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    Clinical Trial Results:
    A 2-Part, Phase 2, Open-Label Study of the Safety, Tolerability, and Efficacy of Itacitinib Immediate Release in Participants With Primary Myelofibrosis or Secondary Myelofibrosis (Post–Polycythemia Vera Myelofibrosis or Post–Essential Thrombocythemia Myelofibrosis) Who Have Received Prior Ruxolitinib and/or Fedratinib Monotherapy

    Summary
    EudraCT number
    		 2020-003123-42
    Trial protocol
    		 AT   FR   DE   ES   BE   PL   IT  
    Global end of trial date
    24 Aug 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Sep 2024
    First version publication date
    05 Sep 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    INCB 39110-213/LIMBER-213
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Incyte Corporation
    Sponsor organisation address
    1801 Augustine Cut-Off, Wilmington, United States, DE 19803
    Public contact
    Study Director, Incyte Corporation, 1 8554633463, medinfo@incyte.com
    Scientific contact
    Study Director, Incyte Corporation, 1 8554633463, medinfo@incyte.com
    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
    24 Aug 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Aug 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Part 1 was conducted to evaluate the safety and tolerability of itacitinib immediate release (IR) and to select the recommended phase 2 dose (RP2D) for Part 2 of the study. Part 2 was to be conducted to evaluate the efficacy of itacitinib IR at the RP2D with respect to spleen volume reduction at Week 24.
    Protection of trial subjects
    This study was to be performed in accordance with ethical principles that have their origin in the Declaration of Helsinki and conducted in adherence to the study Protocol, applicable Good Clinical Practices, and applicable laws and country-specific regulations in which the study was being conducted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Jul 2021
    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
    United States: 2
    Country: Number of subjects enrolled
    Italy: 2
    Worldwide total number of subjects
    4
    EEA total number of subjects
    2
    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)
    1
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 This study was conducted at 3 study centers in the United States and Italy.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Itacitinib 300 mg
    Arm description
    		 Participants received itacitinib immediate release 300 milligrams (mg) twice a day (BID) orally (PO) for at least 24 weeks. Participants could remain on treatment as long as they were receiving clinical benefit and had not met any criteria for treatment discontinuation.
    Arm type
    		 Experimental

    Investigational medicinal product name
    itacitinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 and 300 mg immediate release tablets

    Number of subjects in period 1
    		Itacitinib 300 mg
    Started
    4
    Completed
    0
    Not completed
    4
         Adverse event, serious fatal
    2
         Adverse event, non-fatal
    1
         Protocol-specified withdrawal criterion met
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Itacitinib 300 mg
    Reporting group description
    		 Participants received itacitinib immediate release 300 milligrams (mg) twice a day (BID) orally (PO) for at least 24 weeks. Participants could remain on treatment as long as they were receiving clinical benefit and had not met any criteria for treatment discontinuation.

    Reporting group values
    		 Itacitinib 300 mg Total
    Number of subjects
    		 4 4
    Age Categorical
    Units: participants
        <=18 years
    		 0 0
        Between 18 and 65 years
    		 1 1
        >=65 years
    		 3 3
    Sex: Female, Male
    Units: participants
        Female
    		 2 2
        Male
    		 2 2
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0
        Asian
    		 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0
        Black or African American
    		 1 1
        White
    		 3 3
        More than one race
    		 0 0
        Unknown or Not Reported
    		 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 0
        Not Hispanic or Latino
    		 3 3
        Unknown or Not Reported
    		 1 1

    End points

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    End points reporting groups
    Reporting group title
    Itacitinib 300 mg
    Reporting group description
    		 Participants received itacitinib immediate release 300 milligrams (mg) twice a day (BID) orally (PO) for at least 24 weeks. Participants could remain on treatment as long as they were receiving clinical benefit and had not met any criteria for treatment discontinuation.

