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    Clinical Trial Results:
    An Open-Label, Multicenter Study of the Effects of Remission Maintenance Therapy with Ceplene® (Histamine Dihydrochloride), Given in Conjunction with Low-Dose Interleukin-2 (IL-2, Proleukin®), on Immune Response and Minimal Residual Disease (MRD) in Adult Patients with Acute Myeloid Leukemia (AML) in First Complete Remission (CR1)

    Summary
    EudraCT number
    		 2009-012083-14
    Trial protocol
    		 SE   BE   GB   ES   IT   FR  
    Global end of trial date
    04 Jun 2014

    Results information
    Results version number
    		 v2(current)
    This version publication date
    13 Dec 2017
    First version publication date
    28 Apr 2016
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    New Study Sponsor. Need to update contact information.

    Trial information

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    Trial identification
    Sponsor protocol code
    EPC2008-02
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01347996
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    MEDA Pharma GmbH & Co. KG
    Sponsor organisation address
    Benzstrasse 1, Bad Homburg, Germany, 61352
    Public contact
    Group leader study manager, MEDA Pharma GmbH & Co. KG, +49 6172 888 01, 42b@medapharma.de
    Scientific contact
    Head of Corporate Clinical Affairs, MEDA Pharma GmbH & Co. KG, +49 6172 888 01, 42b@medapharma.de
    Sponsor organisation name
    Cytovia, Inc.
    Sponsor organisation address
    12 East 49th street, 11th floor, New York, United States, 10017
    Public contact
    Medical Affairs , Cytovia, Inc., medical.affairs@cytoviaoncology.com
    Scientific contact
    Medical Director, Cytovia, Inc., medical.affairs@cytoviaoncology.com
    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
    15 Oct 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Jun 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Jun 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    1. The quantitative and qualitative pharmacodynamic effects of Ceplene plus low dose IL-2 (Ceplene/IL-2) by monitoring T and NK cell phenotypes and their functionality after the first and third cycles of treatment in adult patients with acute myeloid leukemia (AML) in first complete remission (CR1). 2. Minimal residual disease (MRD) in AML patients receiving Ceplene/IL-2.
    Protection of trial subjects
    Patients were withdrawn from study treatment: • in case of relapse of AML; • in case of unmanageable or irreversible toxicity using the CTCAE v3.0 criteria as de-fined in Appendix 2 of the study protocol. Patients with recurrent Grade 3 or 4 toxicity after dose reductions did no longer receive treatment, but must be followed for up to 2 years for relapse, or death, whichever comes first; • if, in the opinion of the Investigator, it was not in the patient’s best interest to continue (e.g., adverse event, concurrent illness, etc.). The patients could withdraw from treatment at any time and for any reason.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Sep 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Sweden: 41
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    Belgium: 10
    Country: Number of subjects enrolled
    France: 9
    Country: Number of subjects enrolled
    Italy: 19
    Worldwide total number of subjects
    84
    EEA total number of subjects
    84
    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)
    52
    From 65 to 84 years
    32
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 As AML is a rare disease belonging to the group of acute leukemias, which account for less than 3% of all cancers, it was necessary to conduct the study involving study sites across different European countries to assure patient recruitment in a reasonable time period.

    Pre-assignment
    Screening details
    		 Adult (≥18 years of age) AML patients in CR1 (defined as less than 5% blasts in a normocel-lular BM) who had been genetically well-characterized at diagnosis were considered for participation. Patients should have performed conventional cytogenetic AML subtyping and molecular characterization on diagnositic BM samples using RQ-PCR techniques.

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

    Arms
    Arm title
    		 Ceplene/IL-2
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Histamine dihydrochloride / Ceplene®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Ceplene was administered sc 0.5 mg bid after IL-2.

    Investigational medicinal product name
    Interleukin-2 / Proleukin®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    IL-2 was administered subcutaneously (sc), 1 μg/kg [16,400 IU/kg] body weight twice daily (bid) during treatment periods.

