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    Clinical Trial Results:
    A Phase 2, Single-arm, Open-label, Multicenter Study of the Histone Deacetylase Inhibitor (HDACi) JNJ-26481585 in Subjects With Previously Treated Stage Ib-IVa Cutaneous T-cell Lymphoma

    Summary
    EudraCT number
    		 2011-001076-18
    Trial protocol
    		 DE   GB   ES   PT   IT  
    Global end of trial date
    22 Jul 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Jul 2017
    First version publication date
    13 Jul 2017
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    26481585LYM2001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01486277
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Janssen-Cilag International N.V.
    Sponsor organisation address
    Turnhoutseweg 30, Beerse, Belgium, B-2340
    Public contact
    Clinical Registry Group, Janssen-Cilag International NV, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Janssen-Cilag International NV, ClinicalTrialsEU@its.jnj.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
    22 Jul 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Jul 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to determine the overall cutaneous response rate (RR) based on the modified Severity Weighted Assessment Tool (mSWAT) criteria.
    Protection of trial subjects
    The safety assessments included monitoring of adverse events (AEs), changes in clinical laboratory test values (serum chemistry, hematology, pregnancy test), physical examination results and electrocardiogram (ECG).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Nov 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
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Portugal: 3
    Country: Number of subjects enrolled
    United States: 1
    Worldwide total number of subjects
    26
    EEA total number of subjects
    25
    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)
    15
    From 65 to 84 years
    11
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted from 30 November 2011 to 22 July 2016 at 17 sites in 7 countries.

    Pre-assignment
    Screening details
    		 A total of 26 subjects were enrolled in study; out of these 25 subjects were evaluable for response and 1 subject discontinued the study.

    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
    Are arms mutually exclusive
    Yes

    Arm title
    		 Quisinostat 8 milligram (mg)
    Arm description
    		 Subjects with Stage Ib to IVa cutaneous T-cell lymphoma (CTCL) received quisinostat 8 mg orally on Days 1, 3, and 5 of each week in 21-day treatment cycles until disease progression, toxicity, availability of other effective drugs that the subject may receive, or treating physician advice. Subjects who were initially randomized to the JNJ-26481585 (quisinostat) 8 mg dose cohort were allowed to have their dose increased to 12 mg after study was amended to remove 8 mg arm.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Quisinostat 8 mg
    Investigational medicinal product code
    JNJ-26481585
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received quisinostat 8 mg orally on Days 1, 3, and 5 of each week in 21-day treatment cycles.

    Arm title
    		 Quisinostat 12 mg
    Arm description
    		 Subjects with Stage Ib to IVa cutaneous T-cell lymphoma (CTCL) received JNJ-26481585 (quisinostat) 12 mg orally on Days 1, 3, and 5 of each week in 21-day treatment cycles until disease progression, toxicity, availability of other effective drugs that the subject may receive, or treating physician advice.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Quisinostat 12 mg
    Investigational medicinal product code
    JNJ-26481585
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received quisinostat 12 mg orally on Days 1, 3, and 5 of each week in 21-day treatment cycle.

    Number of subjects in period 1
    		Quisinostat 8 milligram (mg) Quisinostat 12 mg
    Started
    6
    20
    Completed
    2
    3
    Not completed
    4
    17
         Adverse event, serious fatal
    1
    3
         Physician decision
    -
    2
         Other
    3
    10
         Lost to follow-up
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Quisinostat 8 milligram (mg)
    Reporting group description
    		 Subjects with Stage Ib to IVa cutaneous T-cell lymphoma (CTCL) received quisinostat 8 mg orally on Days 1, 3, and 5 of each week in 21-day treatment cycles until disease progression, toxicity, availability of other effective drugs that the subject may receive, or treating physician advice. Subjects who were initially randomized to the JNJ-26481585 (quisinostat) 8 mg dose cohort were allowed to have their dose increased to 12 mg after study was amended to remove 8 mg arm.

    Reporting group title
    Quisinostat 12 mg
    Reporting group description
    		 Subjects with Stage Ib to IVa cutaneous T-cell lymphoma (CTCL) received JNJ-26481585 (quisinostat) 12 mg orally on Days 1, 3, and 5 of each week in 21-day treatment cycles until disease progression, toxicity, availability of other effective drugs that the subject may receive, or treating physician advice.

