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    Clinical Trial Results:
    A Phase I, Open-Label, Multi-Centre Study to Assess the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of the JAK2 Inhibitor, AZD1480, Administered Orally to Patients with Primary Myelofibrosis (PMF) and Post-Polycythaemia Vera/Essential Thrombocythaemia Myelofibrosis (Post-PV/ET MF)

    Summary
    EudraCT number
    2007-006647-45
    Trial protocol
    FR  
    Global end of trial date
    25 Aug 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    12 Aug 2016
    First version publication date
    12 Aug 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D1060C00001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    Room C2B-424 A, 1800 Concord Pike, Wilmington, United States, DE 19850-5437
    Public contact
    Srdan Verstovsek, MD PhD, University of Texas MD Anderson Cancer Center, 001 +1 713-792-2121,
    Scientific contact
    Dr Gregory Curt, MD, AstraZeneca, Gregory.Curt@astrazeneca.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
    06 Feb 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Apr 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Aug 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Primary objectives of the trial are as follows: To assess the safety and tolerability of AZD1480 in patients with PMF and post-PV/ET MF. To determine the PK of AZD1480 following both single and multiple oral dosing of AZD1480 (QD dosing and/or BID dosing). To evaluate the extent of inhibition of phosphorylation of STAT3 following treatment with AZD1480. Secondary objectives are: To explore the role of JAK2 V617F mutation load in patient response. To provide information on preliminary signs of efficacy. Part A of the study had the main aim of determining the maximum tolerated dose (MTD) of AZD1480 with Part B designed to further assess the safety profile and preliminary signs of efficacy information on AZD1480.
    Protection of trial subjects
    Data protection for patients - The Master Informed Consent Form explained that study data will be stored in a computer database, maintaining confidentiality in accordance with national data legislation. All data computer processed by AstraZeneca will be identified by e - code/study number/initials. A study Safery Review Committee met during Part A following each dose step (i.e., following the first cycle of treatment for each dose level). Before the first patient is enrolled into the study, a representative of AstraZeneca visited the investigational study site (as determined necessary by AstraZeneca) and had regular contacts with the study site, including visits.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    19 May 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    1 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 16
    Country: Number of subjects enrolled
    United States: 19
    Worldwide total number of subjects
    35
    EEA total number of subjects
    16
    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
    20
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    65 enrolled. 35 dosed with AZD1480. 33 discontinued. At DCO 2 patients ongoing. 1 patient in the 50 mg QD group and 1 patient in the 15 mg BID group with status (at July 2015): Patient in 15 mg BID group: Stable disease, no SAE. Patient in 50 mg QD group: Stable disease, no SAE, dose currently reduced to 40 mg QD.

    Pre-assignment
    Screening details
    There is a 28 day screening period prior to Cycle 1 Day 1.

    Pre-assignment period milestones
    Number of subjects started
    35
    Number of subjects completed
    35

    Period 1
    Period 1 title
    Baseline (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    Not applicable since this is an open-label trial

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    2.5 mg QD AZD1480
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    AZD1480
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    2.5 mg QD

    Arm title
    5.0 mg QD AZD1480
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    AZD1480
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    5.0 mg QD

    Arm title
    10 mg QD AZD1480
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    AZD1480
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg QD

    Arm title
    20 mg QD AZD1480
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    AZD1480
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    20 mg QD

    Arm title
    30 mg QD AZD1480
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    AZD1480
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    AZD1480

    Arm title
    50 mg QD AZD1480
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    AZD1480
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    50 mg QD

    Arm title
    70 mg QD AZD1480
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    AZD1480
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    70 mg QD

    Arm title
    10 mg BID AZD1480
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    AZD1480
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg BID

    Arm title
    15 mg BID AZD1480
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    AZD1480
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    15 mg BID

    Number of subjects in period 1
    2.5 mg QD AZD1480 5.0 mg QD AZD1480 10 mg QD AZD1480 20 mg QD AZD1480 30 mg QD AZD1480 50 mg QD AZD1480 70 mg QD AZD1480 10 mg BID AZD1480 15 mg BID AZD1480
    Started
    6
    3
    3
    3
    3
    6
    1
    6
    4
    Completed
    0
    0
    0
    0
    0
    1
    0
    0
    1
    Not completed
    6
    3
    3
    3
    3
    5
    1
    6
    3
         Consent withdrawn by subject
    -
    -
    -
    -
    -
    3
    1
    2
    -
         Adverse event, non-fatal
    4
    3
    2
    3
    3
    1
    -
    4
    3
         As per eCRF
    2
    -
    1
    -
    -
    1
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    2.5 mg QD AZD1480
    Reporting group description
    -

    Reporting group title
    5.0 mg QD AZD1480
    Reporting group description
    -

    Reporting group title
    10 mg QD AZD1480
    Reporting group description
    -

    Reporting group title
    20 mg QD AZD1480
    Reporting group description
    -

    Reporting group title
    30 mg QD AZD1480
    Reporting group description
    -

    Reporting group title
    50 mg QD AZD1480
    Reporting group description
    -

    Reporting group title
    70 mg QD AZD1480
    Reporting group description
    -

    Reporting group title
    10 mg BID AZD1480
    Reporting group description
    -