    Number of subjects in period 1
    		Ceplene/IL-2
    Started
    84
    Completed
    33
    Not completed
    51
         Consent withdrawn by subject
    3
         Relapse
    37
         Adverse event, non-fatal
    9
         Any other reasons
    2

    Baseline characteristics

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

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 84 84
    Age categorical
    Units: Subjects
        <= 60 years
    		 41 41
        > 60 years
    		 43 43
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 58.08 ( 14.359 ) -
    Gender categorical
    Units: Subjects
        Female
    		 44 44
        Male
    		 40 40

    End points

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    End points reporting groups
    Reporting group title
    Ceplene/IL-2
    Reporting group description
    		 -

    Subject analysis set title
    Samples with cell counts at day 1
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The subjects with evaluable cell counts at Day 1.

    Subject analysis set title
    Samples with cell counts at day 21
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The subjects with evaluable cell counts at Day 21.

    Subject analysis set title
    Samples at day 1 / subset of cells CD3+ CD4+
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The subjects with evaluable biomarkers at Day 1, subset of cells CD3+ CD4+

    Subject analysis set title
    Samples at day 21 / subset of cells CD3+ CD4+
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The subjects with available biomarkers at day 21 of cycle 1, subset of cells CD3+ CD4+

    Subject analysis set title
    Samples at day 1 / subset of cells CD3+ CD8+
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The subjects with evaluable biomarkers at Day 1, subset of cells CD3+ CD8+

    Subject analysis set title
    Samples at day 21 / subset of cells CD3+ CD8+
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The subjects with evaluable biomarkers at Day 21, subset of cells CD3+ CD8+

    Subject analysis set title
    Samples at day 1 / subset of cells CD3- CD56+ dim CD16+
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The subjects with evaluable biomarkers at Day 1, subset of cells CD3- CD56+ dim CD16+

    Subject analysis set title
    Samples at day 21 / subset of cells CD3- CD56+ dim CD16+
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The subjects with evaluable biomarkers at Day 21, subset of cells CD3- CD56+ dim CD16+

    Subject analysis set title
    Samples at day 1 / subset of cells CD3- CD56+
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The subjects with evaluable biomarkers at Day 1, subset of cells CD3- CD56+

    Subject analysis set title
    Samples at day 21 / subset of cells CD3- CD56+
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The subjects with evaluable biomarkers at Day 21, subset of cells CD3- CD56+

    Subject analysis set title
    Samples at day 1 / subset of cells CD3- CD56+ bright CD16-
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The subjects with evaluable biomarkers at Day 1, subset of cells CD3- CD56+ bright CD16-

    Subject analysis set title
    Samples at day 21 / subset of cells CD3- CD56+ bright CD16-
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The subjects with evaluable biomarkers at Day 1, subset of cells CD3- CD56+ bright CD16-

    Primary: CD3+ CD4+

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    End point title
    		 CD3+ CD4+
    End point description
    End point type
    Primary
    End point timeframe
    Day 1 and day 21 of cycle 1.
    End point values
    		 Samples with cell counts at day 1 Samples with cell counts at day 21
    Number of subjects analysed
    62
    54
    Units: Counts in 10^9/L
        arithmetic mean (standard deviation)
    0.43 ( 0.334 )
    0.59 ( 0.395 )
    Statistical analysis title
    		 Change from Day 1 to Day 21
    Comparison groups
    Samples with cell counts at day 1 v Samples with cell counts at day 21
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.0007 [2]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [1] - 2-sided paired t-test at a significance level of 5% for the available samples with evaluable cell counts on day 1 and day 21. Subjects in the analysis for the paired t-test: 47
    [2] - P-value to be compared to alpha-level 0.0083 (adjusted to multiplicity with respect to the Holm procedure).

