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    Clinical Trial Results:
    A Phase Ib/IIb, open-label, multi-center study of oral Panobinostat (LBH589) administered with 5-Azacitidine (Vidaza®) in adult patients with myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) or acute myeloid leukemia (AML). Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.nov for complete trial results.

    Summary
    EudraCT number
    		 2009-010548-32
    Trial protocol
    		 DE   SE   AT   ES   BE   GB   HU   IT  
    Global end of trial date
    29 Apr 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 May 2020
    First version publication date
    15 May 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CLBH589H2101
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00946647
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma, AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma, AG, +41 613241111, novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma, AG, +41 613241111, novartis.email@novartis.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
    29 Apr 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Apr 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Phase: To determine the maximum tolerated dose (MTD) and/or recommended Phase II dose (RPIID) of oral PAN in combination with a fixed dose of 5-Aza in adult patients with International Prognostic Scoring System intermediate 2 (IPSS INT-2) or high risk MDS, CMML, or AML. Phase ll: To assess preliminary efficacy of treatment with the panobinostat and 5-Aza combination at the RPIID relative to treatment with single agent 5-Aza through the assessment of composite CR (CR or CRi or bone marrow CR).
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Dec 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 4
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    Germany: 11
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    Hungary: 15
    Country: Number of subjects enrolled
    Italy: 8
    Country: Number of subjects enrolled
    Korea, Republic of: 4
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    Sweden: 3
    Country: Number of subjects enrolled
    Switzerland: 4
    Country: Number of subjects enrolled
    Thailand: 3
    Country: Number of subjects enrolled
    United States: 31
    Worldwide total number of subjects
    113
    EEA total number of subjects
    65
    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)
    29
    From 65 to 84 years
    83
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 In phase l a total of 31 patients were treated with escalating dose of PAN,20 mg 30 mg & 40 mg. In phase ll a total of 82 patients were actually randomized with 40 patients assigned to PAN+5-Aza & 42 patients to 5-Aza. Treatment was assigned sequentially for the phase Ib. Randomization applies only for the phase IIb part.

    Pre-assignment
    Screening details
    		 For phase I, approximately 26 patients were planned to be enrolled in cohorts of at least three MTD evaluable patients per dose level. For phase ll, approximately 80 patients were planned to be enrolled, 40 patients per arm.

    Period 1
    Period 1 title
    Phase l part
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 PAN + 5-Aza 20 mg
    Arm description
    		 In this escalating phase, participants took panobinostat of 20 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15 and a fixed dose of 5-Azacytidine (5-Aza) at 75 mg/m2/day for 7 days in Week 1 of each cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    5-Azacytidine (5-Aza)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The dose of 5-Aza was 75 mg/m2. 5-Aza was to be administered subcutaneously daily for seven days.

    Investigational medicinal product name
    oral panobinostat
    Investigational medicinal product code
    LBH589
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Dose of 20 mg delivered once daily on Day 3, 5, 8, 10, 12, and 15, in combination with 5-Aza. Immediate-release hard gelatin capsules in strengths of 5 mg, 10 mg (when available) and 20 mg which were given on a flat scale of mg per given day.

    Arm title
    		 PAN + 5-Aza 30 mg
    Arm description
    		 In this escalating phase, participants took panobinostat of 30 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15 and a fixed dose of 5-Azacytidine (5-Aza) at 75 mg/m2/day for 7 days in Week 1 of each cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    5-Azacytidine (5-Aza)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The dose of 5-Aza was 75 mg/m2. 5-Aza was to be administered subcutaneously daily for seven days.

    Investigational medicinal product name
    oral panobinostat
    Investigational medicinal product code
    LBH589
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Dose of 30 mg starting with 20 mg delivered once daily on Day 3, 5, 8, 10, 12, and 15 in combination with 5-Aza. Immediate-release hard gelatin capsules in strengths of 5 mg, 10 mg (when available) and 20 mg which were given on a flat scale of mg per given day.

    Arm title
    		 PAN + 5-Aza 40 mg
    Arm description
    		 In this escalating phase, participants took panobinostat of 40 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15 and a fixed dose of 5-Azacytidine (5-Aza) at 75 mg/m2/day for 7 days in Week 1 of each cycle
    Arm type
    		 Experimental

    Investigational medicinal product name
    oral panobinostat
    Investigational medicinal product code
    LBH589
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Dose of 40 mg delivered once daily. immediate-release hard gelatin capsules in strengths of 5 mg, 10 mg (when available) and 20 mg which were given on a flat scale of mg per given day.

