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    Clinical Trial Results:
    The TEAM Study (Thiopurine EnhAnced Maintenance therapy) A Phase 1-2 Study of 6-Thioguanine in Combination with Methotrexate and 6-Mercaptopurine During Maintenance Therapy of Childhood, Adolescent, and Adult Lymphoblastic Non-Hodgkin’s Lymphoma and Acute Lymphoblastic Leukemia

    Summary
    EudraCT number
    		 2014-002248-42
    Trial protocol
    		 DK   FI  
    Global end of trial date
    12 Mar 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Mar 2021
    First version publication date
    21 Mar 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    0JMC-2014-6TG/6MP
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02912676
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bonkolab, Rigshospitalet
    Sponsor organisation address
    Blegdamsvej 9, Copenhagen Ø, Denmark, DK-21000
    Public contact
    Bonkolab, Rigshospitalet, Bonkolab, +45 35454652, Kjeld.Schmiegelow@regionh.dk
    Scientific contact
    Bonkolab, Rigshospitalet, Bonkolab, +45 35454652, Kjeld.Schmiegelow@regionh.dk
    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
    31 Aug 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Mar 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Mar 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To explore the feasibility of 6TG as a supplement to maintenance therapy of Acute Lymphoblastic Leukemia and Lymphoblastic Non-Hodgkin’s Lymphoma in order to improve the existing dose adjustment strategies. We hypothesize that MTX/6MP/6TG combination therapy will achieve a higher DNA-TGN level and enhance the effect of 6MP. We will describe toxicities, hematology and thiopurine metabolite levels during MTX/6MP/6TG combination therapy. This study will be the first to assess the applicability of 6TG in combination with standard MTX/6MP maintenance therapy.
    Protection of trial subjects
    During 6TG therapy the frequency of controls was increased from biweekly to every week in order to note any toxicities early. In case of myelo-/hepatotoxicity or infection the recommendations in the NOPHO therapy guidelines were followed with regards to the dosing of 6MP and MTX. In case of toxicity the administration of 6TG was either withheld or reduced depending on the toxicity.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Aug 2016
    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
    Denmark: 33
    Country: Number of subjects enrolled
    Finland: 1
    Worldwide total number of subjects
    34
    EEA total number of subjects
    34
    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)
    3
    Children (2-11 years)
    22
    Adolescents (12-17 years)
    4
    Adults (18-64 years)
    5
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Eligible patients were included, when they reached maintenance therapy phase II (maintenance-II). Patients were included during the entire course of maintenance-II but had to have at least 3 months of remaining therapy upon first visit. Inclusion was completed in December 2018, and the last TEAM patient finished therapy in March 2020.

    Pre-assignment
    Screening details
    		 Patients aged 1–45 years with non-high risk ALL (i.e. standard and intermediate risk) and treated according to the NOPHO ALL2008 protocol were eligible for the study. Eligible patients were included, when they reached maintenance therapy phase II. Patients had to have at least three months of remaining therapy upon first visit.

    Period 1
    Period 1 title
    Before TEAM
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Before TEAM
    Arm description
    		 TEAM-patients before TEAM. Time period before TEAM was defined as two months prior to initiation of 6TG treatment.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    6-mercaptopurine
    Investigational medicinal product code
    Other name
    Xaluprine, Puri-nethol
    Pharmaceutical forms
    Tablet, Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Dosing of daily oral 6MP is targeted to a WBC level of 1.5–3.0 x109/L. Therapy was discontinued 2.5 years from diagnosis.

    Investigational medicinal product name
    Methotrexat
    Investigational medicinal product code
    Other name
    MTX
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dosing of weekly oral MTX is targeted to a WBC level of 1.5–3.0 x109/L. Therapy was discontinued 2.5 years from diagnosis.