    Reporting group title
    15 mg BID AZD1480
    Reporting group description
    -

    Reporting group values
    2.5 mg QD AZD1480 5.0 mg QD AZD1480 10 mg QD AZD1480 20 mg QD AZD1480 30 mg QD AZD1480 50 mg QD AZD1480 70 mg QD AZD1480 10 mg BID AZD1480 15 mg BID AZD1480 Total
    Number of subjects
    6 3 3 3 3 6 1 6 4 35
    Age Categorical
    Age group (years) of subjects eligible are 25+ and have been classified in the demography table according to the following standard classes:>=18-<65>=65 - <74>=75
    Units: Subjects
        Adults (>=18 - <65 years)
    5 1 0 0 3 1 1 2 2 15
        From >=65 - < 74
    1 1 1 2 0 5 0 2 1 13
        >= 75
    0 1 2 1 0 0 0 2 1 7
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    57.5 ± 7.7 66.3 ± 9.6 76.7 ± 10.5 75.7 ± 3.8 49.3 ± 4.2 69.3 ± 3.8 56 ± 0 65.3 ± 11.3 66.5 ± 10.3 -
    Gender Categorical
    Units: Subjects
        Female
    1 1 1 2 1 5 1 2 0 14
        Male
    5 2 2 1 2 1 0 4 4 21
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All patients who recieved treatment.

    Subject analysis set title
    PK Analysis set
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    All patients who receive at least 1 dose of AZD1480 per the protocol, for whom any post-dose data are available and do not violate or deviate from the protocol in ways that would significantly affect the PK analyses will be included in the PK analysis set. The population will be defined by the Study Team Physician, Pharmacokineticist and Statistician prior to any analyses being performed.

    Subject analysis set title
    Evaluable for Clinical Improvement (CI) set
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    A subset of the FAS. These patients are evaluable, defined as either: a) reached day 28 visit and received at least 18 of the planned 26 doses in Cycle 1 and has sufficient safety evaluations as judged by SRC performed during Cycle 1, or b) experienced DLT

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All subjects who recieved at least one dose of AZD1480, according to the treatment recieved.

    Subject analysis sets values
    Full Analysis Set PK Analysis set Evaluable for Clinical Improvement (CI) set Safety Analysis Set
    Number of subjects
    35
    35
    33
    35
    Age Categorical
    Age group (years) of subjects eligible are 25+ and have been classified in the demography table according to the following standard classes:>=18-<65>=65 - <74>=75
    Units: Subjects
        Adults (>=18 - <65 years)
    15
    15
    15
    15
        From >=65 - < 74
    13
    13
    13
    13
        >= 75
    7
    7
    7
    7
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    65.1 ± 10.6
    65.1 ± 10.6
    65.5 ± 10.8
    65.1 ± 10.6
    Gender Categorical
    Units: Subjects
        Female
    14
    14
    13
    14
        Male
    21
    21
    20
    21

    End points

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    End points reporting groups
    Reporting group title
    2.5 mg QD AZD1480
    Reporting group description
    -

    Reporting group title
    5.0 mg QD AZD1480
    Reporting group description
    -

    Reporting group title
    10 mg QD AZD1480
    Reporting group description
    -

    Reporting group title
    20 mg QD AZD1480
    Reporting group description
    -

    Reporting group title
    30 mg QD AZD1480
    Reporting group description
    -

    Reporting group title
    50 mg QD AZD1480
    Reporting group description
    -

    Reporting group title
    70 mg QD AZD1480
    Reporting group description
    -

    Reporting group title
    10 mg BID AZD1480
    Reporting group description
    -

    Reporting group title
    15 mg BID AZD1480
    Reporting group description
    -

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All patients who recieved treatment.

    Subject analysis set title
    PK Analysis set
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    All patients who receive at least 1 dose of AZD1480 per the protocol, for whom any post-dose data are available and do not violate or deviate from the protocol in ways that would significantly affect the PK analyses will be included in the PK analysis set. The population will be defined by the Study Team Physician, Pharmacokineticist and Statistician prior to any analyses being performed.

    Subject analysis set title
    Evaluable for Clinical Improvement (CI) set
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    A subset of the FAS. These patients are evaluable, defined as either: a) reached day 28 visit and received at least 18 of the planned 26 doses in Cycle 1 and has sufficient safety evaluations as judged by SRC performed during Cycle 1, or b) experienced DLT

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All subjects who recieved at least one dose of AZD1480, according to the treatment recieved.