    Reporting group values
    		 Quisinostat 8 milligram (mg) Quisinostat 12 mg Total
    Number of subjects
    		 6 20 26
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 3 12 15
        From 65 to 84 years
    		 3 8 11
        85 years and over
    		 0 0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.2 ± 15.37 57 ± 14.02 -
    Title for Gender
    Units: subjects
        Female
    		 1 4 5
        Male
    		 5 16 21

    End points

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    End points reporting groups
    Reporting group title
    Quisinostat 8 milligram (mg)
    Reporting group description
    		 Subjects with Stage Ib to IVa cutaneous T-cell lymphoma (CTCL) received quisinostat 8 mg orally on Days 1, 3, and 5 of each week in 21-day treatment cycles until disease progression, toxicity, availability of other effective drugs that the subject may receive, or treating physician advice. Subjects who were initially randomized to the JNJ-26481585 (quisinostat) 8 mg dose cohort were allowed to have their dose increased to 12 mg after study was amended to remove 8 mg arm.

    Reporting group title
    Quisinostat 12 mg
    Reporting group description
    		 Subjects with Stage Ib to IVa cutaneous T-cell lymphoma (CTCL) received JNJ-26481585 (quisinostat) 12 mg orally on Days 1, 3, and 5 of each week in 21-day treatment cycles until disease progression, toxicity, availability of other effective drugs that the subject may receive, or treating physician advice.

    Primary: Percentage of Subjects Who Achieved Overall Cutaneous Response Based on Modified Severity Weighted Assessment Tool (mSWAT) Criteria

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    End point title
    		 Percentage of Subjects Who Achieved Overall Cutaneous Response Based on Modified Severity Weighted Assessment Tool (mSWAT) Criteria [1]
    End point description
    Overall cutaneous response rate (RR) is defined as the percentage of evaluable subjects who achieved a complete response {CR (complete disappearance of all cutaneous disease)} or partial response (PR {greater than or equal to [>=] 50 percent (%) reduction in mSWAT score compared with baseline}). mSWAT criteria was used to evaluate the skin tumor burden. The investigator was determine the percentage of total body surface area (TBSA) affected by patches, plaques or tumors in 12 body regions, using the subject's palm and fingers representing 1% of TBSA. The response evaluable population consisted of all subjects who received at least 1 dose of study drug and had a posttreatment disease assessment to allow for comparison to the baseline assessment.
    End point type
    Primary
    End point timeframe
    From screening until progressive disease or confirmed lost to follow-up or death from any cause or start of alternate therapy, or withdrawal from the study (up to 6 months after the enrollment of the last subject)
    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: Only descriptive data was reported and no statistical analysis was performed for this specific end point.
    End point values
    		 Quisinostat 8 milligram (mg) Quisinostat 12 mg
    Number of subjects analysed
    6
    19
    Units: Percentage of subjects
        number (confidence interval 95%)
    16.7 (0.4 to 64.1)
    26.3 (9.2 to 51.2)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Who Achieved Overall Global RR Based on The Consensus Global Response Score

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    End point title
    		 Percentage of Subjects Who Achieved Overall Global RR Based on The Consensus Global Response Score
    End point description
    Overall global RR is defined as the percentage of subjects who achieved CR (complete response) or PR (partial response) based on the consensus global response score for mycosis fungoides/ Sezary Syndrome (MF/SS) [defined as the total score of tumor, lymph nodes, metastasis, blood (TNMB) staging, ie, cutaneous disease, lymph nodes, viscera and blood. Complete response is defined as complete disappearance of all clinical evidence of disease (all categories have CR/ non-involved [NI]) and PR is defined as regression of measurable disease (all categories do not have a CR/NI and no category has a PD and if any other category involved at baseline, at least one has a CR or PR). The response evaluable population consisted of all subjects who received at least 1 dose of study drug and had a posttreatment disease assessment to allow for comparison to the baseline assessment.
    End point type
    Secondary
    End point timeframe
    From screening until progressive disease or confirmed lost to follow-up or death from any cause or start of alternate therapy, or withdrawal from the study (up to 6 months after the enrollment of the last subject)
    End point values
    		 Quisinostat 8 milligram (mg) Quisinostat 12 mg
    Number of subjects analysed
    6
    19
    Units: Percentage of subjects
        number (not applicable)
    0
    13.3
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS)

