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    Clinical Trial Results:
    A Phase II, open label, dose escalation study to investigate the pharmacokinetics, pharmacodynamics, safety and clinical activity of begelomab as an initial treatment of acute Graft-versus-Host Disease in combination with standard steroid therapy

    Summary
    EudraCT number
    		 2017-002715-34
    Trial protocol
    		 IT  
    Global end of trial date
    29 Jul 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Apr 2023
    First version publication date
    14 Apr 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ADN014
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    ADIENNE SA
    Sponsor organisation address
    Via Zurigo, 46, Lugano, Switzerland, 6900
    Public contact
    Clinical Development Director, Renata Palmieri, +41 912104726, renata.palmieri@adienne.com
    Scientific contact
    Clinical Development Director, Renata Palmieri, +41 912104726, renata.palmieri@adienne.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001744-PIP01-14
    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
    15 Feb 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Jul 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jul 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objectives of the trial will be: •to establish the optimal biological dose (OBD) of intravenously infused begelomab in terms of modulation of CD26/CD3 lymphocyte activity; •to investigate efficacy endpoints; •to investigate the pharmacokinetics and pharmacodynamics of begelomab following escalating multiple doses of begelomab; •to investigate the safety and tolerability of multiple doses of begelomab in patients with acute Graft-versus-Host Disease.
    Protection of trial subjects
    The study was planned to comprise up to four dose levels in the dose escalation phase; only two additional dose levels were necessary to reach the Optimal Biiological Dose (OBD). The starting dose level was 4 mg/m^2, the second dose level 8 mg/m^2 and the third dove level was 16 mg/m^2. At the end of the dose escalation phase, the data from all cohorts was analysed to determine the optimal biologically active dose for further evaluation in the extended cohort. Prior to each dose escalation, the Trial Steering Committee (TSC) has met to review all available safety, tolerability, Pharmacokinetic (PK) and Pharmacodynamic (PD) data. A decision to escalate the dose could only be made when none of the dose escalation stopping criteria are expected to be met at the next higher dose level. A minimum of four evaluable subjects from each cohort were needed to reach a dose escalation decision.
    Background therapy
    		 Alongside the study treatments, methylprednisolone intravenous (IV) at the dose of ≤2 mg/kg/day (or other steroid and dose equivalent) was administered to subjects as baseline therapy.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Sep 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
    Italy: 50
    Worldwide total number of subjects
    50
    EEA total number of subjects
    50
    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)
    3
    Adults (18-64 years)
    38
    From 65 to 84 years
    9
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was divided in two phases. At initial stage, up to 6 patients per cohort were enrolled into sequential cohorts receiving increasing multiple doses of begelomab. Only two additional dose levels were necessary in order to reach the OBD. At the second stage, 25 additional patients were enrolled and treated at the OBD.

    Pre-assignment
    Screening details
    		 Patient who underwent allogeneic HSCT who developed clinical manifestations compatible with aGvHD were considered for enrolment, provided they have not been treated with Corticosteroids or other aGvHD therapies and had aGvHD grade greater than 2.

    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
    Are arms mutually exclusive
    Yes

    Arm title
    		 begelomab 4 mg/m^2 FAS
    Arm description
    		 In the first stage of the study (dose escalation phase) patients were treated until achievement of the OBD. The first dose level was 4mg/m^2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    begelomab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    The investigational medicinal product was administered as a 1-hour intravenous infusion into a central vein via a dedicated catheter (i.e. CVC or PICC) once daily for five days after enrolment (Days 1-5) followed by administration every other day for another eleven doses (Days 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27) for a total of 16 doses. First day of treatment is defined as Day 1.

    Arm title
    		 begelomab 8 mg/m^2 FAS
    Arm description
    		 In the first stage of the study (dose escalation phase) patients were treated until achievement of the OBD. The second dose level was 8mg/m^2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    begelomab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    The investigational medicinal product was administered as a 1-hour intravenous infusion into a central vein via a dedicated catheter (i.e. CVC or PICC) once daily for five days after enrolment (Days 1-5) followed by administration every other day for another eleven doses (Days 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27) for a total of 16 doses. First day of treatment is defined as Day 1.

