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    Clinical Trial Results:
    Obinutuzumab containing conditioning regimen for CLL patients and patients with Richter`s transformation requiring an allogeneic stem cell transplantation

    Summary
    EudraCT number
    2015-000568-32
    Trial protocol
    DE  
    Global end of trial date
    30 Sep 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    07 Oct 2020
    First version publication date
    07 Oct 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CLLTX1
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03153514
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Paul-Ehrlich-Institut: 2918/01
    Sponsors
    Sponsor organisation name
    German CLL Study Group, University Hospital Cologne
    Sponsor organisation address
    Gleuelerstr. 176-178, Cologne, Germany, 50935
    Public contact
    CLLTX1 , German CLL Study Group, 0049 0221478 88220, cllstudie@uk-koeln.de
    Scientific contact
    CLLTX1 , German CLL Study Group, 0049 0221478 88220, cllstudie@uk-koeln.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
    07 Aug 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Sep 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to evaluate the feasibility, efficacy and safety of an Obinutuzumab containing conditioning regimen for CLL patients and patients with Richter`s transformation requiring an allogeneic stem cell transplantation.
    Protection of trial subjects
    A premedication with oral acetaminophen/paracetamol (1.000mg) and antihistamines including a H1- (e.g. dimentindene 4mg i.v.) and a H2-antagonist (e.g. ranitidine 50mg i.v.) has to be administered (unless contraindicated) approximately 30 minutes prior to the start of the first infusion of obinutuzumab to avoid infusion related reactions (IRRs). Additionally, prednisolone or prednisone (100mg given i.v. at least one hour before the obinutuzumab infusion) has to be administered. An equivalent dose of dexamethasone (16mg) or methylprednisolone (80mg) is permitted, but hydrocortisone should not be used. In Addition detailed guidance on the Management on graft versus host disease were provided in the study protocol
    Background therapy
    The number of patients who received allogeneic stem cell transplantion has substantially decreased over time; mostly due to the availability of less toxic and novel agents with proven efficacy even after failure to chemoimmunotherapy or to chemofree first-line regimen. However, allogeneic stem cell transplantation continue to have a role for patients who fail, are intolerant, or do not have access to these novel agents Instead of Obinutuzumab, which was explored in this trial to collect data on the influence of obinutuzumab on the development of graft versus host disease, Antithymocyte globulin is used as graft versus host disease (GvHD) prophylaxis in most unrelated donor transplants. Another alternative is the use of Alemtuzumab in addition to calcineurin inhibitors and mycophenolate mofetil. The use of these T-cell depleting agents are associated with an increase rate of relapse. The protective role of Rituximab in the peri-transplant conditioning as well as its role in the treatment of GvHD highlights the potential for a B-cell depleting agent in the peri-transplant setting. Allo-SCT is not only a therapeutic option for patients with poor risk CLL and RT but also offers the possibility of potential cure. As myeloblative conditioning regimens are associated with a high transplant related morbidity and mortality (up to 40%) 8, reduced intensity conditioning regimens are currently preferred for these patients. Graft versus leukaemia (GvL) effect has been demonstrated post allo-SCT by many factors such as reduced relapse in the presence of chronic Graft versus host disease (GvHD), ability to eradicate minimal residual disease with the taper of immunsuppression or donor lymphocyte infusions (DLI) and increased relapse following T-cell depletion Encouragingly a recent follow-up by Dreger et al. on the CLL3X trial highlighted that the long term (6 years post SCT) survival on 90 allografted patients as 58% with an event free survival (EFS) of 38%. They also conclu
    Evidence for comparator
    n/a
    Actual start date of recruitment
    06 Apr 2017
    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
    Germany: 3
    Worldwide total number of subjects
    3
    EEA total number of subjects
    3
    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)
    2
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    3 patients were enrolled between 11/2017 and 04/2018.

    Pre-assignment
    Screening details
    4 pre-treated patients with high risk CLL or Richters transformation were registered for central screening. The central screening was performed by the GCLLSG study office in Cologne Germany and included immunophenotyping, transplant requirement, suitable stem cell donor, comorbidity and renal function. 1 patient was not eligible for participation.

