07) had stable disease according to RECIST 1.1 and PCWG2 criteria. At 10.7 months after apheresis patient deceased due to a ruptured type A acute aortic dissection. Finally, concluded as non-related to the ATMP product.
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 21 (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: 0%
    Non-serious adverse events
    Any toxicity Flu-like symptoms
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 21 (100.00%)
    10 / 21 (47.62%)
    General disorders and administration site conditions
    Any vaccine-related toxicity
         subjects affected / exposed
    21 / 21 (100.00%)
    10 / 21 (47.62%)
         occurrences all number
    21
    10
    Flu-like symptoms
    Additional description: Flu-like symptoms include fever, fatigue, chills, body aches, malaise, loss of appetite and headache.
         subjects affected / exposed
    21 / 21 (100.00%)
    10 / 21 (47.62%)
         occurrences all number
    21
    10

    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? 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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