    Arm title
    		 begelomab 16 mg/m^2 FAS
    Arm description
    		 In the first stage of the study (dose escalation phase) patients were treated until achievement of the OBD. The third dose level was 16mg/m^2. OBD has been reached at this dose level, therefore the second stage of the study (dose expansion phase) has been performed at the same dose level.
    Arm type
    		 Experimental

    Investigational medicinal product name
    begelomab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    The investigational medicinal product was administered as a 1-hour intravenous infusion into a central vein via a dedicated catheter (i.e. CVC or PICC) once daily for five days after enrolment (Days 1-5) followed by administration every other day for another eleven doses (Days 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27) for a total of 16 doses. First day of treatment is defined as Day 1.

    Number of subjects in period 1
    		begelomab 4 mg/m^2 FAS begelomab 8 mg/m^2 FAS begelomab 16 mg/m^2 FAS
    Started
    8
    11
    31
    Completed
    5
    7
    13
    Not completed
    3
    4
    18
         Adverse event, serious fatal
    -
    -
    10
         Physician decision
    1
    -
    1
         Adverse event, non-fatal
    1
    -
    1
         Lost to follow-up
    -
    3
    2
         Lack of efficacy
    1
    1
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    begelomab 4 mg/m^2 FAS
    Reporting group description
    		 In the first stage of the study (dose escalation phase) patients were treated until achievement of the OBD. The first dose level was 4mg/m^2.

    Reporting group title
    begelomab 8 mg/m^2 FAS
    Reporting group description
    		 In the first stage of the study (dose escalation phase) patients were treated until achievement of the OBD. The second dose level was 8mg/m^2.

    Reporting group title
    begelomab 16 mg/m^2 FAS
    Reporting group description
    		 In the first stage of the study (dose escalation phase) patients were treated until achievement of the OBD. The third dose level was 16mg/m^2. OBD has been reached at this dose level, therefore the second stage of the study (dose expansion phase) has been performed at the same dose level.

    Reporting group values
    		 begelomab 4 mg/m^2 FAS begelomab 8 mg/m^2 FAS begelomab 16 mg/m^2 FAS Total
    Number of subjects
    		 8 11 31 50
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    		 1 0 2 3
        Adults (>18)
    		 7 11 29 47
    Age continuous
    Units: years
        median (full range (min-max))
    		 57.5 (12 to 66) 62.0 (22 to 70) 52.0 (14 to 69) -
    Gender categorical
    Units: Subjects
        Female
    		 4 5 18 27
        Male
    		 4 6 13 23
    Subject analysis sets

    Subject analysis set title
    4mg/m^2 Per Protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects registered in the 4.0 mg/m^2 cohort who completed at least the treatment period and had no major protocol deviations that could impact on the data were included in the analysis.

    Subject analysis set title
    8mg/m^2 Per Protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects registered in the 8.0 mg/m^2 cohort who completed at least the treatment period and had no major protocol deviations that could impact on the data were included in the analysis.

    Subject analysis set title
    16mg/m^2 Per Protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects registered in the 16.0 mg/m^2 cohort who completed at least the treatment period and had no major protocol deviations that could impact on the data were included in the analysis.

    Subject analysis set title
    4mg/m^2 Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients who provided informed consent receiving at least one dose of study medication in the 4.0 mg/m^2 cohort were included in the analysis.

    Subject analysis set title
    8mg/m^2 Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients who provided informed consent receiving at least one dose of study medication in the 8.0 mg/m^2 cohort were included in the analysis.

    Subject analysis set title
    16mg/m^2 Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients who provided informed consent receiving at least one dose of study medication in the 16.0 mg/m^2 cohort were included in the analysis.

