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    Clinical Trial Results:
    A Phase I/II, Multi-centre Trial to Assess the Safety, Efficacy, and Pharmacokinetics of Eltrombopag, Administered to Thrombocytopenic Chronic Lymphocytic Leukemia Patients Prior to Alkylating Agents and/or Purine Analogue-based Therapy

    Summary
    EudraCT number
    		 2010-023022-20
    Trial protocol
    		 DE   AT  
    Global end of trial date
    11 Nov 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Dec 2021
    First version publication date
    13 Dec 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CLL2S
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01397149
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Universitätsklinikum Ulm (Ulm University Hospital, Ulm, Germany)
    Sponsor organisation address
    Albert-Einstein-Allee 23, Ulm, Germany, 89081
    Public contact
    Study Chairman, Prof. Dr. S. Stilgenbauer Universitätsklinikum Ulm, Klinik für Innere Medizin III Albert-Einstein, 49 73150045501, stephan.stilgenbauer@uniklinik-ulm.de
    Scientific contact
    Studienzentrale der Deutschen CLL Studiengruppe Klinik I für Innere Medizin, Uniklinik Köln, Prof. Dr. S. Stilgenbauer Universitätsklinikum Ulm, Klinik für Innere Medizin III Albert-Einstein, 49 22147888220, anna-maria.fink@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
    17 Nov 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Nov 2013
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Phase I: The primary objective is to find the safe and potentially efficacious dose of eltrombopag to achieve a durable increase in platelet count. Phase II: The primary objective of phase II is to confirm the effect of the selected dose from Phase I in correcting thrombocytopenia to enable patients to receive alkylating agents and/or purine analogue-based therapy.
    Protection of trial subjects
    Eltrombopag may increase the risk of thrombotic/thromboembolic events. Caution should be used when administering eltrombopag to patients with known risk factors for thromboembolism (e.g., Factor V Leiden, ATIII deficiency, antiphospholipid syndrome and portal hypertension). Eltrombopag administration may cause hepatotoxicity. Serum ALT, AST, and bilirubin should be measured prior to initiation of eltrombopag, and every 2 to 4 weeks thereafter during treatment. If bilirubin is elevated, perform fractionation. Evaluate abnormal serum liver tests with repeat testing within 3 to 5 days. If the abnormalities are confirmed, monitor serum liver tests weekly until the abnormality(ies) resolve, stabilize, or return to baseline levels. Permanently discontinue eltrombopag if ALT levels increase to ≥3X the upper limit of normal (ULN). Exercise caution when administering eltrombopag to patients with hepatic disease. Eltrombopag is a thrombopoietin (TPO) receptor agonist and TPO-receptor agonists may increase the risk for the development or progression of reticulin fiber deposition within the bone marrow. Prior to initiation of eltrombopag, examine the peripheral blood smear closely to establish a baseline level of cellular morphologic abnormalities. Following identification of a stable dose of eltrombopag, examine peripheral blood smears and CBCs monthly for new or worsening morphological abnormalities (e.g., teardrop and nucleated red blood cells, immature white blood cells) or cytopenia(s). If the patient develops new or worsening morphological abnormalities or cytopenia(s), discontinue treatment with eltrombopag and consider a bone marrow biopsy, including staining for fibrosis. Cataracts were observed in toxicology studies of eltrombopag in rodents. Routine monitoring of patients for cataracts is recommended. Patients treated with eltrombopag who experience visual difficulties should have an appropriate ophthalmologic evaluation.
    Background therapy
    		 not applicable.
    Evidence for comparator
    		 not applicable.
    Actual start date of recruitment
    01 Jun 2011
    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: 4
    Worldwide total number of subjects
    4
    EEA total number of subjects
    4
    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)
    3
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment was open from August 2011. The first patient was included in May 2012. The study was open for recruitment for approximately 2 years and 2 months. During this time, only 4 patients were recruited for the phase I escalation part of the trial at 3 sites, which equals a recruitment rate of about one patient per 6 months.