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    End point title
    		 Progression-Free Survival (PFS)
    End point description
    PFS is defined as the interval between the date of administration of the first dose of study drug and the date of disease progression or death from any cause, whichever occurred first. PFS is estimated by Kaplan-Meier (K-M) method. Here, '99999' for upper limit of CI represents that data was not estimable due to low number of events observed during the short follow-up duration. The subjects treated analysis set consisted of all subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    From the date of administration of the first dose of study medication until progressive disease or death from any cause, whichever occurs first (up to 6 months after the enrollment of the last subject)
    End point values
    		 Quisinostat 8 milligram (mg) Quisinostat 12 mg
    Number of subjects analysed
    6
    20
    Units: months
        median (confidence interval 95%)
    3.83 (0.72 to 99999)
    5.09 (2.1 to 8.31)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR)

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    End point title
    		 Duration of Response (DOR)
    End point description
    Duration of response was defined only for subjects who have CR or PR as best overall response in skin based on mSWAT and is defined as the date from the first documentation of CR or PR until the date of first documentation of progressive disease (PD), or death from any cause. Here 'N' represents the number of subjects who received at least 1 dose of study drug and who achieved a response. '99999' for median and CI represents data was not estimable because the 1 subject in this arm was censored from the analysis (Quisinostat 8 mg) and for upper limit of CI (Quisinostat 12 mg) due to low number of events observed during the follow-up.
    End point type
    Secondary
    End point timeframe
    First documentation of CR or PR until the date of first documentation of progressive disease, or death from any cause; as assessed for approximately 6 months after the enrollment of the last subject
    End point values
    		 Quisinostat 8 milligram (mg) Quisinostat 12 mg
    Number of subjects analysed
    1
    5
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    4.86 (3.02 to 99999)
    No statistical analyses for this end point

    Secondary: 9-Month Overall Survival (OS) Rate

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    End point title
    		 9-Month Overall Survival (OS) Rate
    End point description
    The 9-month OS rate was defined as the K-M estimate of the proportion of subjects surviving at least 9 months after the date of administration of the first dose of study drug. The subjects treated analysis set consisted of all subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Month 9
    End point values
    		 Quisinostat 8 milligram (mg) Quisinostat 12 mg
    Number of subjects analysed
    6
    20
    Units: proportion of subjects
        number (confidence interval 95%)
    0.83 (0.27 to 0.97)
    0.83 (0.57 to 0.94)
    No statistical analyses for this end point

    Secondary: Number of Subjects with Pruritus Relief Measured by Pruritus Intensity Assessment (PIA) Questionnaire Scale Scores

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    End point title
    		 Number of Subjects with Pruritus Relief Measured by Pruritus Intensity Assessment (PIA) Questionnaire Scale Scores
    End point description
    Pruritus relief was defined as a reduction from baseline of equal or greater than (>=) 3 points on the 11 point PIA numeric rating scale or complete resolution for >=3 continuous weeks. The PIA scores ranges from '0= no pruritus; 10 = worst imaginable'. The response evaluable population consisted of all subjects who received at least 1 dose of study drug and had a posttreatment disease assessment to allow for comparison to the baseline assessment.
    End point type
    Secondary
    End point timeframe
    From screening until progressive disease or confirmed lost to follow-up or death from any cause or start of alternate therapy, or withdrawal from the study (up to 6 months after the enrollment of the last subject)
    End point values
    		 Quisinostat 8 milligram (mg) Quisinostat 12 mg
    Number of subjects analysed
    6
    19
    Units: subjects
    3
    7
    No statistical analyses for this end point