    Subject analysis set title
    4mg/m^2 LOCF FAS
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All patients enrolled in the 4.0 mg/m^2 cohort were included in the analysis for which a Last Observation Carried Forward (LOCF) imputation method is adopted for any missing assessments of Response to Treatment.

    Subject analysis set title
    8mg/m^2 LOCF FAS
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All patients enrolled in the 8.0 mg/m^2 cohort were included in the analysis for which a Last Observation Carried Forward (LOCF) imputation method is adopted for any missing assessments of Response to Treatment.

    Subject analysis set title
    16mg/m^2 LOCF FAS
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All patients enrolled in the 16.0 mg/m^2 cohort were included in the analysis for which a Last Observation Carried Forward (LOCF) imputation method is adopted for any missing assessments of Response to Treatment.

    Subject analysis sets values
    		 4mg/m^2 Per Protocol 8mg/m^2 Per Protocol 16mg/m^2 Per Protocol 4mg/m^2 Safety Set 8mg/m^2 Safety Set 16mg/m^2 Safety Set 4mg/m^2 LOCF FAS 8mg/m^2 LOCF FAS 16mg/m^2 LOCF FAS
    Number of subjects
    5
    7
    23
    8
    11
    31
    8
    11
    31
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    1
    0
    2
        Adults (>18)
    7
    11
    29
    Age continuous
    Units: years
        median (full range (min-max))
    57.5 (12 to 66)
    62.0 (22 to 70)
    52.0 (14 to 69)
    Gender categorical
    Units: Subjects
        Female
    4
    5
    18
        Male
    4
    6
    13

    End points

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    End points reporting groups
    Reporting group title
    begelomab 4 mg/m^2 FAS
    Reporting group description
    		 In the first stage of the study (dose escalation phase) patients were treated until achievement of the OBD. The first dose level was 4mg/m^2.

    Reporting group title
    begelomab 8 mg/m^2 FAS
    Reporting group description
    		 In the first stage of the study (dose escalation phase) patients were treated until achievement of the OBD. The second dose level was 8mg/m^2.

    Reporting group title
    begelomab 16 mg/m^2 FAS
    Reporting group description
    		 In the first stage of the study (dose escalation phase) patients were treated until achievement of the OBD. The third dose level was 16mg/m^2. OBD has been reached at this dose level, therefore the second stage of the study (dose expansion phase) has been performed at the same dose level.

    Subject analysis set title
    4mg/m^2 Per Protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects registered in the 4.0 mg/m^2 cohort who completed at least the treatment period and had no major protocol deviations that could impact on the data were included in the analysis.

    Subject analysis set title
    8mg/m^2 Per Protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects registered in the 8.0 mg/m^2 cohort who completed at least the treatment period and had no major protocol deviations that could impact on the data were included in the analysis.

    Subject analysis set title
    16mg/m^2 Per Protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects registered in the 16.0 mg/m^2 cohort who completed at least the treatment period and had no major protocol deviations that could impact on the data were included in the analysis.

    Subject analysis set title
    4mg/m^2 Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients who provided informed consent receiving at least one dose of study medication in the 4.0 mg/m^2 cohort were included in the analysis.

    Subject analysis set title
    8mg/m^2 Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients who provided informed consent receiving at least one dose of study medication in the 8.0 mg/m^2 cohort were included in the analysis.

    Subject analysis set title
    16mg/m^2 Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients who provided informed consent receiving at least one dose of study medication in the 16.0 mg/m^2 cohort were included in the analysis.

    Subject analysis set title
    4mg/m^2 LOCF FAS
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All patients enrolled in the 4.0 mg/m^2 cohort were included in the analysis for which a Last Observation Carried Forward (LOCF) imputation method is adopted for any missing assessments of Response to Treatment.

    Subject analysis set title
    8mg/m^2 LOCF FAS
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All patients enrolled in the 8.0 mg/m^2 cohort were included in the analysis for which a Last Observation Carried Forward (LOCF) imputation method is adopted for any missing assessments of Response to Treatment.