    Primary: CD3+ CD8+

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    End point title
    		 CD3+ CD8+
    End point description
    End point type
    Primary
    End point timeframe
    Day 1 and 21 of cycle1.
    End point values
    		 Samples with cell counts at day 1 Samples with cell counts at day 21
    Number of subjects analysed
    62
    54
    Units: Counts in 10^9/L
        arithmetic mean (standard deviation)
    0.4 ( 0.65 )
    0.32 ( 0.41 )
    Statistical analysis title
    		 Change from Day 1 to Day 21.
    Comparison groups
    Samples with cell counts at day 1 v Samples with cell counts at day 21
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.1665 [4]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [3] - 2-sided paired t-test at a significance level of 5% for the available samples with evaluable cell counts on day 1 and day 21. Subjects in the analysis for the paired t-test: 47
    [4] - P-value to be compared to alpha-level 0.05 (adjusted to multiplicity with respect to the Holm procedure).

    Primary: CD3- CD56+

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    End point title
    		 CD3- CD56+
    End point description
    End point type
    Primary
    End point timeframe
    Day 1 and day 21 of cycle 1.
    End point values
    		 Samples with cell counts at day 1 Samples with cell counts at day 21
    Number of subjects analysed
    62
    54
    Units: Counts 10^9/L
        arithmetic mean (standard deviation)
    0.15 ( 0.132 )
    0.44 ( 0.385 )
    Statistical analysis title
    		 Change from Day 1 to day 21
    Comparison groups
    Samples with cell counts at day 21 v Samples with cell counts at day 1
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 < 0.0001 [6]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [5] - 2-sided paired t-test at a significance level of 5% for the available samples with evaluable cell counts on day 1 and day 21. Subjects in the analysis for the paired t-test: 47
    [6] - P-value to be compared to alpha-level 0.0071 (adjusted to multiplicity with respect to the Holm procedure).

    Primary: Cd3zeta

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    End point title
    		 Cd3zeta
    End point description
    End point type
    Primary
    End point timeframe
    Day 1 and day 21 of cycle 1.
    End point values
    		 Samples at day 1 / subset of cells CD3+ CD4+ Samples at day 21 / subset of cells CD3+ CD4+ Samples at day 1 / subset of cells CD3+ CD8+ Samples at day 21 / subset of cells CD3+ CD8+ Samples at day 1 / subset of cells CD3- CD56+ dim CD16+ Samples at day 21 / subset of cells CD3- CD56+ dim CD16+
    Number of subjects analysed
    62
    62
    62
    62
    62
    62
    Units: Median fluorescence intensity
        arithmetic mean (standard deviation)
    1119.42 ( 666.581 )
    1053.74 ( 425.445 )
    1224.52 ( 514.294 )
    1265.4 ( 540.521 )
    2113.34 ( 963.493 )
    2129.1 ( 995.253 )
    Statistical analysis title
    		 Test of the day effect across all subsets.
    Comparison groups
    Samples at day 1 / subset of cells CD3+ CD4+ v Samples at day 21 / subset of cells CD3+ CD4+ v Samples at day 1 / subset of cells CD3+ CD8+ v Samples at day 21 / subset of cells CD3+ CD8+ v Samples at day 1 / subset of cells CD3- CD56+ dim CD16+ v Samples at day 21 / subset of cells CD3- CD56+ dim CD16+
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 = 0.1236 [8]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [7] - Mixed models analysis of variance (ANOVA) for longitudinal data on the differences between day 1 and day 21 values. The models included Phenotype as fixed effect and Patient as random effect. The overall day effect across all subsets was assessed by performing the test of fixed effects on the phenotype. Number of subjects with evaluable biomarkers for the day 1 and day 21 in this analysis: 55
    [8] - P-value to be compared to alpha-level 0.025 (adjusted to multiplicity with respect to the Holm procedure).