    Pre-assignment
    Screening details
    		 Subjects eligible for enrolment in the study must meet all of the following criteria: 1. Confirmed diagnosis of CLL 2. Platelet count <50 000/μl at time of screening (measured and confirmed twice) During the recruitment phase of the study 4 patients were screened and 4 patients were enrolled.

    Period 1
    Period 1 title
    Treatment phase (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was an Phase I, Multicenter, open-label dose escalation study.

    Arms
    Arm title
    		 Eltrombopag
    Arm description
    		 Phase I is a single arm dose-escalation trial part, designed to test 4 doses of eltrombopag (75mg, 150mg, 225mg, 300mg) to find the appropriate, feasible dose of eltrombopag to achieve a durable increase in platelet count (from <50,000/μl to ≥100,000/μl). Eltrombopag will be administered once daily to thrombocytopenic patients with platelet counts < 50,000/μl. Each subject will be dosed at the respective dose level for 2 weeks (unless platelet counts rise to > 400,000/μl). There is no intra-individual dose escalation. At first, three subjects will be enrolled at each dose level. If no unacceptable dose-limiting toxicity (DLT) is observed, escalation to the next higher dose step is performed. In case of observation of non-acceptable toxicity in 2 cases or more, the next lower dose is declared as MTD (or the trial terminated completely if this happens on the first dose level). In case of dose-limiting toxicity in one out of 3 patients, another 3 patients are treated on this level.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Eltrombopag
    Investigational medicinal product code
    B02BX05
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    In phase I, four doses of eltrombopag (75mg, 150mg, 225mg, 300mg) will be tested. Eltrombopag will be administered orally once daily. Each patient will be dosed at each dose level for 2 weeks. It is recommended that investigation product is taken about the same time on each day. Separate subjects must be enrolled for each dose level. No subject is allowed to receive investigational product at more than one dose level. The number of patients and the escalation strategy is described in the study protocol.

    Number of subjects in period 1
    		Eltrombopag
    Started
    4
    Completed
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment phase
    Reporting group description
    		 -

    Reporting group values
    		 Treatment phase Total
    Number of subjects
    		 4 4
    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)
    		 3 3
        From 65-84 years
    		 1 1
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 0 0
        Male
    		 4 4
    Platelet count at baseline
    Major and important Inclusion criterion: Platelet count <50 000/µl at time of screening (measured and confirmed twice).
    Units: Subjects
        platelet count below 50G/L at baseline
    		 4 4
    Binet Stage at diagnosis
    Binet staging system Binet stage A: The patient has fewer than 3 areas of lymph-node involvement but no anemia or thombocytopenia. Binet stage B: The patient has 3 or more areas of lymph-node involvement but no anemia or thombocytopenia. Binet stage C: Presence of anemia and/or thrombocytopenia.
    Units: Subjects
        Binet Stage A
    		 3 3
        Binet Stage C
    		 1 1
    Binet Stage at Baseline
    Binet staging system Binet stage A: The patient has fewer than 3 areas of lymph-node involvement but no anemia or thombocytopenia. Binet stage B: The patient has 3 or more areas of lymph-node involvement but no anemia or thombocytopenia. Binet stage C: Presence of anemia and/or thrombocytopenia.
    Units: Subjects
        Binet Stage C
    		 4 4
    ß-Symptoms at baseline
    Disease-related symptoms (previously defined as ß-symptoms) as defined by any of the following: Unintentional weight loss ≥10% within the previous 6 months. Significant fatigue (ie, ECOG PS 2 or worse; cannot work or unable to perform usual activities). Fevers ≥100.5°F or 38.0 °C for 2 or more weeks without evidence of infection. Night sweats for ≥1 month without evidence of infection.
    Units: Subjects
        ß-symptoms present
    		 2 2
        ß-symptoms absent
    		 2 2
    Eastern Cooperative Oncology Group Performance Status
    GRADE ECOG PERFORMANCE STATUS 0 Fully active, able to carry on all pre-disease performance without restriction 1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work 2 Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 50% of waking hours 3 Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours 4 Completely disabled; cannot carry on any selfcare; totally confined to bed or chair 5 Dead
    Units: Subjects
        ECOG 0
    		 2 2
        ECOG 1
    		 1 1
        ECOG 2
    		 1 1
    Subject analysis sets