    Subject analysis set title
    16mg/m^2 LOCF FAS
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All patients enrolled in the 16.0 mg/m^2 cohort were included in the analysis for which a Last Observation Carried Forward (LOCF) imputation method is adopted for any missing assessments of Response to Treatment.

    Primary: Receptor Occupancy

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    End point title
    		 Receptor Occupancy [1]
    End point description
    Dose of begelomab leading to a maximum Receptor Occupancy as determined with flow cytometry
    End point type
    Primary
    End point timeframe
    Day -1 to Day 180, only day 28 reported
    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: Appropriate descriptive statistics has been used for outcome variables. Continuous variables has been presented using the mean, median, standard deviation, minimum and maximum, and were also discretized for practical purposes. For categorical data, frequencies and percentages were presented.
    End point values
    		 begelomab 4 mg/m^2 FAS begelomab 8 mg/m^2 FAS begelomab 16 mg/m^2 FAS 4mg/m^2 Per Protocol 8mg/m^2 Per Protocol 16mg/m^2 Per Protocol
    Number of subjects analysed
    8
    11
    31
    5
    7
    23
    Units: percent
        median (full range (min-max))
    33.7 (21.8 to 52.5)
    63.8 (22.8 to 80.4)
    55.3 (34.7 to 100.6)
    33.7 (21.8 to 52.5)
    63.8 (22.8 to 80.4)
    54.15 (34.7 to 96.9)
    No statistical analyses for this end point

    Secondary: Cumulative overall response

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    End point title
    		 Cumulative overall response
    End point description
    Overall response is defined as the percentage of patients with graft-versus-host disease (GvHD) complete response (CR) or partial response (PR)
    End point type
    Secondary
    End point timeframe
    Day 28, Day 56, Day 100 and Day 180.
    End point values
    		 begelomab 4 mg/m^2 FAS begelomab 8 mg/m^2 FAS begelomab 16 mg/m^2 FAS 4mg/m^2 Per Protocol 8mg/m^2 Per Protocol 16mg/m^2 Per Protocol 4mg/m^2 LOCF FAS 8mg/m^2 LOCF FAS 16mg/m^2 LOCF FAS
    Number of subjects analysed
    8
    11
    31
    5
    7
    23
    8
    11
    31
    Units: percent
    number (confidence interval 90%)
        Overall Response
    62.5 (28.9 to 88.9)
    63.6 (35.0 to 86.5)
    64.5 (48.2 to 78.7)
    100.0 (54.9 to 100.0)
    100.0 (65.2 to 100.0)
    78.3 (59.6 to 91.0)
    62.5 (28.9 to 88.9)
    72.7 (43.6 to 92.1)
    67.7 (51.5 to 81.3)
        Complete Response
    50.0 (19.3 to 80.7)
    54.5 (27.1 to 80.0)
    41.9 (26.9 to 58.2)
    80.0 (34.3 to 99.0)
    85.7 (47.9 to 99.3)
    47.8 (29.6 to 66.5)
    50.0 (19.3 to 80.7)
    54.5 (27.1 to 80.0)
    41.9 (26.9 to 58.2)
        Partial Response
    12.5 (0.6 to 47.1)
    9.1 (0.5 to 36.4)
    22.6 (11.1 to 38.3)
    20.0 (1.0 to 65.7)
    14.3 (0.7 to 52.1)
    30.4 (15.2 to 49.6)
    12.5 (0.6 to 47.1)
    18.2 (3.3 to 47.0)
    25.8 (13.5 to 41.8)
    No statistical analyses for this end point