    Primary: CD25+

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    End point title
    		 CD25+
    End point description
    End point type
    Primary
    End point timeframe
    Day 1 and day 21 of cycle 1.
    End point values
    		 Samples at day 1 / subset of cells CD3+ CD4+ Samples at day 21 / subset of cells CD3+ CD4+ Samples at day 1 / subset of cells CD3+ CD8+ Samples at day 21 / subset of cells CD3+ CD8+ Samples at day 1 / subset of cells CD3- CD56+ Samples at day 21 / subset of cells CD3- CD56+
    Number of subjects analysed
    62
    62
    62
    62
    58
    61
    Units: Percent
        arithmetic mean (standard deviation)
    7.93 ( 7.009 )
    26.7 ( 13.846 )
    5.99 ( 9.626 )
    5.94 ( 7.432 )
    2.33 ( 3.516 )
    0.74 ( 1.144 )
    Statistical analysis title
    		 Test of the day effect across all subsets.
    Comparison groups
    Samples at day 21 / subset of cells CD3+ CD4+ v Samples at day 1 / subset of cells CD3+ CD8+ v Samples at day 1 / subset of cells CD3+ CD4+ v Samples at day 21 / subset of cells CD3+ CD8+ v Samples at day 1 / subset of cells CD3- CD56+ v Samples at day 21 / subset of cells CD3- CD56+
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 < 0.0001 [10]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [9] - Mixed models analysis of variance (ANOVA) for longitudinal data on the differences between day 1 and day 21 values. The models included Phenotype as fixed effect and Patient as random effect. The overall day effect across all subsets was assessed by performing the test of fixed effects on the phenotype. Number of subjects with evaluable biomarkers for the day 1 and day 21 in this analysis: 55
    [10] - P-value to be compared to alpha-level 0.0056 (adjusted to multiplicity with respect to the Holm procedure).

    Primary: CD69+

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    End point title
    		 CD69+
    End point description
    End point type
    Primary
    End point timeframe
    Day 1 and day 21 of cycle 1.
    End point values
    		 Samples at day 1 / subset of cells CD3+ CD4+ Samples at day 21 / subset of cells CD3+ CD4+ Samples at day 1 / subset of cells CD3+ CD8+ Samples at day 21 / subset of cells CD3+ CD8+ Samples at day 1 / subset of cells CD3- CD56+ Samples at day 21 / subset of cells CD3- CD56+
    Number of subjects analysed
    62
    62
    62
    62
    62
    62
    Units: Percent
        arithmetic mean (standard deviation)
    14.22 ( 11.962 )
    13.12 ( 12.1 )
    21.41 ( 17.481 )
    18.61 ( 13.925 )
    18.3 ( 11.277 )
    13.73 ( 9.448 )
    Statistical analysis title
    		 Test of the day effect across all subsets.
    Comparison groups
    Samples at day 1 / subset of cells CD3+ CD4+ v Samples at day 21 / subset of cells CD3+ CD4+ v Samples at day 1 / subset of cells CD3+ CD8+ v Samples at day 21 / subset of cells CD3+ CD8+ v Samples at day 1 / subset of cells CD3- CD56+ v Samples at day 21 / subset of cells CD3- CD56+
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 = 0.0057 [12]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [11] - Mixed models analysis of variance (ANOVA) for longitudinal data on the differences between Day 1 and Day 21 values. The models included Phenotype as fixed effect and Patient as random effect. The overall Day effect across all subsets was assessed by performing the test of fixed effects on the phenotype. Number of subjects with evaluable biomarkers for the day 1 and day 21 in this analysis: 55
    [12] - P-value to be compared to alpha-level 0.0125 (adjusted to multiplicity with respect to the Holm procedure).