    Subject analysis set title
    Final analysis
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    A final analysis was not conducted, because only 4 patients were enrolled and recruitment was prematurely closed.

    Subject analysis sets values
    		 Final analysis
    Number of subjects
    4
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    3
        From 65-84 years
    1
        85 years and over
    0
    Age continuous
    Units:
        
    ( )
    Gender categorical
    Units: Subjects
        Female
        Male
    Platelet count at baseline
    Major and important Inclusion criterion: Platelet count <50 000/µl at time of screening (measured and confirmed twice).
    Units: Subjects
        platelet count below 50G/L at baseline
    4
    Binet Stage at diagnosis
    Binet staging system Binet stage A: The patient has fewer than 3 areas of lymph-node involvement but no anemia or thombocytopenia. Binet stage B: The patient has 3 or more areas of lymph-node involvement but no anemia or thombocytopenia. Binet stage C: Presence of anemia and/or thrombocytopenia.
    Units: Subjects
        Binet Stage A
    3
        Binet Stage C
    1
    Binet Stage at Baseline
    Binet staging system Binet stage A: The patient has fewer than 3 areas of lymph-node involvement but no anemia or thombocytopenia. Binet stage B: The patient has 3 or more areas of lymph-node involvement but no anemia or thombocytopenia. Binet stage C: Presence of anemia and/or thrombocytopenia.
    Units: Subjects
        Binet Stage C
    4
    ß-Symptoms at baseline
    Disease-related symptoms (previously defined as ß-symptoms) as defined by any of the following: Unintentional weight loss ≥10% within the previous 6 months. Significant fatigue (ie, ECOG PS 2 or worse; cannot work or unable to perform usual activities). Fevers ≥100.5°F or 38.0 °C for 2 or more weeks without evidence of infection. Night sweats for ≥1 month without evidence of infection.
    Units: Subjects
        ß-symptoms present
    2
        ß-symptoms absent
    2
    Eastern Cooperative Oncology Group Performance Status
    GRADE ECOG PERFORMANCE STATUS 0 Fully active, able to carry on all pre-disease performance without restriction 1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work 2 Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 50% of waking hours 3 Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours 4 Completely disabled; cannot carry on any selfcare; totally confined to bed or chair 5 Dead
    Units: Subjects
        ECOG 0
    2
        ECOG 1
    1
        ECOG 2
    1

    End points

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    End points reporting groups
    Reporting group title
    Eltrombopag
    Reporting group description
    		 Phase I is a single arm dose-escalation trial part, designed to test 4 doses of eltrombopag (75mg, 150mg, 225mg, 300mg) to find the appropriate, feasible dose of eltrombopag to achieve a durable increase in platelet count (from <50,000/μl to ≥100,000/μl). Eltrombopag will be administered once daily to thrombocytopenic patients with platelet counts < 50,000/μl. Each subject will be dosed at the respective dose level for 2 weeks (unless platelet counts rise to > 400,000/μl). There is no intra-individual dose escalation. At first, three subjects will be enrolled at each dose level. If no unacceptable dose-limiting toxicity (DLT) is observed, escalation to the next higher dose step is performed. In case of observation of non-acceptable toxicity in 2 cases or more, the next lower dose is declared as MTD (or the trial terminated completely if this happens on the first dose level). In case of dose-limiting toxicity in one out of 3 patients, another 3 patients are treated on this level.

    Subject analysis set title
    Final analysis
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    A final analysis was not conducted, because only 4 patients were enrolled and recruitment was prematurely closed.