    Secondary: Duration of Overall Response

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    End point title
    		 Duration of Overall Response [2]
    End point description
    Defined as the time in days from first response (from Day 28) until GvHD progression or death
    End point type
    Secondary
    End point timeframe
    Day 28 to Day 180
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Duration of overall response is defined as the time from first response until GvHD progression or death and it is calculated only for patients with disease progression or death. In the "begelomab 4 mg/m^2 FAS" and "4mg/m^2 Per Protocol" groups no patients progressed or died, therefore it is not possible to calculate the endpoint, which is reported as missing in the tables. System only allows to enter numbers in the field, therefore it was decided to exclude groups as "NA" is not reportable.
    End point values
    		 begelomab 8 mg/m^2 FAS begelomab 16 mg/m^2 FAS 8mg/m^2 Per Protocol 16mg/m^2 Per Protocol
    Number of subjects analysed
    11
    31
    7
    23
    Units: day
        median (full range (min-max))
    73.0 (73 to 73)
    73.5 (7 to 172)
    73 (73 to 73)
    73.5 (7 to 172)
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Proportion of participants who survive until Day 28, Day 56, Day 100 and Day 180
    End point type
    Secondary
    End point timeframe
    Day 28 to Day 180
    End point values
    		 begelomab 4 mg/m^2 FAS begelomab 8 mg/m^2 FAS begelomab 16 mg/m^2 FAS 4mg/m^2 Per Protocol 8mg/m^2 Per Protocol 16mg/m^2 Per Protocol
    Number of subjects analysed
    8
    11
    31
    5
    7
    23
    Units: percent
    number (confidence interval 90%)
        Day 28
    100 (100 to 100)
    90.0 (57.9 to 98.0)
    96.8 (84.4 to 99.4)
    100.0 (100.0 to 100.0)
    100.0 (100.0 to 100.0)
    100.0 (100.0 to 100.0)
        Day 56
    100 (100 to 100)
    90.0 (57.9 to 98.0)
    88.7 (73.2 to 95.5)
    100.0 (100.0 to 100.0)
    100.0 (100.0 to 100.0)
    95.2 (77.7 to 99.1)
        Day 100
    83.3 (38.8 to 96.5)
    80.0 (48.9 to 93.3)
    76.6 (59.2 to 87.3)
    100.0 (100.0 to 100.0)
    100.0 (100.0 to 100.0)
    85.7 (67.1 to 94.2)
        Day 180
    83.3 (38.8 to 96.5)
    70.0 (39.6 to 87.2)
    56.5 (38.8 to 70.8)
    100.0 (100.0 to 100.0)
    100.0 (100.0 to 100.0)
    61.9 (42.2 to 76.6)
    No statistical analyses for this end point

    Secondary: Percentage of reduction of steroid dose

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    End point title
    		 Percentage of reduction of steroid dose
    End point description
    Percentage reduction of the steroid dose compared with respect to initial dosing at Day 28, Day 56, Day 100 and Day 180
    End point type
    Secondary
    End point timeframe
    Day 28 to Day 180
    End point values
    		 begelomab 4 mg/m^2 FAS begelomab 8 mg/m^2 FAS begelomab 16 mg/m^2 FAS 4mg/m^2 Per Protocol 8mg/m^2 Per Protocol 16mg/m^2 Per Protocol
    Number of subjects analysed
    8
    11
    31
    5
    7
    23
    Units: percent
    median (full range (min-max))
        Day 28
    -16.7 (-58.0 to 150)
    -69.0 (-83.0 to -63.0)
    -63.0 (-93.0 to 99.0)
    -16.7 (-58.0 to 150.0)
    -71.3 (-83.0 to -67.0)
    -63.0 (-93.0 to 40.0)
        Day 56
    -80.3 (-83.0 to -78.0)
    -83.3 (-86.0 to 15.0)
    -70.0 (-97.0 to -20.0)
    -80.3 (-83.0 to -78.0)
    -84.7 (-86.0 to -83.0)
    -68.3 (-97.0 to -20.0)
        Day 100
    -93.3 (-93.3 to -93.3)
    -96.6 (-96.7 to -96.5)
    -84.0 (-99.0 to -58.0)
    -93.3 (-93.3 to -93.3)
    -96.6 (-96.7 to -96.5)
    -84.0 (-99.0 to -58.0)
        Day 180
    291.7 (-67.0 to 650.0)
    -98.0 (-98.0 to -85.0)
    -62.5 (-80.0 to 400.0)
    291.7 (-67.0 to 650.0)
    -98.0 (-98.0 to -85.0)
    -66.7 (-80.0 to 400.0)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events (AE) and Serious Adverse Events (SAE) incidence from baseline to Days 28, 100 and 180 or last available data
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    begelomab 4 mg/m^2 FAS
    Reporting group description
    		 In the first stage of the study (dose escalation phase) patients were treated until achievement of the OBD. The first dose level was 4mg/m^2. The investigational medicinal product was administered as a 1-hour intravenous infusion into a central vein via a dedicated catheter (i.e. CVC or PICC) once daily for five days after enrolment (Days 1-5) followed by administration every other day for another eleven doses (Days 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27) for a total of 16 doses.