    Primary: Pharamcokinetic parameters following single dosing

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    End point title
    Pharamcokinetic parameters following single dosing [1]
    End point description
    Single dose: AUC(0-inf),AUC(0-24)
    End point type
    Primary
    End point timeframe
    0 to 24 hour sampling (Day 1: 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hrs post dose)
    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: There are 12 warnings which are due to no statstical analysis being posted.&nbsp; There are no statistical analysis to post for this study
    End point values
    2.5 mg QD AZD1480 5.0 mg QD AZD1480 10 mg QD AZD1480 20 mg QD AZD1480 30 mg QD AZD1480 50 mg QD AZD1480 70 mg QD AZD1480 10 mg BID AZD1480 15 mg BID AZD1480
    Number of subjects analysed
    6
    3
    3
    3
    3
    6
    1
    0 [2]
    0 [3]
    Units: ug.h/L
    geometric mean (standard deviation)
        AUC (ug.h/L)
    83.5 ± 36.6
    312 ± 79.5
    378 ± 290
    517 ± 294
    2040 ± 657
    3650 ± 2980
    6300 ± 0
    ±
    ±
        AUC0-24 (ug.h/L)
    70.2 ± 28.7
    308 ± 76
    285 ± 252
    508 ± 280
    2000 ± 624
    3540 ± 2570
    6260 ± 0
    ±
    ±
    Notes
    [2] - NA
    [3] - NA
    No statistical analyses for this end point

    Primary: Pharmacokinetic parameters following single dosing (2)

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    End point title
    Pharmacokinetic parameters following single dosing (2) [4]
    End point description
    Single dose Tmax
    End point type
    Primary
    End point timeframe
    0 to 24 hour sampling (Day 1: 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hrs post dose)
    Notes
    [4] - 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: There are 12 warnings which are due to no statstical analysis being posted.&nbsp; There are no statistical analysis to post for this study
    End point values
    2.5 mg QD AZD1480 5.0 mg QD AZD1480 10 mg QD AZD1480 20 mg QD AZD1480 30 mg QD AZD1480 50 mg QD AZD1480 70 mg QD AZD1480 10 mg BID AZD1480 15 mg BID AZD1480
    Number of subjects analysed
    6
    3
    3
    3
    3
    6
    1
    6
    4
    Units: hr
    median (full range (min-max))
        tmax(h)
    0.625 (0.5 to 1.5)
    0.75 (0.5 to 2)
    0.75 (0.5 to 0.75)
    0.75 (0.5 to 1.03)
    1 (1 to 1.5)
    0.89 (0.75 to 1.5)
    0.75 (0.75 to 0.75)
    0.625 (0.5 to 1)
    0.875 (0.5 to 1)
    No statistical analyses for this end point

    Primary: PK parameters following multiple dosing (3)

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    End point title
    PK parameters following multiple dosing (3) [5]
    End point description
    Multiple dose Cmax,ss and Cmin,ss
    End point type
    Primary
    End point timeframe
    On Days 1 and 28 at 0, 1, 2, 3, 6, 8, 12 and 24 hrs post dose and 0, 2, 4 hrs post-dose on Days 4 and 10.
    Notes
    [5] - 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: There are 12 warnings which are due to no statstical analysis being posted.&nbsp; There are no statistical analysis to post for this study
    End point values
    2.5 mg QD AZD1480 5.0 mg QD AZD1480 10 mg QD AZD1480 20 mg QD AZD1480 30 mg QD AZD1480 50 mg QD AZD1480 70 mg QD AZD1480 10 mg BID AZD1480 15 mg BID AZD1480
    Number of subjects analysed
    5
    3
    3
    3
    3
    5
    1
    5
    4
    Units: ug/L
    geometric mean (standard deviation)
        Cmax,ss (ug/L)
    51.3 ± 18
    134 ± 36.3
    176 ± 179
    241 ± 346
    658 ± 265
    924 ± 461
    1500 ± 0
    218 ± 72.3
    334 ± 68.2
        Cmin,ss (ug/L)
    0.177 ± 0.05
    1.47 ± 0.32
    1.2 ± 0.75
    7 ± 12.4
    19.4 ± 6.56
    56.2 ± 280
    26.4 ± 0
    7.37 ± 4.77
    7.69 ± 35.4
    No statistical analyses for this end point

    Primary: Pharmacokinetic parameters following multiple dose (4)

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    End point title
    Pharmacokinetic parameters following multiple dose (4) [6]
    End point description
    Multiple Dose Tmax,ss
    End point type
    Primary
    End point timeframe
    On days 1 and 28 at 0, 1, 2, 3, 4, 6, 8,, 12, 24 hrs post-dose, and at 0, 2, 4 hrs post-dose on days 4 and 10
    Notes
    [6] - 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: There are 12 warnings which are due to no statstical analysis being posted.&nbsp; There are no statistical analysis to post for this study
    End point values
    2.5 mg QD AZD1480 5.0 mg QD AZD1480 10 mg QD AZD1480 20 mg QD AZD1480 30 mg QD AZD1480 50 mg QD AZD1480 70 mg QD AZD1480 10 mg BID AZD1480 15 mg BID AZD1480
    Number of subjects analysed
    6
    3
    3
    3
    3
    6
    1
    6
    4
    Units: hr
    median (full range (min-max))
        tmax,ss (h)
    0.5 (0.5 to 1)
    0.78 (0.75 to 1)
    0.77 (0.75 to 1)
    1 (0.75 to 3)
    0.75 (0.52 to 1)
    0.78 (0.25 to 2.25)
    1.5 (1.5 to 1.5)
    1 (0.5 to 1.5)
    0.875 (0.75 to 1.5)
    No statistical analyses for this end point