    Number of subjects in period 1
    		Before TEAM
    Started
    34
    Completed
    32
    Not completed
    2
         Consent withdrawn by subject
    2
    Period 2
    Period 2 title
    TEAM
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 TEAM
    Arm description
    		 TEAM patients. Time period before TEAM was defined as two months prior to initiation of 6TG treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    6-Thioguanine
    Investigational medicinal product code
    Other name
    6TG
    Pharmaceutical forms
    Oral solution, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Incremental 6TG doses were added to standard MTX/6MP maintenance therapy at a dose of 2.5 mg/m2/day and increased by 2.5 mg/m2/day biweekly until reaching maximum 6TG dose of 12.5 mg/m2/day. DNA-TG target level was DNA-TG above 500 fmol/µg DNA (approximate mean DNA-TG at end of MTX/6MP based maintenance therapy). TEAM patients followed the same WBC target of 1.5–3.0 x109/L. If DNA-TG and/or WBC targets were not reached at maximum 6TG doses (i.e. 12.5 mg/m2/day) 6MP and/or MTX dosages were adjusted.

    Investigational medicinal product name
    6-mercaptopurine
    Investigational medicinal product code
    Other name
    Xaluprine, Puri-nethol
    Pharmaceutical forms
    Oral suspension, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dosing of daily oral 6MP is targeted to a WBC level of 1.5–3.0 x109/L. Therapy was discontinued 2.5 years from diagnosis.

    Investigational medicinal product name
    Methotrexat
    Investigational medicinal product code
    Other name
    MTX
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dosing of weekly oral MTX is targeted to a WBC level of 1.5–3.0 x109/L. Therapy was discontinued 2.5 years from diagnosis.

    Number of subjects in period 2
    		TEAM
    Started
    32
    Completed
    30
    Not completed
    2
         Consent withdrawn by subject
    1
         On-therapy leukemic relaps
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Before TEAM
    Reporting group description
    		 -

    Reporting group values
    		 Before TEAM Total
    Number of subjects
    		 34 34
    Age categorical
    Units: Subjects
        Infants and toddlers (28 days-23 months)
    		 3 3
        Children (2-11 years)
    		 22 22
        Adolescents (12-17 years)
    		 4 4
        Adults (18-64 years)
    		 5 5
    Gender categorical
    Units: Subjects
        Female
    		 12 12
        Male
    		 22 22

    End points

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    End points reporting groups
    Reporting group title
    Before TEAM
    Reporting group description
    		 TEAM-patients before TEAM. Time period before TEAM was defined as two months prior to initiation of 6TG treatment.
    Reporting group title
    TEAM
    Reporting group description
    		 TEAM patients. Time period before TEAM was defined as two months prior to initiation of 6TG treatment.

    Primary: DNA-TG

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    End point title
    		 DNA-TG
    End point description
    End point type
    Primary
    End point timeframe
    DNA-TG was measured weekly or biweekly during the time period from initiation of 6TG until discontinuation of all therapy
    End point values
    		 Before TEAM TEAM
    Number of subjects analysed
    32
    32
    Units: fmol/µg
        arithmetic mean (full range (min-max))
    530 (157 to 1279)
    764 (273 to 1402)
    Statistical analysis title
    		 Mean difference
    Comparison groups
    Before TEAM v TEAM
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 < 0.0001
    Method
    		 Welch´s t-test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    251
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 160
         upper limit
    		 341
    Variability estimate
    Standard error of the mean
    Notes
    [1] - Paired t-test

    Secondary: Ery-TGN

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    End point title
    		 Ery-TGN
    End point description
    End point type
    Secondary
    End point timeframe
    Ery-TGN was measured weekly or biweekly during the time period from initiation of 6TG until discontinuation of all therapy
    End point values
    		 Before TEAM TEAM
    Number of subjects analysed
    32
    32
    Units: nmol/mmol hbg
        arithmetic mean (full range (min-max))
    240 (100 to 485)
    721 (339 to 1396)
    Statistical analysis title
    		 Mean difference
    Comparison groups
    Before TEAM v TEAM
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 < 0.0001
    Method
    		 Welch´s t-test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    470
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 349
         upper limit
    		 590
    Variability estimate
    Standard error of the mean
    Notes
    [2] - Paired t-test

    Secondary: 6MP dose

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    End point title
    		 6MP dose
    End point description
    End point type
    Secondary
    End point timeframe
    6MP dose was adjusted weekly or biweekly during the time period from initiation of 6TG until discontinuation of all therapy
    End point values
    		 Before TEAM TEAM
    Number of subjects analysed
    32
    32
    Units: mg/m2/day
        arithmetic mean (full range (min-max))
    53 (6 to 121)
    45 (7 to 79)
    Statistical analysis title
    		 Mean difference
    Comparison groups
    Before TEAM v TEAM
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.09
    Method
    		 Welch´s t-test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19
         upper limit
    		 1
    Variability estimate
    Standard error of the mean
    Notes
    [3] - Paired t-test

