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    Clinical Trial Results:
    JeRiCHO (JAK-inhibition in recurrent classical Hodgkin Lymphoma): A phase II, open-label, prospective, non-randomized, multicenter clinical trial with the JAK-inhibitor ruxolitinib in patients with relapsed or refractory Hodgkin Lymphoma (HL).

    Summary
    EudraCT number
    2013-003369-33
    Trial protocol
    DE  
    Global end of trial date
    30 Jun 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    25 Jun 2020
    First version publication date
    25 Jun 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Uni-Koeln-1698
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02164500
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University of Cologne
    Sponsor organisation address
    Albertus Magnus-Platz, Köln, Germany, 50923
    Public contact
    Trial Coordination Center of the German Hodgkin Study Group (GHSG), German Hodgkin Study Group (GHSG), 0049 22147888200, ghsg@uk-koeln.de
    Scientific contact
    Trial Coordination Center of the German Hodgkin Study Group (GHSG), German Hodgkin Study Group (GHSG), 0049 22147888200, ghsg@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
    20 Mar 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jun 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To determine the objective response rate (complete response + partial response) of ruxolitinib in patients with relapsed or refractory classical Hodgkin lymphoma
    Protection of trial subjects
    Written informed consent prior to study entry; 2-stage design with comprehensive interim risk-benefit assessment and formal futility criterion after stage 1; standardized dose reduction in case of adverse events
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    20 Oct 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy
    Long term follow-up duration
    12 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 14
    Worldwide total number of subjects
    14
    EEA total number of subjects
    14
    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)
    8
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Recruitment for stage 1 was open between 28 Oct 2015 and 12 May 2017. It was planned to enroll 12 response-eligible patients in stage 1. We enrolled 14 patients, of whom 2 were not eligible for primary endpoint analysis. The trial was terminated after stage-1 analysis. No patients were enrolled in stage 2.

    Pre-assignment
    Screening details
    Main inclusion criteria: Relapsed or refractory histologically confirmed cHL that is progressing or active and requires treatment after ≥ 1 appropriate therapy including ASCT if eligible; Age ≥ 18 years; ECOG ≤ 2; adequate organ function. Main exclusion criteria: Relevant concurrent disease; pregnancy or lactation.

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

    Arms
    Arm title
    Experimental
    Arm description
    Continuous 28-day cycles of ruxolitinib until disease progression, withdrawal of consent or intolerable toxicity
    Arm type
    Experimental

    Investigational medicinal product name
    Ruxolitinib
    Investigational medicinal product code
    Other name
    Jakavi (R)
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ruxolitinib was applied twice a day (approximately 12 hours apart: morning and night) with a starting dose of 25 mg per application. Ruxolitinib dose was to be decreased (5 mg bid steps) per standardized dosing paradigm in case of adverse events. Ruxolitinib tablets were administered orally without regards to food in an outpatient setting. The dosage strength was 5 mg/tablet ruxolitinib (free base equivalent). Ruxolitinib was dispensed on day 1 of each cycle by the study center personnel. Patients were provided with an adequate supply of ruxolitinib for self-administration at home.

    Number of subjects in period 1
    Experimental
    Started
    14
    Start of ruxolitinib treatment
    14
    Completed
    12
    Not completed
    2
         cHL diagnosis disconfirmed
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Stage 1
    Reporting group description
    -

    Reporting group values
    Stage 1 Total
    Number of subjects
    14 14
    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)
    8 8
        From 65-84 years
    6 6
        85 years and over
    0 0
    Gender categorical
    Units: Subjects
        Female
    2 2
        Male
    12 12
    ECOG performance status
    Units: Subjects
        ECOG 0
    2 2
        ECOG 1
    11 11
        ECOG 2
    1 1
    Prior ASCT
    Units: Subjects
        No
    6 6
        Yes
    8 8
    Prior allogeneic SCT
    Units: Subjects
        No
    12 12
        Yes
    2 2
    Prior brentuximab vedotin
    Units: Subjects
        No
    1 1
        Yes
    13 13
    Number of prior HL therapies
    Units: Therapy lines
        median (full range (min-max))
    3 (2 to 11) -