    Primary: Inhibition of phosphorylation of STAT3 (count)

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    End point title
    Inhibition of phosphorylation of STAT3 (count) [7]
    End point description
    Number of patient with a 50% reduction in PSTAT3 levels
    End point type
    Primary
    End point timeframe
    Visits 2 and 6 (2 and 4 hours post dose)
    Notes
    [7] - 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: There are 12 warnings which are due to no statstical analysis being posted.&nbsp; There are no statistical analysis to post for this study
    End point values
    2.5 mg QD AZD1480 5.0 mg QD AZD1480 10 mg QD AZD1480 20 mg QD AZD1480 30 mg QD AZD1480 50 mg QD AZD1480 70 mg QD AZD1480 10 mg BID AZD1480 15 mg BID AZD1480
    Number of subjects analysed
    6
    3
    3
    3
    3
    6
    1
    6
    4
    Units: Percent of patients with a 50% reduction
        2 Hour Post dose (count)
    0
    0
    0
    0
    1
    3
    0
    0
    0
        4 Hour Post dose (count)
    0
    0
    0
    0
    0
    0
    0
    1
    0
    No statistical analyses for this end point

    Primary: Pharmacokinetic parameters following single dosing (1a)

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    End point title
    Pharmacokinetic parameters following single dosing (1a) [8]
    End point description
    Single dose CL/F
    End point type
    Primary
    End point timeframe
    0 to 24 hour sampling (Dat 1: 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24hrs post dose)
    Notes
    [8] - 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: There are 12 warnings which are due to no statstical analysis being posted.&nbsp; There are no statistical analysis to post for this study
    End point values
    2.5 mg QD AZD1480 5.0 mg QD AZD1480 10 mg QD AZD1480 20 mg QD AZD1480 30 mg QD AZD1480 50 mg QD AZD1480 70 mg QD AZD1480 10 mg BID AZD1480 15 mg BID AZD1480
    Number of subjects analysed
    6
    3
    3
    3
    3
    6
    1
    6
    4
    Units: L/h
    geometric mean (standard deviation)
        CL/F (L/h)
    35.2 ± 13.9
    16 ± 4.25
    34.8 ± 22.5
    38.7 ± 16.7
    14.7 ± 5.52
    13.8 ± 8.5
    11.1 ± 0
    22.6 ± 9.05
    29.7 ± 13
    No statistical analyses for this end point

    Primary: Pharmacokinetic parameters following single dosing (1b)

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    End point title
    Pharmacokinetic parameters following single dosing (1b) [9]
    End point description
    Single Dose Vz/F
    End point type
    Primary
    End point timeframe
    0 to 24 hour sampling (Day 1: 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hrs post dose)
    Notes
    [9] - 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: There are 12 warnings which are due to no statstical analysis being posted.&nbsp; There are no statistical analysis to post for this study
    End point values
    2.5 mg QD AZD1480 5.0 mg QD AZD1480 10 mg QD AZD1480 20 mg QD AZD1480 30 mg QD AZD1480 50 mg QD AZD1480 70 mg QD AZD1480 10 mg BID AZD1480 15 mg BID AZD1480
    Number of subjects analysed
    6
    3
    3
    3
    3
    6
    1
    0 [10]
    0 [11]
    Units: Litres
    geometric mean (standard deviation)
        Vz/F (L)
    222 ± 125
    108 ± 28.1
    138 ± 161
    284 ± 92.3
    97 ± 15
    105 ± 82.2
    57.9 ± 0
    ±
    ±
    Notes
    [10] - NA
    [11] - NA
    No statistical analyses for this end point

    Primary: Pharmacokinetic parameters following single dose (1c)

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    End point title
    Pharmacokinetic parameters following single dose (1c) [12]
    End point description
    Single dose Cmax
    End point type
    Primary
    End point timeframe
    0 to 24 hour sampling (Day 1: 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hrs post-dose)
    Notes
    [12] - 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: There are 12 warnings which are due to no statstical analysis being posted.&nbsp; There are no statistical analysis to post for this study
    End point values
    2.5 mg QD AZD1480 5.0 mg QD AZD1480 10 mg QD AZD1480 20 mg QD AZD1480 30 mg QD AZD1480 50 mg QD AZD1480 70 mg QD AZD1480 10 mg BID AZD1480 15 mg BID AZD1480
    Number of subjects analysed
    6
    3
    3
    3
    3
    6
    1
    6
    4
    Units: ug/L
    geometric mean (standard deviation)
        Cmax (ug/L)
    69.9 ± 32.7
    133 ± 54.7
    157 ± 145
    268 ± 227
    739 ± 307
    1320 ± 379
    2600 ± 0
    273 ± 62.2
    324 ± 79.5
    No statistical analyses for this end point