    Pre-assignment period milestones
    Number of subjects started
    3
    Number of subjects completed
    3

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

    Arms
    Arm title
    Obinutuzumab
    Arm description
    Patients received cycle 1 at the time of the stem cell transplantation. Cycle 2 was administered in case of active disease and/or MRD positivity after cycle 1. Patients were staged at day +60 post-transplant and MRD was determined per central laboratory assessment. Patients found to have active disease or identified as MRD positive, defined as those who have a MRD ≥ 10-4, were offered 4 additional doses of obinutuzumab along with immunetaper ± DLI. Patients who did not receive cycle 2 because staging at day +60 post-transplant showed no active disease and/or MRD positivity received cycle 2 after staging day +90/ 180/ 270 post-transplant if found to have active disease/MRD positivity at this time point.
    Arm type
    single-arm

    Investigational medicinal product name
    Obinutuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for concentrate for solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Obinutuzumab will be administered as depicted in Table 2 of the protocol. Regarding the administration of a premedication before the start of obinutuzumab, for adjustments in case of an IRR as well as further guidelines regarding obinutuzumab administration please refer to chapter 5.2.2 Premedication before obinutuzumab therapy and chapter 5.2.3 Infusion-related reactions and anaphylaxis. For obinutuzumab storage and preparation please refer to chaper 8.5 Drug storage and preparation. If the first infusion of obinutuzumab was well tolerated (defined by an absence of IRRs during a final infusion rate of ≥ 100mg/h), subsequent infusions will be administered at an initial rate of 100mg/h. The infusion rate is increased by 100mg/h increments at 30 minute intervals, as tolerated, to a maximum rate of 400mg/h. At the investigator’s discretion the subsequent obinutuzumab infusions may be split and administered over two days with infusion rates as described in the protocol

    Number of subjects in period 1
    Obinutuzumab
    Started
    3
    Completed
    3

    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
    3 3
    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)
    2 2
        From 65-84 years
    1 1
        85 years and over
    0 0
        18-64
    0 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    57 (56.5 to 61) -
    Gender categorical
    Units: Subjects
        Female
    0 0
        Male
    3 3

    End points

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    End points reporting groups
    Reporting group title
    Obinutuzumab
    Reporting group description
    Patients received cycle 1 at the time of the stem cell transplantation. Cycle 2 was administered in case of active disease and/or MRD positivity after cycle 1. Patients were staged at day +60 post-transplant and MRD was determined per central laboratory assessment. Patients found to have active disease or identified as MRD positive, defined as those who have a MRD ≥ 10-4, were offered 4 additional doses of obinutuzumab along with immunetaper ± DLI. Patients who did not receive cycle 2 because staging at day +60 post-transplant showed no active disease and/or MRD positivity received cycle 2 after staging day +90/ 180/ 270 post-transplant if found to have active disease/MRD positivity at this time point.

    Primary: Rate of patients free from disease progression (PD-free rate) at 12 months post-transplant

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    End point title
    Rate of patients free from disease progression (PD-free rate) at 12 months post-transplant [1]
    End point description
    Patients will be followed for Progression. Patients free of disease Progression will be counted .
    End point type
    Primary
    End point timeframe
    12 months post transplant
    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: Because of the low number of patients no statistical analyses were done.
    End point values
    Obinutuzumab
    Number of subjects analysed
    3
    Units: numbers
    3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Timeframe for AE
    Adverse event reporting additional description
    AE additional description
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    CLLTX1
    Reporting group description
    -

