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    Clinical Trial Results:
    A Randomized, Open-Label Phase II/III Study With Dendritic Cells Loaded With Allogeneic Tumour Cell Lysate (PheraLys) in Subjects With Mesothelioma as Maintenance Treatment (MesoPher) After Chemotherapy. DENIM (DENdritic Cell Immunotherapy for Mesothelioma)

    Summary
    EudraCT number
    2017-001774-41
    Trial protocol
    NL   GB   BE   FR   IT  
    Global end of trial date
    24 Jun 2022

    Results information
    Results version number
    v1(current)
    This version publication date
    24 Jun 2023
    First version publication date
    24 Jun 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MM04
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Amphera BV
    Sponsor organisation address
    Onderwijsboulevard 225, 's-Hertogenbosch, Netherlands, 5223 DE
    Public contact
    Clinical trial office, Amphera B.V., Info@amphera.nl
    Scientific contact
    Clinical trial office, Amphera B.V., Info@amphera.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
    24 Jun 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Jun 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Jun 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to evaluate the overall survival rate (determined from the time of randomization in the study) of subjects who receive dendritic cell immunotherapy with MesoPher plus best supportive care (BSC) compared to BSC alone.
    Protection of trial subjects
    From earlier studies it is known that the adverse event profile of MesoPher is very benign. Adverse events consisted mainly of mild to moderate, transient injection site reactions and infusion related reactions. In previous studies MesoPher did not induce any product related serious adverse events. An Independent Data Monitoring Committee met every 6 months to review the safety and efficacy data of the study.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    18 Jun 2018
    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
    Netherlands: 127
    Country: Number of subjects enrolled
    Belgium: 33
    Country: Number of subjects enrolled
    France: 16
    Worldwide total number of subjects
    176
    EEA total number of subjects
    176
    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)
    53
    From 65 to 84 years
    123
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 6 study centers in 5 countries were initiated in this study. Due to COVID-19 restrictions, 2 centers did not recruit any patients.

    Pre-assignment
    Screening details
    For inclusion in the study, patients had to have stable disease or better after standard chemotherapy treatment. After screening (medical history, physical exam, CT-scan), eligible patients were randomised. Patients assigned to the MesoPher arm travelled to the EMC for leukapheresis and MesoPher production.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    The study was masked as formal blinding was not possible due to the nature of the treatment. The sponsor, lead statistician and coordinating investigator were blinded to aggregate data until database lock to ensure study decisions were not affected by knowledge of treatment assignment.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    MesoPher + Best supportive care
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Autologous dendritic cells pulsed with allogeneic tumour cell lysate
    Investigational medicinal product code
    Other name
    MesoPher
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intravenous use, Intradermal use
    Dosage and administration details
    Patients received a maximum of 5 administrations of MesoPher, 3 doses every other week and 2 more doses at week 18 and week 30. MesoPher was given in addition to best supportive care. The dose of 25 million viable cells per administration was given 2/3 intravenous and 1/3 intradermal.

    Arm title
    Best supportive care
    Arm description
    -
    Arm type
    Best supportive care

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    MesoPher + Best supportive care Best supportive care
    Started
    88
    88
    Completed
    23
    27
    Not completed
    65
    61
         Consent withdrawn by subject
    2
    2
         Death
    61
    59
         Lost to follow-up
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    MesoPher + Best supportive care
    Reporting group description
    -

    Reporting group title
    Best supportive care
    Reporting group description
    -

    Reporting group values
    MesoPher + Best supportive care Best supportive care Total
    Number of subjects
    88 88 176
    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)
    23 30 53
        From 65-84 years
    65 58 123
        85 years and over
    0 0 0
    Age continuous
    Age (mean)
    Units: years
        arithmetic mean (standard deviation)
    68.8 ± 7.53 67.2 ± 8.97 -
    Gender categorical
    Units: Subjects
        Female
    10 17 27
        Male
    78 71 149
    Histology
    Histologic type of mesothelioma
    Units: Subjects
        Epithelioid
    73 75 148
        Sarcomatoid
    7 4 11
        Biphasic
    8 8 16
        Other
    0 1 1
    ECOG performance
    Units: Subjects
        ECOG 0
    38 27 65
        ECOG 1
    50 60 110
        Not reported
    0 1 1
    Subject analysis sets