    Primary: Pharmacokinetic parameters following multiple dose(3a)

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    End point title
    Pharmacokinetic parameters following multiple dose(3a) [13]
    End point description
    CLss/F following multiple dose
    End point type
    Primary
    End point timeframe
    On Days 1 and 28 at 0, 1, 2, 3, 4, 6, 8, 12, 24 hrs post-dose and at 0, 2, 4 hours post dose on Days 4 and 10.
    Notes
    [13] - 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: There are 12 warnings which are due to no statstical analysis being posted.&nbsp; There are no statistical analysis to post for this study
    End point values
    2.5 mg QD AZD1480 5.0 mg QD AZD1480 10 mg QD AZD1480 20 mg QD AZD1480 30 mg QD AZD1480 50 mg QD AZD1480 70 mg QD AZD1480 10 mg BID AZD1480 15 mg BID AZD1480
    Number of subjects analysed
    6
    3
    3
    3
    3
    6
    1
    6
    4
    Units: L/h
    geometric mean (standard deviation)
        CLss/F (L/h)
    37.8 ± 6
    15.8 ± 4.4
    30.1 ± 21.7
    20.8 ± 21
    17 ± 5.26
    16 ± 8.94
    9.75 ± 0
    20 ± 6.91
    20.4 ± 13.8
    No statistical analyses for this end point

    Primary: Inhibition of PSTAT3 - number with >=50% reduction

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    End point title
    Inhibition of PSTAT3 - number with >=50% reduction [14]
    End point description
    50% reduction in PSTAT3
    End point type
    Primary
    End point timeframe
    Visits 2 and 6 (2 and 4 hours post dose)
    Notes
    [14] - 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: There are 12 warnings which are due to no statstical analysis being posted.&nbsp; There are no statistical analysis to post for this study
    End point values
    2.5 mg QD AZD1480 5.0 mg QD AZD1480 10 mg QD AZD1480 20 mg QD AZD1480 30 mg QD AZD1480 50 mg QD AZD1480 70 mg QD AZD1480 10 mg BID AZD1480 15 mg BID AZD1480
    Number of subjects analysed
    6
    3
    3
    3
    3
    6
    1
    6
    4
    Units: percent
        2 Hour Post Dose
    0
    0
    0
    0
    33
    50
    0
    0
    0
        4 Hour Pose Dose
    0
    0
    0
    0
    0
    0
    0
    17
    0
    No statistical analyses for this end point

    Primary: Pharmacokinetic parameters following single dosing (1d)

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    End point title
    Pharmacokinetic parameters following single dosing (1d) [15]
    End point description
    Single Dose AUC0-12
    End point type
    Primary
    End point timeframe
    0-12 hour sampling (Day 1:0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hrs post dose)
    Notes
    [15] - 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: There are 12 warnings which are due to no statstical analysis being posted.&nbsp; There are no statistical analysis to post for this study
    End point values
    2.5 mg QD AZD1480 5.0 mg QD AZD1480 10 mg QD AZD1480 20 mg QD AZD1480 30 mg QD AZD1480 50 mg QD AZD1480 70 mg QD AZD1480 10 mg BID AZD1480 15 mg BID AZD1480
    Number of subjects analysed
    6
    3
    3
    3
    3
    6
    1
    6
    4
    Units: ug.h/L
    geometric mean (standard deviation)
        AUC0-12 (ug.h/L)
    69.2 ± 27.5
    295 ± 68.2
    278 ± 257
    472 ± 257
    1860 ± 546
    3090 ± 2060
    5800 ± 0
    425 ± 190
    497 ± 191
    No statistical analyses for this end point

    Primary: Pharmacokinetic parameters following single dosing (2a)

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    End point title
    Pharmacokinetic parameters following single dosing (2a) [16]
    End point description
    Single dose T1/2
    End point type
    Primary
    End point timeframe
    24 hours (Day 1: 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24 hrs post dose)
    Notes
    [16] - 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: There are 12 warnings which are due to no statstical analysis being posted.&nbsp; There are no statistical analysis to post for this study
    End point values
    2.5 mg QD AZD1480 5.0 mg QD AZD1480 10 mg QD AZD1480 20 mg QD AZD1480 30 mg QD AZD1480 50 mg QD AZD1480 70 mg QD AZD1480 10 mg BID AZD1480 15 mg BID AZD1480
    Number of subjects analysed
    6
    3
    3
    3
    3
    6
    1
    0 [17]
    0 [18]
    Units: hr
    arithmetic mean (standard deviation)
        T1/2 (h)
    8.06 ± 2.26
    4.76 ± 1.15
    2.45 ± 1.35
    5.46 ± 2.37
    4.62 ± 0.87
    5.81 ± 0.899
    3.61 ± 0
    ±
    ±
    Notes
    [17] - NA
    [18] - NA
    No statistical analyses for this end point