    Serious adverse events
    CLLTX1
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Infusion related reaction
    Additional description: Infusion related reaction
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Cytomegalovirus gastritis
    Additional description: Cytomegalovirus gastritis
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cytomegalovirus infection
    Additional description: Cytomegalovirus infection
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Escherichia sepsis
    Additional description: Escherichia sepsis
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Herpes simplex
    Additional description: Herpes simplex
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nasopharyngitis
    Additional description: Nasopharyngitis
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Parainfluenzae virus infection
    Additional description: Parainfluenzae virus infection
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
    Additional description: Pneumonia
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia cytomegaloviral
    Additional description: Pneumonia cytomegaloviral
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia respiratory syncytial viral
    Additional description: Pneumonia respiratory syncytial viral
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    CLLTX1
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    Investigations
    Blood creatinine increased
    Additional description: Blood creatinine increased
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Blood folate decreased
    Additional description: Blood folate decreased
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Hepatic enzyme increased
    Additional description: Hepatic enzyme increased
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Renal function test abnormal
    Additional description: Renal function test abnormal
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Vascular disorders
    Hypertensive crisis
    Additional description: Hypertensive crisis
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Nervous system disorders
    Headache
    Additional description: Headache
         subjects affected / exposed
    2 / 3 (66.67%)
         occurrences all number
    2
    Taste disorder
    Additional description: Taste disorder
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Tremor
    Additional description: Tremor
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anaemia
    Additional description: Anaemia
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Haemolysis
    Additional description: Haemolysis
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Leukopenia
    Additional description: Leukopenia
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Neutropenia
    Additional description: Neutropenia
         subjects affected / exposed
    2 / 3 (66.67%)
         occurrences all number
    2
    Thrombocytopenia
    Additional description: Thrombocytopenia
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    General disorders and administration site conditions
    Oedema
    Additional description: Oedema
         subjects affected / exposed
    2 / 3 (66.67%)
         occurrences all number
    2
    Pyrexia
    Additional description: Pyrexia
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Immune system disorders
    Acute graft versus host disease in intestine
    Additional description: Acute graft versus host disease in intestine
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Autoimmune disorder
    Additional description: Autoimmune disorder
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Graft versus host disease
    Additional description: Graft versus host disease
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Graft versus host disease in eye
    Additional description: Graft versus host disease in eye
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Graft versus host disease in gastrointestinal tract
    Additional description: Graft versus host disease in gastrointestinal tract
         subjects affected / exposed
    2 / 3 (66.67%)
         occurrences all number
    5
    Graft versus host disease in liver
    Additional description: Graft versus host disease in liver
         subjects affected / exposed
    3 / 3 (100.00%)
         occurrences all number
    6
    Graft versus host disease in lung
    Additional description: Graft versus host disease in lung
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Graft versus host disease in skin
    Additional description: Graft versus host disease in skin
         subjects affected / exposed
    3 / 3 (100.00%)
         occurrences all number
    6
    Gastrointestinal disorders
    Abdominal pain upper
    Additional description: Abdominal pain upper
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Diarrhoea
    Additional description: Diarrhoea
         subjects affected / exposed
    2 / 3 (66.67%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
    Additional description: Cough
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Obstructive airways disorder
    Additional description: Obstructive airways disorder
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Oropharyngeal pain
    Additional description: Oropharyngeal pain
         subjects affected / exposed
    2 / 3 (66.67%)
         occurrences all number
    2
    Renal and urinary disorders
    Urinary retention
    Additional description: Urinary retention
         subjects affected / exposed
    2 / 3 (66.67%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Pain in extremity
    Additional description: Pain in extremity
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Infections and infestations
    Clostridium difficile infection
    Additional description: Clostridium difficile infection
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Cytomegalovirus infection
    Additional description: Cytomegalovirus infection
         subjects affected / exposed
    2 / 3 (66.67%)
         occurrences all number
    2
    Gastroenteritis norovirus
    Additional description: Gastroenteritis norovirus
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Infection
    Additional description: Infection
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Nail bed infection
    Additional description: Nail bed infection
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Neutropenic infection
    Additional description: Neutropenic infection
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Rhinovirus infection
    Additional description: Rhinovirus infection
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Sinusitis
    Additional description: Sinusitis
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Upper respiratory tract infection
    Additional description: Upper respiratory tract infection
         subjects affected / exposed
    2 / 3 (66.67%)
         occurrences all number
    2
    Metabolism and nutrition disorders
    Folate deficiency
    Additional description: Folate deficiency
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Hyperkalaemia
    Additional description: Hyperkalaemia
         subjects affected / exposed
    2 / 3 (66.67%)
         occurrences all number
    2
    Vitamin d deficiency
    Additional description: Vitamin d deficiency
         subjects affected / exposed
    2 / 3 (66.67%)
         occurrences all number
    2

    More information

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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.
    In this study, the recruitment was stopped after 3 of the 40 planned patients have been enrolled. As a consequence of the low number of of patients enrolled, it was decided that any statistical analysis cannot be performed.
    For support, Contact us.
    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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