    Subject analysis set title
    FAS
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Includes all rrandomised patients

    Subject analysis sets values
    FAS
    Number of subjects
    176
    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)
    53
        From 65-84 years
    123
        85 years and over
    0
    Age continuous
    Age (mean)
    Units: years
        arithmetic mean (standard deviation)
    68.0 ± 8.30
    Gender categorical
    Units: Subjects
        Female
    27
        Male
    149
    Histology
    Histologic type of mesothelioma
    Units: Subjects
        Epithelioid
    148
        Sarcomatoid
    11
        Biphasic
    16
        Other
    1
    ECOG performance
    Units: Subjects
        ECOG 0
    65
        ECOG 1
    110
        Not reported
    1

    End points

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    End points reporting groups
    Reporting group title
    MesoPher + Best supportive care
    Reporting group description
    -

    Reporting group title
    Best supportive care
    Reporting group description
    -

    Subject analysis set title
    FAS
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Includes all rrandomised patients

    Primary: Overall survival

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    End point title
    Overall survival
    End point description
    End point type
    Primary
    End point timeframe
    From randomization (about 3 to 4 months after diagnosis) until death. For subjects who were alive at the end of the study or lost to follow-up, OS was censored on the last date when subjects were known to be alive.
    End point values
    MesoPher + Best supportive care Best supportive care
    Number of subjects analysed
    88
    88
    Units: days
        median (confidence interval 95%)
    513 (377 to 620)
    558 (435 to 668)
    Statistical analysis title
    OS analysis
    Comparison groups
    MesoPher + Best supportive care v Best supportive care
    Number of subjects included in analysis
    176
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6185
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.765
         upper limit
    1.572
    Variability estimate
    Standard error of the mean

    Secondary: Progression free survival

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    End point title
    Progression free survival
    End point description
    The time of disease progression was the time of the first CT scan showing progressive disease in either the target or non-target lesions or if there where new lesions.
    End point type
    Secondary
    End point timeframe
    From randomisation until disease progression; in the absence of progression, until death or end of study.
    End point values
    MesoPher + Best supportive care Best supportive care
    Number of subjects analysed
    88
    88
    Units: days
        median (confidence interval 95%)
    166 (99 to 178)
    99 (93 to 136)
    Statistical analysis title
    PFS analysis
    Comparison groups
    MesoPher + Best supportive care v Best supportive care
    Number of subjects included in analysis
    176
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5963
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.656
         upper limit
    1.232
    Variability estimate
    Standard error of the mean

    Secondary: Disease control rate

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    End point title
    Disease control rate
    End point description
    Subjects with either CR, PR or SD as best disease response during the study.
    End point type
    Secondary
    End point timeframe
    From randomisation until disease progression; in the absence of progression, until death or end of the study.
    End point values
    MesoPher + Best supportive care Best supportive care
    Number of subjects analysed
    88
    88
    Units: Subjects
    50
    35
    Statistical analysis title
    Disease control rate
    Comparison groups
    MesoPher + Best supportive care v Best supportive care
    Number of subjects included in analysis
    176
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.0203
    Method
    Cochran-Mantel-Haenszel
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from randomisation until progressive disease, death or end of the study, whichever came first.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    MesoPher
    Reporting group description
    All subjects randomised to Arm A who underwent at least eukapheresis. If they did not (and consequently did not receive MesoPher either) they are excluded from the safety analysis set

    Reporting group title
    Best standard of care
    Reporting group description
    All subjects randomised to arm B.