    Secondary: European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Score

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    End point title
    		 European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Score
    End point description
    EORTC QLQ-C30 is a questionnaire to assess quality of life of cancer patients. For the multiple item measure, 100-point scale is used. For Global Health the functional scales (physical, role, emotional, cognitive and social functioning), higher scores represent better health. The subjects treated analysis set consisted of all subjects who received at least 1 dose of study drug. Here 'n' repersents the number of subjects analyzed for this specific specific category for this endpoint. '99999' for standard deviation represents that data could not be estimated and '99999' for follow up categories of quinostat 8 mg reporting group represents that data was not analyzed as subjects were moved to quinostat 12 mg group after amendment.
    End point type
    Secondary
    End point timeframe
    From screening until progressive disease or confirmed lost to follow-up or death from any cause or start of alternate therapy, or withdrawal from the study (up to 6 months after the enrollment of the last subject)
    End point values
    		 Quisinostat 8 milligram (mg) Quisinostat 12 mg
    Number of subjects analysed
    6
    20
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Physical functioning: Cycle 16 (n=1,1)
    100 ± 99999
    100 ± 99999
        Physical functioning: Follow up (n=0,2)
    99999 ± 99999
    100 ± 0
        Role functioning: Cycle 16 (n=1,1)
    100 ± 99999
    100 ± 99999
        Role functioning: Follow up (n=0,2)
    99999 ± 99999
    91.7 ± 11.79
        Emotional functioning: Cycle 16 (n=1,1)
    100 ± 99999
    91.7 ± 99999
        Emotional functioning: Follow up (n=0,2)
    99999 ± 99999
    91.7 ± 11.79
        Cognitive functioning: Cycle 16 (n=1,1)
    100 ± 99999
    100 ± 99999
        Cognitive functioning: Follow up (n=0,2)
    99999 ± 99999
    100 ± 0
        Social functioning: Cycle 16 (n=1,1)
    100 ± 99999
    100 ± 99999
        Social functioning: Follow up (n=0,2)
    99999 ± 99999
    91.7 ± 11.79
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Approximately 5 years
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Quisinostat 8 mg
    Reporting group description
    		 Subjects with Stage Ib to IVa cutaneous T-cell lymphoma (CTCL) received quisinostat 8 mg orally on Days 1, 3, and 5 of each week in 21-day treatment cycles until disease progression, toxicity, availability of other effective drugs that the subject may receive, or treating physician advice. Subjects who were initially randomized to the JNJ-26481585 (quisinostat) 8 mg dose cohort were allowed to have their dose increased to 12 mg after study was amended to remove 8 mg arm.

    Reporting group title
    Quisinostat 12 mg
    Reporting group description
    		 Subjects with Stage Ib to IVa cutaneous T-cell lymphoma (CTCL) received quisinostat 8 mg orally on Days 1, 3, and 5 of each week in 21-day treatment cycles until disease progression, toxicity, availability of other effective drugs that the subject may receive, or treating physician advice. Subjects who were initially randomized to the JNJ-26481585 (quisinostat) 8 mg dose cohort were allowed to have their dose increased to 12 mg after study was amended to remove 8 mg arm.