    Secondary: MTX dose

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    End point title
    		 MTX dose
    End point description
    End point type
    Secondary
    End point timeframe
    measured weekly during the time period from initiation of 6TG until discontinuation of all therapy
    End point values
    		 Before TEAM TEAM
    Number of subjects analysed
    32
    32
    Units: mg/m2/day
        arithmetic mean (full range (min-max))
    19 (4 to 41)
    19 (5 to 38)
    Statistical analysis title
    		 Mean difference
    Comparison groups
    Before TEAM v TEAM
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.99
    Method
    		 Welch´s t-test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.8
         upper limit
    		 2.7
    Variability estimate
    Standard error of the mean
    Notes
    [4] - Paired t-test

    Secondary: Ery-MeMP

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    End point title
    		 Ery-MeMP
    End point description
    End point type
    Secondary
    End point timeframe
    Measured weekly during the time period from initiation of 6TG until discontinuation of all therapy
    End point values
    		 Before TEAM TEAM
    Number of subjects analysed
    32
    32
    Units: nmol/mmol hgb
        arithmetic mean (full range (min-max))
    8462 (177 to 21520)
    5931 (142 to 14385)
    Statistical analysis title
    		 Mean difference
    Comparison groups
    Before TEAM v TEAM
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.06
    Method
    		 Welch´s t-test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.948
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.011
         upper limit
    		 115
    Variability estimate
    Standard error of the mean
    Notes
    [5] - Paired t-test

    Secondary: WBC

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    End point title
    		 WBC
    End point description
    End point type
    Secondary
    End point timeframe
    Measured weekly or biweekly during the time period from initiation of 6TG until discontinuation of all therapy
    End point values
    		 Before TEAM TEAM
    Number of subjects analysed
    32
    32
    Units: billion cells per litre
        arithmetic mean (full range (min-max))
    3.1 (1.9 to 5.7)
    3.2 (2.2 to 5.5)
    Statistical analysis title
    		 Mean difference
    Comparison groups
    Before TEAM v TEAM
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.78
    Method
    		 Welch´s t-test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.31
         upper limit
    		 0.41
    Variability estimate
    Standard error of the mean
    Notes
    [6] - Paired t-test

    Secondary: ANC

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    End point title
    		 ANC
    End point description
    End point type
    Secondary
    End point timeframe
    Measured weekly or biweekly during the time period from initiation of 6TG until discontinuation of all therapy
    End point values
    		 Before TEAM TEAM
    Number of subjects analysed
    32
    32
    Units: Billion cells per litre
        arithmetic mean (full range (min-max))
    1.8 (0.7 to 3.7)
    1.9 (1.0 to 3.7)
    Statistical analysis title
    		 Mean difference
    Comparison groups
    Before TEAM v TEAM
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 = 0.4
    Method
    		 Welch´s t-test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.19
         upper limit
    		 0.45
    Variability estimate
    Standard error of the mean
    Notes
    [7] - Paired-t-test

    Secondary: TBC

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    End point title
    		 TBC
    End point description
    End point type
    Secondary
    End point timeframe
    Measured weekly or biweekly during the time period from initiation of 6TG until discontinuation of all therapy
    End point values
    		 Before TEAM TEAM
    Number of subjects analysed
    32
    32
    Units: Billion cells per litre
        arithmetic mean (full range (min-max))
    247 (108 to 371)
    261 (56 to 383)
    Statistical analysis title
    		 Mean difference
    Comparison groups
    Before TEAM v TEAM
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    P-value
    		 = 0.02
    Method
    		 Welch´s t-test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.7
         upper limit
    		 35
    Variability estimate
    Standard error of the mean
    Notes
    [8] - Paired-t-test

    Secondary: Hgb

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    End point title
    		 Hgb
    End point description
    End point type
    Secondary
    End point timeframe
    Measured weekly or biweekly during the time period from initiation of 6TG until discontinuation of all therapy
    End point values
    		 Before TEAM TEAM
    Number of subjects analysed
    32
    32
    Units: mmol/L
        arithmetic mean (full range (min-max))
    7.6 (6.3 to 9.3)
    7.7 (6.3 to 9.0)
    Statistical analysis title
    		 Mean difference
    Comparison groups
    Before TEAM v TEAM
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 = 0.1
    Method
    		 Welch´s t-test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.04
         upper limit
    		 0.4
    Variability estimate
    Standard error of the mean
    Notes
    [9] - Paired t-test