    Secondary: JAK2 V617 mutation status

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    End point title
    JAK2 V617 mutation status
    End point description
    JAK2 V617F Mutation status (mutation detected/not detected) in patients
    End point type
    Secondary
    End point timeframe
    Determined locally during the screening period
    End point values
    2.5 mg QD AZD1480 5.0 mg QD AZD1480 10 mg QD AZD1480 20 mg QD AZD1480 30 mg QD AZD1480 50 mg QD AZD1480 70 mg QD AZD1480 10 mg BID AZD1480 15 mg BID AZD1480
    Number of subjects analysed
    6
    3
    3
    3
    3
    6
    1
    6
    4
    Units: count (%)
        Unknown (count)
    0
    0
    0
    0
    0
    0
    0
    3
    4
        JAK2 V617F Mutation Detected (count)
    4
    2
    2
    1
    2
    5
    1
    1
    0
        JAK2 V617F Mutation Not Detected (count)
    2
    1
    1
    2
    1
    1
    0
    2
    0
        Unknown (%)
    0
    0
    0
    0
    0
    0
    0
    50
    100
        JAK2 V617F Mutation Detected (%)
    67
    67
    67
    33
    67
    83
    100
    17
    0
        JAK2 V617F Mutation Not Detected (%)
    33
    33
    33
    67
    33
    17
    0
    33
    0
    No statistical analyses for this end point

    Secondary: Efficacy: Clinical Improvement (CI) overall

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    End point title
    Efficacy: Clinical Improvement (CI) overall
    End point description
    To be evaluble for clinical improvement, patients must be evaluable for improvement in hemoglobin, spleen size, transfusionrequirements, platelet count, or ANC*Clinical improvement by IWG criteria in hemoglobin, spleen size, transfusion requirements, platelet count, or ANC
    End point type
    Secondary
    End point timeframe
    This single summary is formed form emerging data gathered during the course of the study
    End point values
    2.5 mg QD AZD1480 5.0 mg QD AZD1480 10 mg QD AZD1480 20 mg QD AZD1480 30 mg QD AZD1480 50 mg QD AZD1480 70 mg QD AZD1480 10 mg BID AZD1480 15 mg BID AZD1480
    Number of subjects analysed
    4
    3
    3
    3
    3
    6
    1
    6
    4
    Units: count (%)
        Clinical Improvement (count)
    0
    2
    0
    0
    0
    2
    0
    1
    0
        Clinical Improvement (%)
    0
    67
    0
    0
    0
    33
    0
    17
    0
        No Clinical Improvement (count)
    4
    1
    3
    3
    3
    4
    1
    5
    4
        No Clinical Improvement (%)
    100
    33
    100
    100
    100
    67
    100
    83
    100
    No statistical analyses for this end point

    Secondary: 50% Clinical Improvement in spleen size from baseline

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    End point title
    50% Clinical Improvement in spleen size from baseline
    End point description
    To be evaluable for improvement in spleen size, spleen size by palpatation needs to be >= 5cm at baseline. Spleen size reduction needs to be maintained for a minimum of 8 weeks (56 days) from baseline.
    End point type
    Secondary
    End point timeframe
    8 weeks
    End point values
    2.5 mg QD AZD1480 5.0 mg QD AZD1480 10 mg QD AZD1480 20 mg QD AZD1480 30 mg QD AZD1480 50 mg QD AZD1480 70 mg QD AZD1480 10 mg BID AZD1480 15 mg BID AZD1480
    Number of subjects analysed
    4
    1
    2
    3
    3
    5
    1
    3
    3
    Units: cm
        Clinical Improvement (count)
    0
    0
    0
    0
    0
    0
    0
    1
    0
        Clinical Improvement (%)
    0
    0
    0
    0
    0
    0
    0
    33
    0
        No Clinical Improvement (ount)
    4
    1
    2
    3
    3
    5
    1
    2
    3
        No clinical Improvement (%)
    100
    100
    100
    100
    100
    100
    100
    67
    100
    No statistical analyses for this end point

    Secondary: Clinical Improvement: haemoglobin

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    End point title
    Clinical Improvement: haemoglobin
    End point description
    To be evaluable for improvement in haemoglobin, patients had to have haemoglobin levels of <10g/L at baseline. The increase in haemoglobin has to be maintained for at least 56 days (8 weeks).
    End point type
    Secondary
    End point timeframe
    8 weeks (56 days)
    End point values
    2.5 mg QD AZD1480 5.0 mg QD AZD1480 10 mg QD AZD1480 20 mg QD AZD1480 30 mg QD AZD1480 50 mg QD AZD1480 70 mg QD AZD1480 10 mg BID AZD1480 15 mg BID AZD1480
    Number of subjects analysed
    3
    3
    1
    2
    1
    5
    1
    4
    1
    Units: g/L
        Clinical Improvement (count)
    0
    0
    0
    0
    0
    1
    0
    0
    0
        Clinical Improvement (%)
    0
    0
    0
    0
    0
    20
    0
    0
    0
        No Clinical improvement (count)
    3
    3
    1
    2
    1
    4
    1
    4
    1
        no clinical improvement (%)
    100
    100
    100
    100
    100
    80
    100
    100
    100
    No statistical analyses for this end point