    End points

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    End points reporting groups
    Reporting group title
    Experimental
    Reporting group description
    Continuous 28-day cycles of ruxolitinib until disease progression, withdrawal of consent or intolerable toxicity

    Primary: Objective response rate (ORR) after 2 cycles by central review

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    End point title
    Objective response rate (ORR) after 2 cycles by central review [1]
    End point description
    Objective response was defined as complete or partial remission in the centrally reviewed PET/CT-based restaging after 2 cycles of ruxolitinib. The primary endpoint was to be analyzed per-protocol, excluding patients who received less than 2 cycles ruxolitinib unless due to progressive disease.
    End point type
    Primary
    End point timeframe
    PET/CT-based restaging was to be performed at day 26-30 of the second cycle (last day of cycle +/- 2 days).
    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: According to the trial protocol, the null hyothesis H0: ORR ≤ 5% was to be tested in a 2-stage design. The trial was terminated after stage 1 although the required responders were observed (1 responder required, 2 responders observed). Thus, only descriptive analyses of the primary endpoint in the stage-1 per-protocol population were done.
    End point values
    Experimental
    Number of subjects analysed
    12 [2]
    Units: Subjects
        Objective response (complete or partial remission)
    2
        No objective response (no change or progression)
    10
    Notes
    [2] - Per-protocol analysis excluding 2 patients due to disconfirmation of cHL diagnosis
    No statistical analyses for this end point

    Secondary: Best response

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    End point title
    Best response
    End point description
    End point type
    Secondary
    End point timeframe
    From the restaging after two cycles onwards, restagings with a modality at the investigator’s discretion (local standard of care) were to be performed every three months until end of study treatment.
    End point values
    Experimental
    Number of subjects analysed
    14
    Units: Subjects
        Complete remission
    0
        Partial remission
    3
        No change
    3
        Progressive disease
    7
        Not done
    1
    No statistical analyses for this end point

    Secondary: Progression-free survival

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    End point title
    Progression-free survival
    End point description
    Progression-free survival was analyzed according to Kaplan-Meier.
    End point type
    Secondary
    End point timeframe
    Progression-free survival was calculated for each patient as time between the date of completion of staging and the date of first progression, relapse or death or, in cases of continuing response, the date of the last documented follow-up.
    End point values
    Experimental
    Number of subjects analysed
    14
    Units: months
        median (confidence interval 95%)
    3.6 (1.9 to 7.6)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were assessed from start of study treatment up until the 28-day follow-up visit or the start of a new HL therapy, whichever occurred first.
    Adverse event reporting additional description
    Expected AEs of CTCAE grades 3/4 were assessed on the therapy administration CRFs by predefined CTCAE categories. Unexpected and serious AEs were assessed on specific forms and coded according to MedDRA.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    10.2
    Reporting groups
    Reporting group title
    Experimental
    Reporting group description
    Patients received continuous 28-day cycles of oral ruxolitinib, with 25 mg bid (approximately 12 hours apart: morning and night) as starting dose. Ruxolitinib dose was to be decreased (5 mg bid steps) per standardized dosing paradigm in case of adverse events. Treatment was continued until disease progression, withdrawal of consent or intolerable toxicity.

    Serious adverse events
    Experimental
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 14 (64.29%)
         number of deaths (all causes)
    6
         number of deaths resulting from adverse events
    0
    Respiratory, thoracic and mediastinal disorders
    Bronchopulmonary disease
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Paresis
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Febrile infection
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Stomatitis
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Urinary hesitation
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    Experimental
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 14 (28.57%)
    Cardiac disorders
    Cardiac disorder
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Respiratory tract disorder
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    3
    Blood and lymphatic system disorders
    Leukopenia
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Jan 2016
    Updated ICF, implementation of regulatory authority and ethics committee authorizations
    19 Sep 2016
    Amendment of dose reduction section due to changes in SmPC of ruxolitinib
    22 Feb 2018
    Amendment of the frequency of side effects due to changes in SmPC of ruxolitinib

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    26 May 2017
    Recruitment of stage 1 completed
    -

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The trial was terminated after stage 1 due to slow recruitment and low response rates/PFS in line with protocol guidance although required responders were observed (1 required, 2 observed). Only descriptive analysis in stage-1 population were done.
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