    Primary: Dose limiting toxicity

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    End point title
    		 Dose limiting toxicity [1]
    End point description
    During the course of the trial, the first three patients were treated on the first dose level, and received treatment with 75 mg eltrombopag for 14 days, before start of their planned therapy for CLL. No dose limiting toxicity was observed in these patients, and dose level 100 mg was therefore opened on 19.03.2013 One additional patient received treatment on the second dose level, also with no DLT observed, when the study was prematurely stopped due to low recruitment rate. Please refer to part 13.1 of the report for a detailed description of patients therapy course
    End point type
    Primary
    End point timeframe
    August 2011-November 2013
    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 statistical analysis was not done, due to the early termination of the trial with only four patients. The study had to be closed early due to insufficient recruitment. Only four patients were included in the Phase I part in two dose levels. Phase II of this trial was not started. Thus, it is not possible to draw any conclusions on the efficacy or safety of this supportive treatment.
    End point values
    		 Final analysis
    Number of subjects analysed
    4
    Units: number
        Patients with DLT
    0
        Patients without DLT
    4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    August 2011-November 2013
    Adverse event reporting additional description
    A statistical analysis of SAE and AE has not been done, because only 4 pateinst have been enrolled.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 not done
    Dictionary version
    n.a.
    Reporting groups
    Reporting group title
    Eltrombopag
    Reporting group description
    		 Phase I is a single arm dose-escalation trial part, designed to test 4 doses of eltrombopag (75mg, 150mg, 225mg, 300mg) to find the appropriate, feasible dose of eltrombopag to achieve a durable increase in platelet count (from <50,000/μl to ≥100,000/μl). Eltrombopag will be administered once daily to thrombocytopenic patients with platelet counts < 50,000/μl. Each subject will be dosed at the respective dose level for 2 weeks (unless platelet counts rise to > 400,000/μl). There is no intra-individual dose escalation. At first, three subjects will be enrolled at each dose level. If no unacceptable dose-limiting toxicity (DLT) is observed, escalation to the next higher dose step is performed. In case of observation of non-acceptable toxicity in 2 cases or more, the next lower dose is declared as MTD (or the trial terminated completely if this happens on the first dose level). In case of dose-limiting toxicity in one out of 3 patients, another 3 patients are treated on this level.

    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: The trial was terminated early. An analysis regarding the safety of this trial was not conducted.
    Serious adverse events
    		 Eltrombopag
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 4 (50.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Hypertensive crisis
    Additional description: Onset date was 01.01.2013, outcome recovered.
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Autoimmune haemolytic anaemia
    Additional description: Onset date 22.10.2013, outcome ongoing at time point of study closure
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Eltrombopag
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 4 (0.00%)

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Feb 2013
    The initial study protocol was amended once during the course of the trial. The amendment consisted mainly in a change of inclusion/exclusion criteria and allowed the investigators to enrol also patients with more than three previous therapy lines for the treatment of CLL. Inclusion criteria after change according to protocol amendment: 3. Patient is planned to receive alkylating agents and/or fludarabine-based therapy as 2nd or higher-line treatment Exclusion criteria after change according to protocol amendment: 3. No prior therapy for CLL

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    11 Nov 2013
    Recruitment was open from August 2011. The first patient was included in May 2012. The study was open for recruitment for approximately 2 years and 2 months. During this time, only 4 patients were recruited for the phase I escalation part of the trial at 3 sites, which equals a recruitment rate of about one patient per 6 months. Due to this very low recruitment rate the study was closed prematurely in November 2013, and the phase II part of the trial was not started The information about the premature closure of the trial was sent to the respective competent authorities and ethic committees on 11.11.2013 (according to e.g. national legislation § 13 GCP-V, Abs. 8).
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to the premature closure of the trial with only 4 enrolled patients, no relevant conclusions can be drawn from this study. No major unexpected safety problems were detected in these patients.
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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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