    Primary: IFN-gamma+

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    End point title
    		 IFN-gamma+
    End point description
    End point type
    Primary
    End point timeframe
    Day 1 and day 21 of cycle 1.
    End point values
    		 Samples at day 1 / subset of cells CD3+ CD4+ Samples at day 21 / subset of cells CD3+ CD4+ Samples at day 1 / subset of cells CD3+ CD8+ Samples at day 21 / subset of cells CD3+ CD8+ Samples at day 1 / subset of cells CD3- CD56+ Samples at day 21 / subset of cells CD3- CD56+
    Number of subjects analysed
    58
    62
    58
    62
    58
    62
    Units: Percent
        arithmetic mean (standard deviation)
    21.28 ( 15.725 )
    18.82 ( 16.401 )
    58.17 ( 24.432 )
    59.97 ( 20.454 )
    47.75 ( 21.738 )
    50.87 ( 18.241 )
    Statistical analysis title
    		 Test of the day effect across all subsets.
    Comparison groups
    Samples at day 21 / subset of cells CD3+ CD4+ v Samples at day 1 / subset of cells CD3+ CD8+ v Samples at day 21 / subset of cells CD3+ CD8+ v Samples at day 1 / subset of cells CD3- CD56+ v Samples at day 1 / subset of cells CD3+ CD4+ v Samples at day 21 / subset of cells CD3- CD56+
    Number of subjects included in analysis
    360
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    P-value
    		 = 0.0007 [14]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [13] - Mixed models analysis of variance (ANOVA) for longitudinal data on the differences between Day 1 and Day 21 values. The models included Phenotype as fixed effect and Patient as random effect. The overall Day effect across all subsets was assessed by performing the test of fixed effects on the phenotype. Number of subjects with evaluable biomarkers for the day 1 and day 21 in this analysis: 55
    [14] - P-value to be compared to alpha-level 0.01 (adjusted to multiplicity with respect to the Holm procedure).

    Primary: NKp46

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    End point title
    		 NKp46
    End point description
    End point type
    Primary
    End point timeframe
    Day 1 and day 21 of cycle 1.
    End point values
    		 Samples at day 1 / subset of cells CD3- CD56+ dim CD16+ Samples at day 21 / subset of cells CD3- CD56+ dim CD16+ Samples at day 1 / subset of cells CD3- CD56+ bright CD16- Samples at day 21 / subset of cells CD3- CD56+ bright CD16-
    Number of subjects analysed
    62
    62
    62
    62
    Units: Median fluorescence intensity
        arithmetic mean (standard deviation)
    707.55 ( 443.458 )
    1081.76 ( 579.131 )
    955.59 ( 697.57 )
    985.45 ( 698.282 )
    Statistical analysis title
    		 Test of the day effect across all subsets.
    Comparison groups
    Samples at day 1 / subset of cells CD3- CD56+ dim CD16+ v Samples at day 21 / subset of cells CD3- CD56+ dim CD16+ v Samples at day 1 / subset of cells CD3- CD56+ bright CD16- v Samples at day 21 / subset of cells CD3- CD56+ bright CD16-
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    		 other [15]
    P-value
    		 < 0.0001 [16]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [15] - Mixed models analysis of variance (ANOVA) for longitudinal data on the differences between Day 1 and Day 21 values. The models included Phenotype as fixed effect and Patient as random effect. The overall Day effect across all subsets was assessed by performing the test of fixed effects on the phenotype. Number of subjects with evaluable biomarkers for the day 1 and day 21 in this analysis: 55
    [16] - P-value to be compared to alpha-level 0.0063 (adjusted to multiplicity with respect to the Holm procedure).