    Secondary: Clinical improvement: transfusion requirements

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    End point title
    Clinical improvement: transfusion requirements
    End point description
    To be evaluable for improvement in transfusion requirements, patients must have required at least one transfusion of packed RBCs or whole blood one month prior to first dose of AZD1480.
    End point type
    Secondary
    End point timeframe
    56 days ( 8 weeks)
    End point values
    2.5 mg QD AZD1480 5.0 mg QD AZD1480 10 mg QD AZD1480 20 mg QD AZD1480 30 mg QD AZD1480 50 mg QD AZD1480 70 mg QD AZD1480 10 mg BID AZD1480 15 mg BID AZD1480
    Number of subjects analysed
    1
    3
    0 [19]
    1
    0 [20]
    1
    1
    2
    1
    Units: counts
        Clinical Improvement (count)
    0
    2
    0
    1
    0
    0
    0
        Clinical improvement (%)
    0
    67
    0
    100
    0
    0
    0
        No Clinical Improvement (count)
    1
    1
    1
    0
    1
    2
    1
        No clinical Improvement (%)
    100
    33
    100
    0
    100
    100
    100
    Notes
    [19] - non evaluable
    [20] - Non evaluable
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs (SAEs and non-serious AEs) will be collected throughout the study, from informed consent until 30 days after study treatment is discontinued.
    Adverse event reporting additional description
    The death wasn't deemed causally related. Dose: 15 mg BID Time from start of treatment to death (days): 129 Primary cause of death : ACCIDENT Secondary cause of death: HEMORRHAGHE: ANEMIA AGGRAVATION (GRADE 4)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    2.5 mg QD AZD1480
    Reporting group description
    2.5 mg QD AZD1480

    Reporting group title
    5.0 mg QD AZD1480
    Reporting group description
    5.0 mg QD AZD1480

    Reporting group title
    20 mg QD AZD1480
    Reporting group description
    20 mg QD AZD1480

    Reporting group title
    10 mg QD AZD1480
    Reporting group description
    10 mg QD AZD1480

    Reporting group title
    30 mg QD AZD1480
    Reporting group description
    30 mg QD AZD1480

    Reporting group title
    50 mg QD AZD1480
    Reporting group description
    50 mg QD AZD1480

    Reporting group title
    70 mg QD AZD1480
    Reporting group description
    70 mg QD AZD1480

    Reporting group title
    10 mg BID AZD1480
    Reporting group description
    10 mg BID AZD1480

    Reporting group title
    15 mg BID AZD1480
    Reporting group description
    15 mg BID AZD1480

