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    Clinical Trial Results:
    Treosulfan and 4 Gy TBI based conditioning with Rapamycin-based GvHD prophylaxis for allogeneic stem cell transplantation in patients with haematological malignancies

    Summary
    EudraCT number
    		 2011-001534-42
    Trial protocol
    		 IT  
    Global end of trial date
    16 Jun 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Jul 2021
    First version publication date
    08 Jul 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TrRaMM4Gy
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    IRCCS Ospedale San Raffaele
    Sponsor organisation address
    Via Olgettina, 60, Milano, Italy, 20132
    Public contact
    Dept. of Haematology/Transplant Unit, IRCCS Ospedale San Raffaele, 0039 0226434289, ciceri.clinicaltrials@hsr.it
    Scientific contact
    Dept. of Haematology/Transplant Unit, IRCCS Ospedale San Raffaele, 0039 0226434289, ciceri.clinicaltrials@hsr.it
    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
    16 May 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Jun 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Efficay: Evaluation of progression free survival (PFS) at 365 days; Evaluation of engraftment; Evaluation of Overall survival (OS) and relapse incidence (RI) Safety: Evaluation of of non-relapse mortality (NRM); Evaluation of cumulative incidence and severity of acute and chronic graft vs. host disease (GvHD).
    Protection of trial subjects
    NA
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jun 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 1 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 67
    Worldwide total number of subjects
    67
    EEA total number of subjects
    67
    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)
    64
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Adult patients with hematologic malignancies (leukemia, myeloma, lymphoma), candidates for allogeneic transplantation from related or unrelated mismatched donor

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

    Arms
    Arm title
    		 TrRaMM4Gy
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Treosulfan
    Investigational medicinal product code
    Other name
    Dihydroxybusulfan
    Pharmaceutical forms
    Powder and solvent for suspension for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    The investigational drug treosulfan is available as dry substance in vials of 1 g and 5 g and must be dissolved in 20 ml or 100 ml of water for injection respectively. A dosage of 14 g/m² will be administered intravenously within 120 minutes on 3 consecutive days (day -6, -5, -4). Alkalisation of the urine by infusion of sodium bicarbonate solution is not recommended because of the pH-dependent activation of treosulfan

    Investigational medicinal product name
    Rapamycin
    Investigational medicinal product code
    Other name
    Rapamune, Sirolimus
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The investigational drug rapamycin is available as 1 mg tablet. It will be administred as a starting dose of 4 mg die from the day before the start of the conditioning (day -7), with a target serum concentration of 8-15 ng/ml by HPLC. Levels will be monitored three times weekly during hospitalization and then as clinically indicated. Rapamycin will be continued till day +60 unless contraindicated because of toxicity or in case of disease progression or relapse. The drug will be tapered beginning at day +60 and eliminated by day +100, unless aGvHD occurred.

    Number of subjects in period 1
    		TrRaMM4Gy
    Started
    67
    Completed
    64
    Not completed
    3
         Physician decision
    2
         Screening failure
    1

    Baseline characteristics

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

    Reporting group values
    		 Overall study Total
    Number of subjects
    		 67 67
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 64 64
        From 65-84 years
    		 3 3
    Gender categorical
    Units: Subjects
        Female
    		 25 25
        Male
    		 42 42

    End points

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    End points reporting groups
    Reporting group title
    TrRaMM4Gy
    Reporting group description
    		 -

    Primary: Primary - progression-free survival

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    End point title
    		 Primary - progression-free survival [1]
    End point description
    Progression events are defined as relapse of disease in patients in CR at the moment of transplant and progressive desease in the others. Relapse is defined according to “WHO diagnostic criteria”. Progressive diseases is defined as increasing of 25% of the bulk of disease parameters (blast for leukemia, linfonodes diameters for lymphoma, monoclonal paraprotein in MM).
    End point type
    Primary
    End point timeframe
    Progression-free survival (PFS) within 1 year after transplantation is measured from time of start of HSCT (= day -7) to time of progression event.
    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: This study is a non-controlled phase II study. For efficacy comparison, mainly EBMT registry data or published papers will be used.
    End point values
    		 TrRaMM4Gy
    Number of subjects analysed
    64
    Units: percent
        median (standard deviation)
    43 ( 13 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Between day -6 and day +28 the patient will be asked and examined by the investigator for the occurrence of AEs. This time period is assumed to be appropriate for the evaluation of adverse events directly related to the conditioning regimen.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    3.0
    Reporting groups
    Reporting group title
    TrRaMM4Gy
    Reporting group description
    		 -

    Serious adverse events
    		 TrRaMM4Gy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 26 (0.00%)
         number of deaths (all causes)
    18
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 TrRaMM4Gy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    26 / 26 (100.00%)
    General disorders and administration site conditions
    Hospitalisation
    Additional description: • Hospitalisation for diagnostic or regular therapy as provided in the clinical trial plan. It is assumed that patients will be hospitalised at least from day -6 to day +28.
         subjects affected / exposed
    26 / 26 (100.00%)
         occurrences all number
    26

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Dec 2014
    Substantial Amendment n.1 of 05-DEC-2014 1) Closure of arms B and C due to problems in enrollment 2) Reduction of sample size 3) Elimination of the pharmacokinetic sub-study "Substudy to evaluate the pharmacokinetics of ATG Fresenius". 4) Review of inclusion / exclusion criteria

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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