    Primary: NKp30

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    End point title
    		 NKp30
    End point description
    End point type
    Primary
    End point timeframe
    Day 1 and day 21 of cycle 1.
    End point values
    		 Samples at day 1 / subset of cells CD3- CD56+ dim CD16+ Samples at day 21 / subset of cells CD3- CD56+ dim CD16+ Samples at day 1 / subset of cells CD3- CD56+ bright CD16- Samples at day 21 / subset of cells CD3- CD56+ bright CD16-
    Number of subjects analysed
    62
    62
    62
    62
    Units: Median fluorescence intensity
        arithmetic mean (standard deviation)
    391.38 ( 201.465 )
    493.21 ( 198.144 )
    418.69 ( 156.635 )
    580.34 ( 205.83 )
    Statistical analysis title
    		 Test of the day effect across all subsets.
    Comparison groups
    Samples at day 1 / subset of cells CD3- CD56+ dim CD16+ v Samples at day 21 / subset of cells CD3- CD56+ dim CD16+ v Samples at day 1 / subset of cells CD3- CD56+ bright CD16- v Samples at day 21 / subset of cells CD3- CD56+ bright CD16-
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    		 other [17]
    P-value
    		 < 0.0001 [18]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [17] - Mixed models analysis of variance (ANOVA) for longitudinal data on the differences between Day 1 and Day 21 values. The models included Phenotype as fixed effect and Patient as random effect. The overall Day effect across all subsets was assessed by performing the test of fixed effects on the phenotype. Number of subjects with evaluable biomarkers for the day 1 and day 21 in this analysis: 55
    [18] - P-value to be compared to alpha-level 0.005 (adjusted to multiplicity with respect to the Holm procedure).

    Primary: NKG2D

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    End point title
    		 NKG2D
    End point description
    End point type
    Primary
    End point timeframe
    Day 1 and day 21 of cycle 1.
    End point values
    		 Samples at day 1 / subset of cells CD3- CD56+ dim CD16+ Samples at day 21 / subset of cells CD3- CD56+ dim CD16+ Samples at day 1 / subset of cells CD3- CD56+ bright CD16- Samples at day 21 / subset of cells CD3- CD56+ bright CD16-
    Number of subjects analysed
    60
    61
    60
    61
    Units: Median fluorescence intensity
        arithmetic mean (standard deviation)
    1700.6 ( 920.939 )
    1868.02 ( 1027.784 )
    2504.17 ( 1228.668 )
    2513.34 ( 1284.663 )
    Statistical analysis title
    		 Test of the day effect across all subsets.
    Comparison groups
    Samples at day 21 / subset of cells CD3- CD56+ dim CD16+ v Samples at day 1 / subset of cells CD3- CD56+ bright CD16- v Samples at day 1 / subset of cells CD3- CD56+ dim CD16+ v Samples at day 21 / subset of cells CD3- CD56+ bright CD16-
    Number of subjects included in analysis
    242
    Analysis specification
    Pre-specified
    Analysis type
    		 other [19]
    P-value
    		 = 0.10013 [20]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [19] - Mixed models analysis of variance (ANOVA) for longitudinal data on the differences between Day 1 and Day 21 values. The models included Phenotype as fixed effect and Patient as random effect. The overall Day effect across all subsets was assessed by performing the test of fixed effects on the phenotype. Number of subjects with evaluable biomarkers for the day 1 and day 21 in this analysis: 54
    [20] - P-value to be compared to alpha-level 0.0167 (adjusted to multiplicity with respect to the Holm procedure).

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The duration of the treatment phase per patient was approximately 18 months. Patients were followed for relapse for up to 2 years (after enrollment) or until death, whichever came first.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14
    Reporting groups
    Reporting group title
    Safety population
    Reporting group description
    		 -