    Reporting group title
    begelomab 8 mg/m^2 FAS
    Reporting group description
    		 In the first stage of the study (dose escalation phase) patients were treated until achievement of the OBD. The second dose level was 8mg/m^2. The investigational medicinal product was administered as a 1-hour intravenous infusion into a central vein via a dedicated catheter (i.e. CVC or PICC) once daily for five days after enrolment (Days 1-5) followed by administration every other day for another eleven doses (Days 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27) for a total of 16 doses.

    Reporting group title
    begelomab 16 mg/m^2 FAS
    Reporting group description
    		 In the first stage of the study (dose escalation phase) patients were treated until achievement of the OBD. The third dose level was 16mg/m^2. OBD has been reached at this dose level, therefore the second stage of the study (dose expansion phase) has been performed at the same dose level. The investigational medicinal product was administered as a 1-hour intravenous infusion into a central vein via a dedicated catheter (i.e. CVC or PICC) once daily for five days after enrolment (Days 1-5) followed by administration every other day for another eleven doses (Days 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27) for a total of 16 doses.

    Serious adverse events
    		 begelomab 4 mg/m^2 FAS begelomab 8 mg/m^2 FAS begelomab 16 mg/m^2 FAS
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 8 (62.50%)
    7 / 11 (63.64%)
    14 / 31 (45.16%)
         number of deaths (all causes)
    1
    3
    12
         number of deaths resulting from adverse events
    1
    3
    12
    Investigations
    Platelet count decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Myelofibrosis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 11 (0.00%)
    0 / 31 (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
    Leukaemia recurrent
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute leukaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Injury, poisoning and procedural complications
    Delayed graft function
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Encephalopathy
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 11 (0.00%)
    0 / 31 (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
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 11 (0.00%)
    0 / 31 (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
    Microangiopathic haemolytic anaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 11 (9.09%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Immune system disorders
    Acute graft versus host disease
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    2 / 31 (6.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    Acute graft versus host disease in intestine
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Acute graft versus host disease in liver
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Graft versus host disease
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Infections and infestations
    Cerebral toxoplasmosis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Coronavirus infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pneumonia
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 11 (9.09%)
    2 / 31 (6.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pneumonia klebsiella
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    2 / 31 (6.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    Septic shock
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 11 (18.18%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 begelomab 4 mg/m^2 FAS begelomab 8 mg/m^2 FAS begelomab 16 mg/m^2 FAS
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 8 (100.00%)
    10 / 11 (90.91%)
    31 / 31 (100.00%)
    Vascular disorders
    any
         subjects affected / exposed
    3 / 8 (37.50%)
    2 / 11 (18.18%)
    9 / 31 (29.03%)
         occurrences all number
    4
    2
    9
    General disorders and administration site conditions
    any
         subjects affected / exposed
    3 / 8 (37.50%)
    4 / 11 (36.36%)
    13 / 31 (41.94%)
         occurrences all number
    5
    5
    26
    Immune system disorders
    any
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    4 / 31 (12.90%)
         occurrences all number
    0
    0
    6
    Reproductive system and breast disorders
    any