    Primary: Part 1: Number of participants with any treatment-emergent adverse event (TEAE)

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    End point title
    		 Part 1: Number of participants with any treatment-emergent adverse event (TEAE) [1]
    End point description
    An adverse event was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not it was considered drug-related. An AE could therefore have been any unfavorable or unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study treatment. A TEAE was defined as an AE that was reported for the first time or the worsening of a pre-existing event after the first dose of study treatment.
    End point type
    Primary
    End point timeframe
    up to 724 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: Statistical analysis was not conducted for this endpoint.
    End point values
    		 Itacitinib 300 mg
    Number of subjects analysed
    4
    Units: participants
    4
    No statistical analyses for this end point

    Primary: Part 1: Number of participants with any Grade 3 or higher TEAE

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    End point title
    		 Part 1: Number of participants with any Grade 3 or higher TEAE [2]
    End point description
    A TEAE was defined as an AE that was reported for the first time or the worsening of a pre-existing event after the first dose of study treatment. The severity of AEs was assessed using Common Terminology Criteria for Adverse Events (CTCAE) v5.0 Grades 1 through 5. The investigator made an assessment of intensity for each AE and SAE reported during the study and assigned it to 1 of the following categories: Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; treatment not indicated. Grade 2: moderate; minimal, local, or noninvasive treatment indicated; limiting age-appropriate activities of daily living. Grade 3: severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living. Grade 4: life-threatening consequences; urgent treatment indicated. Grade 5: fatal.
    End point type
    Primary
    End point timeframe
    up to 724 days
    Notes
    [2] - 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: Statistical analysis was not conducted for this endpoint.
    End point values
    		 Itacitinib 300 mg
    Number of subjects analysed
    4
    Units: participants
    4
    No statistical analyses for this end point

    Primary: Part 2: Splenic response rate (SRR) at Week 24

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    End point title
    		 Part 2: Splenic response rate (SRR) at Week 24 [3]
    End point description
    SRR was defined as the percentage of participants who had a reduction in spleen volume (by imaging) of at least 35% when compared with Baseline.
    End point type
    Primary
    End point timeframe
    Baseline; Week 24
    Notes
    [3] - 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: Analysis was not conducted because Part 2 never opened for enrollment.
    End point values
    		 Itacitinib 300 mg
    Number of subjects analysed
    0 [4]
    Units: percentage of participants
    Notes
    [4] - Analysis was not conducted because Part 2 never opened for enrollment.
    No statistical analyses for this end point

    Secondary: Part 2: Number of participants with any TEAE

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    End point title
    		 Part 2: Number of participants with any TEAE
    End point description
    An adverse event was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not it was considered drug-related. An AE could therefore have been any unfavorable or unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study treatment. A TEAE was defined as an AE that was reported for the first time or the worsening of a pre-existing event after the first dose of study treatment.
    End point type
    Secondary
    End point timeframe
    up to at least 24 weeks
    End point values
    		 Itacitinib 300 mg
    Number of subjects analysed
    0 [5]
    Units: participants
    Notes
    [5] - Analysis was not conducted because Part 2 never opened for enrollment.
    No statistical analyses for this end point

    Secondary: Part 2: Number of participants with any Grade 3 or higher TEAE

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    End point title
    		 Part 2: Number of participants with any Grade 3 or higher TEAE
    End point description
    A TEAE was defined as an AE that was reported for the first time or the worsening of a pre-existing event after the first dose of study treatment. The severity of AEs was assessed using Common Terminology Criteria for Adverse Events (CTCAE) v5.0 Grades 1 through 5. The investigator made an assessment of intensity for each AE and SAE reported during the study and assigned it to 1 of the following categories: Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; treatment not indicated. Grade 2: moderate; minimal, local, or noninvasive treatment indicated; limiting age-appropriate activities of daily living. Grade 3: severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living. Grade 4: life-threatening consequences; urgent treatment indicated. Grade 5: fatal.
    End point type
    Secondary
    End point timeframe
    up to at least 24 weeks
    End point values
    		 Itacitinib 300 mg
    Number of subjects analysed
    0 [6]
    Units: participants
    Notes
    [6] - Analysis was not conducted because Part 2 never opened for enrollment.
    No statistical analyses for this end point