    Secondary: ALAT

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    End point title
    		 ALAT
    End point description
    End point type
    Secondary
    End point timeframe
    Measured weekly or biweekly during the time period from initiation of 6TG until discontinuation of all therapy
    End point values
    		 Before TEAM TEAM
    Number of subjects analysed
    32
    32
    Units: U/L
        arithmetic mean (full range (min-max))
    139 (26 to 373)
    118 (20 to 265)
    Statistical analysis title
    		 Mean difference
    Comparison groups
    Before TEAM v TEAM
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    P-value
    		 = 0.23
    Method
    		 Welch´s t-test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -35
         upper limit
    		 9
    Variability estimate
    Standard error of the mean
    Notes
    [10] - Paired t-test

    Secondary: Coagulation factors II-VII-X

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    End point title
    		 Coagulation factors II-VII-X
    End point description
    End point type
    Secondary
    End point timeframe
    Measured weekly or biweekly during the time period from initiation of 6TG until discontinuation of all therapy
    End point values
    		 Before TEAM TEAM
    Number of subjects analysed
    32
    32
    Units: IU/L
        arithmetic mean (full range (min-max))
    0.7 (0.4 to 0.9)
    0.7 (0.5 to 0.9)
    Statistical analysis title
    		 Mean difference
    Comparison groups
    Before TEAM v TEAM
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 = 0.42
    Method
    		 Welch´s t-test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.04
         upper limit
    		 0.08
    Variability estimate
    Standard error of the mean
    Notes
    [11] - Paired t-test

    Secondary: INR

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    End point title
    		 INR
    End point description
    End point type
    Secondary
    End point timeframe
    Measured weekly during the time period from initiation of 6TG until discontinuation of all therapy
    End point values
    		 Before TEAM TEAM
    Number of subjects analysed
    32
    32
    Units: No unit for INR
        arithmetic mean (full range (min-max))
    1.2 (1.0 to 1.6)
    1.2 (1.1 to 1.3)
    Statistical analysis title
    		 Mean difference
    Comparison groups
    Before TEAM v TEAM
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    P-value
    		 = 0.06
    Method
    		 Welch´s t-test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.15
         upper limit
    		 0.002
    Variability estimate
    Standard error of the mean
    Notes
    [12] - Paired t-test

    Secondary: Bilirubin

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    End point title
    		 Bilirubin
    End point description
    End point type
    Secondary
    End point timeframe
    Measured weekly or biweekly during the time period from initiation of 6TG until discontinuation of all therapy
    End point values
    		 Before TEAM TEAM
    Number of subjects analysed
    32
    32
    Units: micromole(s)/litre
        arithmetic mean (full range (min-max))
    11 (4 to 32)
    12 (5 to 29)
    Statistical analysis title
    		 Mean difference
    Comparison groups
    Before TEAM v TEAM
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    P-value
    		 = 0.95
    Method
    		 Welch´s t-test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.8
         upper limit
    		 1.9
    Variability estimate
    Standard error of the mean
    Notes
    [13] - Paired t-test

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From inclusion untill 24 hours after the last 6TG dose. Follow-up for 5 years - off-study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    All subjects
    Reporting group description
    		 -

    Serious adverse events
    		 All subjects
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 34 (14.71%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Blood and lymphatic system disorders
    Leukemic relaps
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteonecrosis
         subjects affected / exposed
    4 / 34 (11.76%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 All subjects
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    33 / 34 (97.06%)
    Ear and labyrinth disorders
    Acute Otitis Media
         subjects affected / exposed
    5 / 34 (14.71%)
         occurrences all number
    5
    Eye disorders
    Herpes ophthalmic
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    20 / 34 (58.82%)
         occurrences all number
    20
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    10 / 34 (29.41%)
         occurrences all number
    10
    Molluscum contagiosum
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Infections and infestations
    Fever
         subjects affected / exposed
    20 / 34 (58.82%)
         occurrences all number
    20

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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