    Serious adverse events
    		 Quisinostat 8 mg Quisinostat 12 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 6 (16.67%)
    7 / 20 (35.00%)
         number of deaths (all causes)
    1
    3
         number of deaths resulting from adverse events
    Investigations
    Troponin T Increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Lymphoedema
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Hospitalisation
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden Death
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Impairment
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Tract Infection
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    		 Quisinostat 8 mg Quisinostat 12 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 6 (100.00%)
    20 / 20 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    3
    Infected Neoplasm
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 20 (10.00%)
         occurrences all number
    1
    2
    Lymphoedema
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    2
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 6 (33.33%)
    2 / 20 (10.00%)
         occurrences all number
    3
    2
    Chills
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Cyst
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Face Oedema
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    Fatigue
         subjects affected / exposed
    1 / 6 (16.67%)
    3 / 20 (15.00%)
         occurrences all number
    1
    3
    Feeling Cold
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Feeling Hot
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Influenza Like Illness
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Irritability
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Malaise
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Oedema Peripheral
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 20 (15.00%)
         occurrences all number
    0
    3
    Pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Pyrexia
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 20 (5.00%)
         occurrences all number
    2
    1
    Temperature Regulation Disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Penile Oedema
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    2
    Balanitis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    2
    Scrotal Ulcer
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Testicular Oedema
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 20 (10.00%)
         occurrences all number
    1
    2
    Oropharyngeal Pain
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2
    Productive Cough
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2
    Vocal Cord Inflammation
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2
    Insomnia
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 20 (15.00%)
         occurrences all number
    0
    3
    Mood Swings
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Sleep Disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Investigations
    Blood Urine Present
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Grip Strength Decreased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Glomerular Filtration Rate Decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Weight Decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2
    Weight Increased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Foot Fracture
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Laceration
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Procedural Pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Cardiac disorders
    Cyanosis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Palpitations
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2
    Hepatojugular Reflux
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Sinus Bradycardia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Tachycardia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    Ventricular Extrasystoles
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Nervous system disorders
    Cluster Headache
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Dizziness
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    3
    Dysgeusia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Headache
         subjects affected / exposed
    0 / 6 (0.00%)
    5 / 20 (25.00%)
         occurrences all number
    0
    5
    Lethargy
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 20 (15.00%)
         occurrences all number
    0
    5
    Hypoaesthesia
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 20 (5.00%)
         occurrences all number
    2
    1
    Memory Impairment
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Tremor
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Migraine
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    Lymphadenopathy
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2
    Thrombocytopenia
         subjects affected / exposed
    0 / 6 (0.00%)
    4 / 20 (20.00%)
         occurrences all number
    0
    4
    Ear and labyrinth disorders
    Deafness
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Hypoacusis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Eye Irritation
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Eye Swelling
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Eyelid Pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Lacrimation Increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    3
    Visual Acuity Reduced
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal Discomfort
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Abdominal Distension
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    Abdominal Pain
         subjects affected / exposed
    0 / 6 (0.00%)
    4 / 20 (20.00%)
         occurrences all number
    0
    6
    Abdominal Pain Upper
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Change of Bowel Habit
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Constipation
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Diarrhoea
         subjects affected / exposed
    2 / 6 (33.33%)
    5 / 20 (25.00%)
         occurrences all number
    2
    7
    Faeces Discoloured
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Flatulence
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Gastritis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Lip Dry
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    2 / 6 (33.33%)
    7 / 20 (35.00%)
         occurrences all number
    2
    8
    Umbilical Hernia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 20 (10.00%)
         occurrences all number
    1
    4
    Hepatobiliary disorders
    Hepatic Function Abnormal
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    3
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    Dermatitis Exfoliative
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Dry Skin
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 20 (10.00%)
         occurrences all number
    2
    2
    Eczema
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Erythema
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Pain of Skin
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Pruritus
         subjects affected / exposed
    3 / 6 (50.00%)
    7 / 20 (35.00%)
         occurrences all number
    5
    10
    Scab
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Skin Exfoliation
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    Skin Fissures
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Skin Irritation
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    Skin Plaque
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    2
    Telangiectasia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Anuria
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Azotaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Nocturia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Renal Impairment
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    2
    Groin Pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Back Pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Myalgia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Musculoskeletal Pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Pain in Extremity
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Infections and infestations
    Ear Infection
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Impetigo
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    2
    Influenza
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    Localised Infection
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Lung Infection
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 20 (10.00%)
         occurrences all number
    1
    3
    Onychomycosis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Oral Candidiasis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    2
    Otitis Externa
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Respiratory Tract Infection
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    Sinusitis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Urinary Tract Infection
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Hyperglycaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    2
    Hyperkalaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Hyperuricaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Hypomagnesaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Hypophosphataemia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Nov 2011
    Amendment included that the 8 milligram (mg) dose cohort and randomization procedure was removed. Subjects enrolled in the 8 mg cohort was allowed to receive the 12 mg dose without evidence of disease progression. The Simon 2-stage Minimax Design was no longer be incorporated because the 8 mg dose cohort has been eliminated. The sample size for the study was adjusted because of the removal of the low-dose cohort and elimination of the 2-stage design. The primary purpose of the interim analysis was to provide an early assessment of safety and efficacy of the recommended Phase 2 dose and a lower dose in order to minimize exposing subjects to an ineffective treatment. It is expected that accrual and treatment was proceeded quickly relative to the data available to base decisions on risk and benefit, thus eliminating the need for an interim analysis. Any exploratory statistical comparisons between the 2 treatment groups are no longer relevant because of the elimination of the 8 mg dose cohort. The lymph node classification international society for cutaneous lymphomas/european organization for research and treatment of cancer (ISCL/EORTC) has been modified to include central lymph nodes. A concern of repeated radiological assessment (CT/MRI) over a short time period was raised by investigators. This change allows the use of data obtained before informed consent if the tests were performed within a reasonable timeframe before the first dose of study medication. Reducing the recovery time following prior systemic therapy from at least 3 weeks to 2 weeks gave more flexibility in enrolling subjects to this study. Clarification of dose modification for toxicity in response to suggestions by health authorities and investigators. Clarification that biomarker analyses are dependent on the availability of assays. Biomarker analyses may not be performed if it is considered they was provided no useful scientific information. Minor errors were noted.
    03 Sep 2014
    Amendment was done to modify the long-term extension phase to allow subjects who were on study to continue receiving treatment beyond the 2-year clinical cutoff.

    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.
    Study was amended to remove the 8 mg dose level arm and subjects enrolled at 8 mg were allowed to dose escalate to 12 mg. The removal of the 8 mg dose arm eliminated the potential for assessment of a dose response relationship on efficacy and safety.
    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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