    Serious adverse events
    MesoPher Best standard of care
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 87 (8.05%)
    8 / 88 (9.09%)
         number of deaths (all causes)
    61
    59
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Blood potassium decreased
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Pericardial effusion
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 87 (1.15%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 88 (1.14%)
         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
    Pleural effusion
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus urinary
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 88 (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
    Pneumonia
         subjects affected / exposed
    0 / 87 (0.00%)
    3 / 88 (3.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypomagnesaemia
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 88 (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
    MesoPher Best standard of care
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    82 / 87 (94.25%)
    52 / 88 (59.09%)
    Cardiac disorders
    Chest pain
         subjects affected / exposed
    13 / 87 (14.94%)
    11 / 88 (12.50%)
         occurrences all number
    16
    11
    General disorders and administration site conditions
    Injection site reaction
         subjects affected / exposed
    73 / 87 (83.91%)
    0 / 88 (0.00%)
         occurrences all number
    202
    0
    Infusion related reaction
         subjects affected / exposed
    64 / 87 (73.56%)
    0 / 88 (0.00%)
         occurrences all number
    143
    0
    Fatigue
         subjects affected / exposed
    10 / 87 (11.49%)
    6 / 88 (6.82%)
         occurrences all number
    11
    6
    Influenza like illness
         subjects affected / exposed
    4 / 87 (4.60%)
    5 / 88 (5.68%)
         occurrences all number
    4
    5
    Pyrexia
         subjects affected / exposed
    5 / 87 (5.75%)
    1 / 88 (1.14%)
         occurrences all number
    6
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 87 (2.30%)
    5 / 88 (5.68%)
         occurrences all number
    3
    5
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    5 / 87 (5.75%)
    2 / 88 (2.27%)
         occurrences all number
    5
    3
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    13 / 87 (14.94%)
    14 / 88 (15.91%)
         occurrences all number
    13
    16
    Cough
         subjects affected / exposed
    8 / 87 (9.20%)
    8 / 88 (9.09%)
         occurrences all number
    9
    8
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 87 (5.75%)
    2 / 88 (2.27%)
         occurrences all number
    6
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    12 / 87 (13.79%)
    2 / 88 (2.27%)
         occurrences all number
    12
    2
    Back pain
         subjects affected / exposed
    8 / 87 (9.20%)
    6 / 88 (6.82%)
         occurrences all number
    9
    6
    Flank pain
         subjects affected / exposed
    7 / 87 (8.05%)
    4 / 88 (4.55%)
         occurrences all number
    8
    4

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Jan 2018
    Main changes included: • Data collection after the follow-up period was extended to include not only subject’s survival status but also subsequent anticancer treatment data and response (if available). • Mandatory contraception was extended from 3 months to 12 months after the last study drug administration. • As the primary endpoint is overall survival, survival data had to be collected within the remit of the protocol. Therefore, follow-up after week 30 was until death for each subject.
    23 Jan 2018
    Main changes included: • A syphilis test was added at screening and the hepatitis A test was removed to align with the information in the IMPD. • It was clarified that subjects had to undergo of DTH skin test after 3 DC treatments to determine if DC treatment resulted in a detectable immune response.
    25 Apr 2018
    Main changes included: • Additional immunomonitoring and biomarker samples were added at leukapheresis. Further, it was specified that leukapheresis could be repeated if MesoPher production failed or did not meet release specifications. Serology had to be within 4 weeks of leukapheresis procedure. • Modified RECIST criteria were removed as diagnostic criteria.
    09 May 2018
    Main changes included: • It was clarified that concurrent bevacizumab during chemotherapy and during the first 6 weeks after completion of chemotherapy was allowed but subjects who received bevacizumab were only eligible if they stopped bevacizumab due to non-tolerance before or by the end of the chemotherapy period. Subjects who benefitted from bevacizumab use could continue treatment with bevacizumab and were consequently not eligible for the study.
    02 Dec 2019
    Main changes included: • Circumstances in which delayed leukapheresis could be permitted were defined. • Procedures for manufactured product out of date were defined. Procedures for cases in which repeat leukapheresis was not possible were defined.
    15 May 2021
    Main changes included: • It was clarified that the intention is that subjects would continue to be followed-up for survival, tumour response and possibly subsequent treatments after the end of study (12 months after randomization of the last subject into the study, when at least 101 events had occurred). • The COVID-19 pandemic had a serious effect on the recruitment rate in the study. To reach the originally planned 230 subjects would take unrealistically long. Hence the number of patients to be recruited was reduced to at least 164. • In view of the reduction in sample size, the interim analysis with the aim to re-estimate the sample size, was no longer relevant and was thus removed. • As a consequence of travel restrictions in relation to the COVID-19 pandemic, 4 instead of 6 study centers were involved in the study (centers in the UK and Italy were closed without having recruited subjects). • A number of additional sensitivity analysis were added.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    16 Mar 2020
    Recruitment of new patients was temporarily halted due to the COVID-19 pandemic.
    06 May 2020

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None
    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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