    Serious adverse events
    		 Safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    14 / 84 (16.67%)
         number of deaths (all causes)
    29
         number of deaths resulting from adverse events
    0
    Nervous system disorders
    Quadriparesis
         subjects affected / exposed
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    6 / 84 (7.14%)
         occurrences causally related to treatment / all
    4 / 8
         deaths causally related to treatment / all
    0 / 0
    Chills
         subjects affected / exposed
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Enteritis
         subjects affected / exposed
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pharyngitis
         subjects affected / exposed
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumococcal sepsis
         subjects affected / exposed
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 84 (3.57%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 84 (2.38%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    82 / 84 (97.62%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    42 / 84 (50.00%)
         occurrences all number
    55
    Hypotension
         subjects affected / exposed
    9 / 84 (10.71%)
         occurrences all number
    15
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    6 / 84 (7.14%)
         occurrences all number
    8
    Nervous system disorders
    Headache
         subjects affected / exposed
    30 / 84 (35.71%)
         occurrences all number
    54
    Dizziness
         subjects affected / exposed
    8 / 84 (9.52%)
         occurrences all number
    11
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    26 / 84 (30.95%)
         occurrences all number
    28
    Injection site reaction
         subjects affected / exposed
    25 / 84 (29.76%)
         occurrences all number
    46
    Injection site nodule
         subjects affected / exposed
    18 / 84 (21.43%)
         occurrences all number
    28
    Injection site erythema
         subjects affected / exposed
    15 / 84 (17.86%)
         occurrences all number
    18
    Injection site pain
         subjects affected / exposed
    8 / 84 (9.52%)
         occurrences all number
    8
    Granuloma
         subjects affected / exposed
    8 / 84 (9.52%)
         occurrences all number
    8
    Pyrexia
         subjects affected / exposed
    39 / 84 (46.43%)
         occurrences all number
    57
    Asthenia
         subjects affected / exposed
    5 / 84 (5.95%)
         occurrences all number
    6
    Chest discomfort
         subjects affected / exposed
    5 / 84 (5.95%)
         occurrences all number
    5
    Chills
         subjects affected / exposed
    9 / 84 (10.71%)
         occurrences all number
    15
    Blood and lymphatic system disorders
    Eosinophilia
         subjects affected / exposed
    28 / 84 (33.33%)
         occurrences all number
    30
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    17 / 84 (20.24%)
         occurrences all number
    25
    Diarrhoea
         subjects affected / exposed
    8 / 84 (9.52%)
         occurrences all number
    12
    Abdominal pain upper
         subjects affected / exposed
    6 / 84 (7.14%)
         occurrences all number
    9
    Vomiting
         subjects affected / exposed
    5 / 84 (5.95%)
         occurrences all number
    6
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    13 / 84 (15.48%)
         occurrences all number
    20
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    12 / 84 (14.29%)
         occurrences all number
    13
    Night sweats
         subjects affected / exposed
    5 / 84 (5.95%)
         occurrences all number
    6
    Pruritus
         subjects affected / exposed
    6 / 84 (7.14%)
         occurrences all number
    7
    Psychiatric disorders
    Depression
         subjects affected / exposed
    5 / 84 (5.95%)
         occurrences all number
    5
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    10 / 84 (11.90%)
         occurrences all number
    10
    Myalgia
         subjects affected / exposed
    8 / 84 (9.52%)
         occurrences all number
    8
    Back pain
         subjects affected / exposed
    7 / 84 (8.33%)
         occurrences all number
    8
    Muscle spasms
         subjects affected / exposed
    5 / 84 (5.95%)
         occurrences all number
    5
    Musculoskeletal pain
         subjects affected / exposed
    6 / 84 (7.14%)
         occurrences all number
    6
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    25 / 84 (29.76%)
         occurrences all number
    48
    Bronchitis
         subjects affected / exposed
    5 / 84 (5.95%)
         occurrences all number
    5
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 84 (8.33%)
         occurrences all number
    9

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Dec 2009
    Amendment to Study Protocol (Version 2.0) 1) To allow for quantitative measure-ments of genetic markers of AML using molecular techniques for assessment of minimal residual disease (MRD) 2) To allow for patients enrollment with-out consolidation therapy
    01 Aug 2011
    Amendment to Study Protocol (Version 3.0) 1) Expand the allowable window of time between the end of consolidation therapy to enrollment from 8 to 12 weeks. 2) Define “evaluable patient” for the vari-ous study endpoints 3) Clarify timing aspects regarding the planned interim analysis. 4) Eliminate the inclusion criterion for partial thromboplastin time (PTT) within normal limits. 5) Drop the requirement to determine per-formance status by criteria other than Karnofsky score

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    20 Aug 2012
    organisational reasons after transfer of sponsorship: halt of recruitment, patients already included continued according to protocol
    -

    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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