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    Clinical Trial Results:
    Open-label, Multicenter Phase I/II Study: Salvage Therapy of Progressive and Relapsed Aggressive Non-Hodgkin-Lymphoma by Combination of Lenalidomide (Revlimid®) with Rituximab, Dexamethason, High-dose ARA-C and Cisplatinum

    Summary
    EudraCT number
    		 2009-010824-25
    Trial protocol
    		 DE  
    Global end of trial date
    08 Apr 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Dec 2022
    First version publication date
    15 Dec 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    34 DSHNHL 2008-R6
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02983097
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GMIHO Gesellschaft für Medizinische Innovation – Hämatologie und Onkologie mbH
    Sponsor organisation address
    Almstadtstraße 7, Berlin, Germany, 10119
    Public contact
    Medical Consulting, GMIHO Gesellschaft für Medizinische Innovation – Hämatologie und Onkologie mbH, 0049 35125933100, info@gmiho.de
    Scientific contact
    Medical Consulting, GMIHO Gesellschaft für Medizinische Innovation – Hämatologie und Onkologie mbH, 0049 35125933100, info@gmiho.de
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    31 Dec 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Dec 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Apr 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To provide efficient remission induction in second line treatment of aggressive NHL giving a higher fraction of patients the chance to achieve remission and subsequently to receive salvage therapy (autologous or allogeneic SCT)
    Protection of trial subjects
    The conduct of this study was in compliance with the Good Clinical Praactice Guidelines and under the guiding principles detailed in the Declaration of Helsinki. The study was also carried out in keeping with applicable local law(s) and regulation(s). Patients were closely evaluated for toxicity. In patients with significant neurotoxicity from first line treatment or other neurologic impairment, vincristine should be omitted and may be replaced by a single dose cyclophosphamide 100 mg/m^2. The purpose of the prephase treatment was to prevent tumour lysis syndrome in patients with extensive tumors, to improve the performance status of the patient and to reduce the toxicity of the first chemotherapy cycle.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Nov 2010
    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
    Germany: 35
    Worldwide total number of subjects
    35
    EEA total number of subjects
    35
    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)
    29
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 From 11th November 2010 through 30th October 2013 a total of 35 patients were enrolled in phase I of the study at 6 of 13 participating centers in Germany. Thereof, 34 patients were dosed in 5 cohorts.

    Pre-assignment
    Screening details
    		 Six cohorts of minimum 6 patients each to be treated at maximal 5 dose levels (0-4) were planned. In cohorts 3 to 6, additional patients were to be recruited to ensure at least 18 eligible therapy cycles.

    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
    		 Treatment period
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Revlimid®
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    At dose level 0 three cycles of R2-DHAP were to be given, the first cycle was R- DHAP alone followed by cycle 2 and 3 supplemented with lenalidomide 5 mg/d at days 1 to 7. Mobilization of stem cells was done after cycle one or two of R²-DHAP. Therapy was repeated every 21 days. At dose levels 1 to 2 lenalidomide was given at days 1 to 7 at a dose of 5 mg/d or 15 mg/d, respectively. At dose level 4, 15 mg of lenalidomide was to be given from day -6 to day 7. At dose level 5 20 mg of lenalidomide was to be given from day -6 to day 7.

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab plus DHAP was given as usual: Rituximab 375 mg/m^2 on day 1. Therapy was repeated every 21 days.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cisplatinum 100 mg/m^2 on day 2. Therapy was repeated every 21 days.

    Investigational medicinal product name
    Cytarabine
    Investigational medicinal product code
    Other name
    ARA-C
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    ARA-C 2 x 2000 mg/m^2 on day 3. Therapy was repeated every 21 days.

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Cytarabine
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dexamethasone 40 mg on days 2 to 5. Therapy was repeated every 21 days.

    Number of subjects in period 1
    		Treatment period
    Started
    35
    Completed
    34
    Not completed
    1
         Protocol deviation
    1

    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
    		 35 35
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 29 29
        From 65-84 years
    		 6 6
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 13 13
        Male
    		 22 22

    End points

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    End points reporting groups
    Reporting group title
    Treatment period
    Reporting group description
    		 -

    Primary: Maximal tolerable dose

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    End point title
    		 Maximal tolerable dose [1]
    End point description
    The following algorithm was used to establish the MTD: At least six patients were planned to be treated in each of 6 cohorts. a. If no serious toxicity (see below) occurred, the next cohort was treated at the next higher dose level. b. If one case of serious toxicity occurred, the next cohort of patients was treated at the same dose level. c. If two or more cases of serious toxicity occurred, the next cohort was treated at the next lower dose level; if this would have occurred at dose level 0, the study was to be terminated.
    End point type
    Primary
    End point timeframe
    18 cycles at every dose level
    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: The phase I part of the study was conducted to determine the dose of lenalidomide given together with R-DHAP. Data from dose escalation of the study showed evidence for the feasibility and safety of adding lenalidomide to a combination of standard R-DHAP. Dose level 2 (15 mg lenalidomide on days 1 to 7) was assessed as the maximum tolerable dose of lenalidomide given in combination with standard R-DHAP.
    End point values
    		 Treatment period
    Number of subjects analysed
    34
    Units: Number of patients
        Cohort 1
    6
        Cohort 2
    6
        Cohort 3
    7
        Cohort 4
    8
        Cohort 5
    7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    from day 1 to day 85
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.1
    Frequency threshold for reporting non-serious adverse events: 0%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: In total, 51 AEs were documented for 22 out of 34 patients included in the safety analysis set (64.7%). Most frequently reported AEs were hypokalemia (5 events), leukopenia (3 events), thrombocytopenia (3 events). Among the AEs, 14 were serious (SAEs) and occurred in 10 patients. For 3 of them a relationship to treatment with lenalidomide was assessed as at least possible and unexpected (SUSAR) including the dose-limiting toxicity of one patient.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 May 2012
    Version 9.0 dated 23 Jul 2012 (Amendment 1) Changes: - Revise of exclusion criteria bone marrow involvement > 25%. CNS involvement has become exclusion criteria instead. - Disruption of treatment due to lymphoma progress was excluded as a toxicity event - With regards to published data of other trials biometry of the trial has been revised in due consideration of interpretability. The mode of analysis has been changed. Analysis will be performed on a per-therapy-cycle instead of a per-patient basis. At least 18 evaluable cycles have to be available for analysis to complete a patient cohort; therefore at least 6 patients have to be recruited in each cohort. If patients drop out of the study prematurely, or if any therapy cycle is deemed not evaluable, additional patients will be recruited as to fulfill the criterion of having a minimum of 18 evaluable therapy cycles.

    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.
    The study was terminated by 8 April 2015 after successfully completing and analyzing part I of the study due to emerging, more promising treatment options apart from R-DHAP.
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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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