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    Clinical Trial Results:
    Prophylactic application of donor-derived central memory T lymphocytes (TCM) after allogeneic HSCT to prevent infectious complications

    Summary
    EudraCT number
    		 2015-001522-41
    Trial protocol
    		 DE  
    Global end of trial date
    30 Dec 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Apr 2024
    First version publication date
    03 Apr 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PACT2014-001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Universitätsklinikum Würzburg
    Sponsor organisation address
    Josef-Schneider-Str. 2, Würzburg, Germany, 97080
    Public contact
    Hematology/Oncology, University Hospital Wuerzburg - Departement of Medicine II, 0049 93120144500, grigoleit_g@ukw.de
    Scientific contact
    Hematology/Oncology, University Hospital Wuerzburg - Departement of Medicine II, 0049 93120144500, grigoleit_g@ukw.de
    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
    20 Dec 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Nov 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Dec 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the toxicity and feasibility of prophylactic administration of donor derived central memory T Cells after T cell depleted allo-SCT
    Protection of trial subjects
    Subject will be enrolled in a strict sequential order with a one month safety period between treatment of first patient and treatment of second patient. If first treatment of third patient will be given, first patient will receive his third treatment. Afterwards patients can be enrolled simultaneously. After the eighth patient received last treatment all data available till then will be reviewed by DSMB to assess whether side effect related to study medication or significant GvHD occurred. Based on limited data regarding the risk of GvHD for which TCM account within the TM population, we consider the TCM compart- ment for safety reasons as potentially alloreactive and treat it in analogy to the naive T cell compartment.
    Background therapy
    		 Adoptive T cell therapy , antigen-specific T cells . donor-derived central memory T lymphocytes (TCM).
    Evidence for comparator
    		 not applicable
    Actual start date of recruitment
    23 Dec 2015
    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
    Germany: 16
    Worldwide total number of subjects
    16
    EEA total number of subjects
    16
    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)
    9
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 First patient entry: 28-APR-2016, Last patient entry: 23-JUL-2020

    Pre-assignment
    Screening details
    		 All patients will be documented in the Screening Log. In case a patient will not be included, this will be documented with the specific reason for non-inclusion. Each patient included into the study is uniquely identified in the study by a combination of study code, his/her center and patient number (e.g. PACT-WU01).

    Pre-assignment period milestones
    Number of subjects started
    		 21 [1]
    Intermediate milestone: Number of subjects
    Screening-Phase: 21
    Number of subjects completed
    		 16

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Physician decision: 1
    Reason: Number of subjects
    		 Adverse event, serious fatal: 2
    Reason: Number of subjects
    		 Protocol deviation: 2
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 2 protocol deviations, 2 serious fatal events and 1 physician decision to exclude the patient
    Period 1
    Period 1 title
    Treatment and Follow-up (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    no blinding

    Arms
    Arm title
    		 Donor-derived central memory T lymphocytes (TCM) after allogen
    Arm description
    		 The first patient group will be treated with 5x103 T cells/kg bw at day 30 (+/- 5) and escalating doses of 1x104 T cells/kg bw and 5x104 T cells/kg bw at day 60 (+/- 5) and day 90 (+/- 5). If no significant GVHD occurs, the second patient group will be treated with 5x104 T cells/kg bw at day 30 (+/- 5) and escalating doses of 1x105 T cells/kg bw and 5x105 T cells/kg bw at day 60 (+/- 5) and day 90 (+/- 5).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Donor-derived central memory T lymphocytes (TCM) after allogenic HSCT
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Infusion
    Dosage and administration details
    The first patient group will be treated with 5x103 T cells/kg bw at day 30 (+/- 5) and escalating doses of 1x104 T cells/kg bw and 5x104 T cells/kg bw will be administered atday 60 (+/- 5) and day 90 (+/- 5) when no side effects will have occurred after the previous transfer. The second patient group (15 pts) will be treated with 5x104 T cells/kg bw at day 30 (+/- 5) and will be administered escalating doses of 1x105 T cells/kg bw and 5x105 T cells/kg bw at day 60 (+/- 5) and day 90 (+/- 5) when no side effects will have occurred after the previous transfer.

    Number of subjects in period 1
    		Donor-derived central memory T lymphocytes (TCM) after allogen
    Started
    16
    Completed
    9
    Not completed
    7
         Adverse event, serious fatal
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment and Follow-up
    Reporting group description
    		 -

    Reporting group values
    		 Treatment and Follow-up Total
    Number of subjects
    		 16 16
    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
    Age at time of informed consent
    Units: years
        arithmetic mean (standard deviation)
    		 62.6 ± 8.7 -
    Gender categorical
    Units: Subjects
        Female
    		 1 1
        Male
    		 15 15
    Diagnosis at inclusion
    Diagnosis for inclusion in the study: AML: Acute myeloid leukemia MDS: Myelodysplastic syndrome
    Units: Subjects
        AML
    		 3 3
        MDS
    		 13 13
    Subject analysis sets

    Subject analysis set title
    Intention-to-treat population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients who received at least one dose of donor derived TCM.