    Secondary: Part 2: Total symptom score (TSS) response rate at Week 24

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    End point title
    		 Part 2: Total symptom score (TSS) response rate at Week 24
    End point description
    TSS response was defined as the percentage of participants who achieved at least 50% reduction in TSS over the 28 days immediately before the end of Week 24 compared with the 7 days immediately before the initiation of itacitinib immediate release (aseline).B
    End point type
    Secondary
    End point timeframe
    Baseline; Week 24
    End point values
    		 Itacitinib 300 mg
    Number of subjects analysed
    0 [7]
    Units: percentage of participants
    Notes
    [7] - Analysis was not conducted because Part 2 never opened for enrollment.
    No statistical analyses for this end point

    Secondary: Part 2: Percentage of participants categorized as improved on the Week 24 Patient Global Impression of Change (PGIC)

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    End point title
    		 Part 2: Percentage of participants categorized as improved on the Week 24 Patient Global Impression of Change (PGIC)
    End point description
    The PGIC consists of a single question pertaining to a participant's overall status since the start of the study. The questionnaire gives participants 7 options to describe their overall status including: very much improved, much improved, minimally improved, no change, minimally worse, much worse, and very much worse.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 24
    End point values
    		 Itacitinib 300 mg
    Number of subjects analysed
    0 [8]
    Units: percentage of participants
    Notes
    [8] - Analysis was not conducted because Part 2 never opened for enrollment.
    No statistical analyses for this end point

    Secondary: Part 2: Mean change (from Day 1 versus Week 12 and Week 24) in the 5 multi-item functional scale scores and the multi-item global health status scale score (EORTC QLQ-C30)

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    End point title
    		 Part 2: Mean change (from Day 1 versus Week 12 and Week 24) in the 5 multi-item functional scale scores and the multi-item global health status scale score (EORTC QLQ-C30)
    End point description
    The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) was to be used to assess the improvement in quality of life.
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 12 and 24
    End point values
    		 Itacitinib 300 mg
    Number of subjects analysed
    0 [9]
    Units: score on a scale
        arithmetic mean (standard deviation)
    ( )
    Notes
    [9] - Analysis was not conducted because Part 2 never opened for enrollment.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    up to 724 days
    Adverse event reporting additional description
    Treatment-emergent adverse events (TEAEs), defined as AEs that were reported for the first time or the worsening of pre-existing events after the first dose of study treatment, were reported for the Safety Evaluable Population.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22
    Reporting groups
    Reporting group title
    Total
    Reporting group description
    		 Total

    Reporting group title
    itacitinib 300 mg
    Reporting group description
    		 itacitinib 300 mg

    Serious adverse events
    		 Total itacitinib 300 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 4 (75.00%)
    3 / 4 (75.00%)
         number of deaths (all causes)
    2
    2
         number of deaths resulting from adverse events
    2
    2
    Vascular disorders
    Shock haemorrhagic
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Leukocytosis
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Cytokine storm
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intra-abdominal haematoma
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatotoxicity
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Interstitial lung disease
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Infections and infestations
    Sepsis
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    Enterocolitis infectious
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Failure to thrive
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Total itacitinib 300 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 4 (100.00%)
    4 / 4 (100.00%)
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Blood bilirubin increased
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Sinus bradycardia
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    2
    2
    Thrombocytopenia
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Asthenia
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Gastrointestinal disorders
    Mouth haemorrhage
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Vomiting
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Hepatobiliary disorders
    Hepatotoxicity
         subjects affected / exposed
    2 / 4 (50.00%)
    2 / 4 (50.00%)
         occurrences all number
    2
    2
    Renal and urinary disorders
    Nephropathy toxic
         subjects affected / exposed
    2 / 4 (50.00%)
    2 / 4 (50.00%)
         occurrences all number
    4
    4
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Infections and infestations
    Candida infection
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Metabolism and nutrition disorders
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Jan 2022
    The study sponsor decided not to proceed with the study any further; the primary purpose of this amendment was to update the Schedule of Activities for study participants ongoing as of the date of this decision to simplify and minimize the required assessments.

    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 sponsor terminated study enrollment following an assessment regarding the expected duration of recruitment for the Phase 2 portion of the study combined with the availability of other study options for this patient population.
    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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