    Serious adverse events
    2.5 mg QD AZD1480 5.0 mg QD AZD1480 20 mg QD AZD1480 10 mg QD AZD1480 30 mg QD AZD1480 50 mg QD AZD1480 70 mg QD AZD1480 10 mg BID AZD1480 15 mg BID AZD1480
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 6 (33.33%)
    2 / 3 (66.67%)
    3 / 3 (100.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    4 / 6 (66.67%)
    0 / 1 (0.00%)
    3 / 6 (50.00%)
    1 / 4 (25.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Investigations
    HAEMOGLOBIN DECREASED
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    BASAL CELL CARINOMA
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    CRANIOCEREBRAL INJURY
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    UPPER LIMB FRACTUR
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial flutter/ fibrillation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CARDIAC FAILURE CHRONIC
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CORONARY ARTERY DISEASE
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TACHYCARDIA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    APHASIA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    AMNESIA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorder, central
    Additional description: ATAXIA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DYSARTHRIA
    Additional description: DYSARTHRIA
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    ANAEMI
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    NEUTROPENIA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SPLENIC INFARCTION
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    PYREXIA
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional State
    Additional description: Confusional State
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    PNEUMONIA
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DEHYDRATION
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GOUT
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    2.5 mg QD AZD1480 5.0 mg QD AZD1480 20 mg QD AZD1480 10 mg QD AZD1480 30 mg QD AZD1480 50 mg QD AZD1480 70 mg QD AZD1480 10 mg BID AZD1480 15 mg BID AZD1480
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 6 (100.00%)
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    6 / 6 (100.00%)
    1 / 1 (100.00%)
    6 / 6 (100.00%)
    4 / 4 (100.00%)
    General disorders and administration site conditions
    FATIGUE
    Additional description: FATIGUE
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    0
    0
    ASTHENIA
    Additional description: ASTHENIA
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    4 / 6 (66.67%)
    0 / 4 (0.00%)
         occurrences all number
    2
    1
    2
    1
    1
    1
    0
    4
    0
    Mucosal inflammation NOS
    Additional description: MUCOSAL INFLAMMATION
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    1
    0
    1
    0
    PYREXIA
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    1
    0
    0
    0
    HYPERTHERMIA
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    1
    0
    OEDEMA PERIPHERAL
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 6 (33.33%)
    1 / 1 (100.00%)
    3 / 6 (50.00%)
    2 / 4 (50.00%)
         occurrences all number
    1
    1
    2
    0
    0
    2
    1
    3
    2
    OEDEMA
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 1 (100.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    DYSPNOEA
    Additional description: DYSPNOEA
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    2 / 6 (33.33%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    1
    1
    1
    1
    0
    2
    1
    EPITAXIS
    Additional description: EPITAXIS
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    1
    0
    0
    0
    0
    0
    Psychiatric disorders
    CONFUSIONAL STATE
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    INSOMNIA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    1
    Investigations
    Weight increase
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    1
    CARDIAC MURMUR
    Additional description: CARDIAC MURMUR
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    1
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    EXCORIATION
    Additional description: EXCORIATION
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    0
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    3 / 6 (50.00%)
    1 / 1 (100.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    3
    1
    1
    0
    HEADACHE
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    1 / 1 (100.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    1
    1
    0
    PARAESTHES
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    1
    1
    1
    0
    0
    0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    4 / 6 (66.67%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    1
    1
    0
    4
    0
    1
    0
    NEUTROPENIA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    0
    Thrombocytopenia, unspecified
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    3 / 6 (50.00%)
    0 / 1 (0.00%)
    2 / 6 (33.33%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    0
    0
    0
    3
    0
    2
    1
    Eye disorders
    RETINAL HAEMORRHAGE
    Additional description: RETINAL HAEMORRHAGE
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    1
    CATARAC
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    2 / 6 (33.33%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    2
    1
    CONJUNCTIVAL HAEMORRHAG
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    0
    1
    DRY EYE
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    3 / 6 (50.00%)
    0 / 1 (0.00%)
    3 / 6 (50.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    0
    3
    0
    HAEMORRHAGE
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    0
    KERATITI
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    2 / 6 (33.33%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    2
    0
    1
    0
    Gastrointestinal disorders
    Diarrhoea NOS
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 6 (33.33%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    1
    0
    0
    2
    0
    1
    1
    Vomiting alone
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    1
    0
    ASCITES
    Additional description: ASCITES
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    0
    Abdominal wall disorder
    Additional description: ABDOMINAL DISTENSION
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    0
    ABDOMINAL PAIN
    Additional description: ABDOMINAL PAIN
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    2 / 6 (33.33%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    2
    0
    0
    0
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    2 / 6 (33.33%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    0
    0
    0
    CONSTIPATION
    Additional description: CONSTIPATION
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    0
    GASTROOESOPHAGEAL REFLUX DISEASE
    Additional description: GASTROOESOPHAGEAL REFLUX DISEASE
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    1
    Haemorrhoids
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 6 (33.33%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    0
    NAUSEA
    Additional description: NAUSEA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    0
    Hepatobiliary disorders
    HYPERBILIRUBINAEMIA
    Additional description: HYPERBILIRUBINAEMIA
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    1
    Skin and subcutaneous tissue disorders
    ECCHYMOSI
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    0
    PETECHIAE
    Additional description: PETECHIAE
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    1
    Pruritis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    1
    0
    RASH
    Additional description: RASH
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    0
    1
    Renal and urinary disorders
    PROTEINURIA
         subjects affected / exposed
    3 / 6 (50.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    1
    1
    0
    0
    1
    0
    0
    0
    HAEMATURIA
    Additional description: HAEMATURIA
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    MUSCLE SPASMS
    Additional description: MUSCLE SPASMS
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    2 / 6 (33.33%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    1
    2
    1
    0
    0
    2
    1
    BONE PAIN
    Additional description: BONE PAIN
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    1
    0
    1
    0
    MUSCULOSKELETAL PAIN
    Additional description: MUSCULOSKELETAL PAIN
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    0
    Myalgia aggravated
    Additional description: MYALGIA
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    1
    Pain
    Additional description: PAIN IN EXTREMITY
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    0
    Infections and infestations
    FOLLICULITIS
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Mar 2009
    This is to simplify the assessment of response in this study by using the most commonly used
    01 Jun 2009
    To provide a more accurate time frame for screening eye exams.
    07 Oct 2009
    To clarify that patients cannot be dosed on Day 4 and Day 10 if there are significant eye,
    04 Mar 2010
    To remove the drug washout on Days 2 and 3. Patients will now dose continuously from Day
    03 Jun 2010
    To correct the pulmonary toxicity DLT definition in the protocol. A decrease in FVC or DLco
    30 Sep 2010
    To add clarification regarding the definition of DLT, and to ensure consistency across other
    15 Feb 2011
    To ensure the exploratory objectives in the synopsis are consistent with the those in the body
    30 Jun 2011
    This is an administrative change whereby the update AZ template does not allow for all

    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.
    All patients were enrolled into Part A only. The study was planned as 2 parts (A and B); however, all patients were enrolled into Part A. No formal statistical analysis was performed.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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