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    any
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 11 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    2
    0
    3
    Psychiatric disorders
    any
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    3 / 31 (9.68%)
         occurrences all number
    0
    0
    4
    Investigations
    any
         subjects affected / exposed
    7 / 8 (87.50%)
    5 / 11 (45.45%)
    18 / 31 (58.06%)
         occurrences all number
    37
    20
    78
    Injury, poisoning and procedural complications
    any
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 11 (9.09%)
    4 / 31 (12.90%)
         occurrences all number
    1
    1
    4
    Cardiac disorders
    any
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 11 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    1
    Nervous system disorders
    any
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 11 (0.00%)
    4 / 31 (12.90%)
         occurrences all number
    2
    0
    5
    Blood and lymphatic system disorders
    any
         subjects affected / exposed
    3 / 8 (37.50%)
    5 / 11 (45.45%)
    14 / 31 (45.16%)
         occurrences all number
    6
    8
    35
    Eye disorders
    any
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 11 (0.00%)
    3 / 31 (9.68%)
         occurrences all number
    1
    0
    3
    Gastrointestinal disorders
    any
         subjects affected / exposed
    2 / 8 (25.00%)
    1 / 11 (9.09%)
    15 / 31 (48.39%)
         occurrences all number
    4
    2
    36
    Hepatobiliary disorders
    any
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    2
    Skin and subcutaneous tissue disorders
    any
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    8 / 31 (25.81%)
         occurrences all number
    0
    0
    14
    Renal and urinary disorders
    any
         subjects affected / exposed
    3 / 8 (37.50%)
    1 / 11 (9.09%)
    2 / 31 (6.45%)
         occurrences all number
    5
    1
    3
    Musculoskeletal and connective tissue disorders
    any
         subjects affected / exposed
    4 / 8 (50.00%)
    1 / 11 (9.09%)
    3 / 31 (9.68%)
         occurrences all number
    6
    1
    4
    Infections and infestations
    any
         subjects affected / exposed
    3 / 8 (37.50%)
    5 / 11 (45.45%)
    10 / 31 (32.26%)
         occurrences all number
    7
    12
    15
    Metabolism and nutrition disorders
    any
         subjects affected / exposed
    8 / 8 (100.00%)
    5 / 11 (45.45%)
    19 / 31 (61.29%)
         occurrences all number
    25
    13
    40

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 May 2018
    Main changes include: - Updated staging system reference used for aGvHD and cGvHD determination - Inclusion/Exclusion criteria updated: - Gastrointestinal biopsy is recommended and no longer mandatory - Time window for prior systemic corticosteroid therapy for GvHD has been extended to 48 hours - Spirometry test has been replaced by pulse oximetry assessment of oxygen saturation - Added criteria to exclude the possibility to enroll in the trial patients affected by steroid-resistant GvHD variant - Removed criteria "Patients with signs of steroid-resistance" due to the impossibility to diagnose steroid resistance within the first 48 hours after the start of systemic corticosteroid therapy - The definition of clinically relevant CMV-viremia has been updated according to the current clinical criteria for preemptive treatment and increased from ≥ 5.000 to ≥10.000 copies/mL in whole blood - To specify that both central venous catheter (CVC) and peripherally inserted central catheter (PICC) can be used for IP administration
    07 Jan 2019
    Main changes include: - Study Phase changed from I-II to II, with rationale explanation in the study protocol - Inclusion/Exclusion Criteria updated: - removed upper limit for inclusion age (previously < 70Yrs) since data on patients higher than 70 years can be relevant for safety purposes. - Time window for prior systemic corticosteroid therapy for GvHD has been extended to 72 hours to allow the sites more time to complete the screening exams and assessments. - The application of topical steroids for indications other than GvHD is no longer prohibited - Patients with known CNS involvement or pleural effusions/ascites are now eligible

    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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