    Subject analysis set title
    Efficacy-evaluable subpopulation
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    all patients from the ITT population with sampled EDTA blood for immunological monitoring over a period of at least eight weeks after the infusion of the first dose of TCM

    Subject analysis sets values
    		 Intention-to-treat population Efficacy-evaluable subpopulation
    Number of subjects
    16
    12
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Age at time of informed consent
    Units: years
        arithmetic mean (standard deviation)
    62.6 ± 8.7
    62.8 ± 9.7
    Gender categorical
    Units: Subjects
        Female
    1
    1
        Male
    15
    11
    Diagnosis at inclusion
    Diagnosis for inclusion in the study: AML: Acute myeloid leukemia MDS: Myelodysplastic syndrome
    Units: Subjects
        AML
    3
    3
        MDS
    13
    9

    End points

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    End points reporting groups
    Reporting group title
    Donor-derived central memory T lymphocytes (TCM) after allogen
    Reporting group description
    		 The first patient group will be treated with 5x103 T cells/kg bw at day 30 (+/- 5) and escalating doses of 1x104 T cells/kg bw and 5x104 T cells/kg bw at day 60 (+/- 5) and day 90 (+/- 5). If no significant GVHD occurs, the second patient group will be treated with 5x104 T cells/kg bw at day 30 (+/- 5) and escalating doses of 1x105 T cells/kg bw and 5x105 T cells/kg bw at day 60 (+/- 5) and day 90 (+/- 5).

    Subject analysis set title
    Intention-to-treat population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients who received at least one dose of donor derived TCM.

    Subject analysis set title
    Efficacy-evaluable subpopulation
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    all patients from the ITT population with sampled EDTA blood for immunological monitoring over a period of at least eight weeks after the infusion of the first dose of TCM

    Primary: Cumulative incidence of acute or chronic overall GvHD

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    End point title
    		 Cumulative incidence of acute or chronic overall GvHD
    End point description
    cumulative incidence of acute or chronic GVHD overall grade ≥3 or higher within 3 months after infusion of the last dose of TCM the incidence of acute GVHD > overall grade II occurring between the time of infu- sion of the T cell prod As the incidence of acute GVHD > overall grade II occurring between the time of infusion of the T cell product and 6 months after the alloHSCT
    End point type
    Primary
    End point timeframe
    6 months
    End point values
    		 Donor-derived central memory T lymphocytes (TCM) after allogen Intention-to-treat population
    Number of subjects analysed
    16
    16
    Units: integer
    0
    0
    Statistical analysis title
    		 Estimation og GvHD rate
    Statistical analysis description
    A sample size of 25 patients is sufficiently for providing statistical evidence that our study procedure ensures an acceptable rate of success for an adaptive transfer. For this we plan a one sample test for single-stage phase II clinical trials. Then a sample size of 25 patients is needed in order to test the null hypothesis H0 that the underlying true success probability is <=0.26 [largest proportion of success that implies that the treatment does not warrant further study] against the alterna
    Comparison groups
    Donor-derived central memory T lymphocytes (TCM) after allogen v Intention-to-treat population
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    Method
    Parameter type
    		 event rate
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0.285
    Variability estimate
    Standard deviation
    Notes
    [1] - Estimation for an event rate

    Secondary: At least one Successful TCM transfers assessed by routine immunological monitoring

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    End point title
    		 At least one Successful TCM transfers assessed by routine immunological monitoring
    End point description
    End point type
    Secondary
    End point timeframe
    A successful transfer is defined as: The percentage of circulating T cells with a TCM phenotype with one of the described specific- ities doubles during eight weeks after infusion of the first, second or third dose as compared to the percentage befor
    End point values
    		 Donor-derived central memory T lymphocytes (TCM) after allogen Intention-to-treat population
    Number of subjects analysed
    16
    12
    Units: 2
        no
    3
    0
        yes
    13
    12
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    9 months
    Adverse event reporting additional description
    All adverse events reported spontaneously by the subject or observed by the investigatoror will be recorded. Investigators will be required to report to the Sponsor all adverse events occurring during the clinical trial, including the post-treatment follow-up period. Serious ad- verse events must be reported to the Sponsor within 24 hours of knowle
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    TCM treated
    Reporting group description
    		 All patients in the study treated with TCM cells

    Serious adverse events
    		 TCM treated
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 16 (81.25%)
         number of deaths (all causes)
    7
         number of deaths resulting from adverse events
    7
    General disorders and administration site conditions
    All events
         subjects affected / exposed
    13 / 16 (81.25%)
         occurrences causally related to treatment / all
    0 / 22
         deaths causally related to treatment / all
    0 / 7
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 TCM treated
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 16 (93.75%)
    General disorders and administration site conditions
    All events
         subjects affected / exposed
    15 / 16 (93.75%)
         occurrences all number
    175

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Dec 2018
    early dose escalation and sample size re-assessment

    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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