    Investigational medicinal product name
    5-Azacytidine (5-Aza)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The dose of 5-Aza was 75 mg/m2. 5-Aza was to be administered subcutaneously daily for seven days.

    Number of subjects in period 1 [1]
    		PAN + 5-Aza 20 mg PAN + 5-Aza 30 mg PAN + 5-Aza 40 mg
    Started
    6
    18
    7
    Completed
    0
    0
    0
    Not completed
    6
    18
    7
         Consent withdrawn by subject
    1
    4
    3
         Disease progression
    3
    6
    1
         Adverse event, non-fatal
    2
    5
    3
         Abnormal values
    -
    2
    -
         Reason missing
    -
    1
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Subjects in the dose escalation phase (part 1/phase l) were fewer than those in the dose escalation phase (part 2/phase ll)
    Period 2
    Period 2 title
    Phase ll part
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Panobinostat + 5-Azacytidine
    Arm description
    		 In phase II: Panobinostat : Rapid Phase II doses at 30 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15. In both phases, dose of 5-Azacytidine was 75 mg/m^2, subcutaneously Daily for Day 1 to Day 7.
    Arm type
    		 Experimental

    Investigational medicinal product name
    5-Azacytidine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The dose of 5-Aza was 75 mg/m2. 5-Aza was to be administered subcutaneously daily for seven days.

    Investigational medicinal product name
    Oral panobinostat
    Investigational medicinal product code
    LBH589
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    30 mg of oral panobinostat once daily on Day 3, 5, 8, 10, 12, and 15 in combination with 5-Aza.

    Arm title
    		 5-Azacytidine
    Arm description
    		 The dose of 5-Aza was fixed at 75 mg/m2/day for 7 days in Week 1 of each cycle. 5-Aza was sourced locally, except in 4 countries (Hungary, Switzerland, UK, and Spain, for which a central purchase was used by Novartis. Dose of 5-Azacytidine : 75 mg/m^2 subcutaneously daily from Day 1 to Day 7.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    5-Azacytidine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The dose of 5-Aza was 75 mg/m2. 5-Aza was to be administered subcutaneously daily for seven days.

    Number of subjects in period 2
    		Panobinostat + 5-Azacytidine 5-Azacytidine
    Started
    40
    42
    Completed
    0
    0
    Not completed
    40
    42
         Adverse event, serious fatal
    7
    4
         Consent withdrawn by subject
    8
    6
         Disease progression
    6
    14
         Subj cond no longer required study drug
    2
    -
         Adverse event, non-fatal
    10
    6
         Administrative problems
    3
    8
         Untreated
    -
    2
         Protocol deviation
    4
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    PAN + 5-Aza 20 mg
    Reporting group description
    		 In this escalating phase, participants took panobinostat of 20 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15 and a fixed dose of 5-Azacytidine (5-Aza) at 75 mg/m2/day for 7 days in Week 1 of each cycle.

    Reporting group title
    PAN + 5-Aza 30 mg
    Reporting group description
    		 In this escalating phase, participants took panobinostat of 30 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15 and a fixed dose of 5-Azacytidine (5-Aza) at 75 mg/m2/day for 7 days in Week 1 of each cycle.

    Reporting group title
    PAN + 5-Aza 40 mg
    Reporting group description
    		 In this escalating phase, participants took panobinostat of 40 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15 and a fixed dose of 5-Azacytidine (5-Aza) at 75 mg/m2/day for 7 days in Week 1 of each cycle

    Reporting group values
    		 PAN + 5-Aza 20 mg PAN + 5-Aza 30 mg PAN + 5-Aza 40 mg Total
    Number of subjects
    		 6 18 7 31
    Age Categorical
    Units: participants
        < 65
    		 1 5 1 7
        >= 65
    		 5 13 6 24
    Sex: Female, Male
    Units: participants
        Female
    		 2 10 4 16
        Male
    		 4 8 3 15
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
    		 5 15 6 26
        Black
    		 0 0 1 1
        Asian
    		 0 0 0 0
        Other
    		 1 3 0 4
    Subject analysis sets

    Subject analysis set title
    PAN + 5-Aza 20 mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    ‌ In this escalating phase, participants took panobinostat of 20 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15 and a fixed dose of 5-Azacytidine (5-Aza) at 75 mg/m2/day for 7 days in Week 1 of each cycle.

    Subject analysis set title
    PAN + 5-Aza 30 mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    ‌ In this escalating phase, participants took panobinostat of 30 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15 and a fixed dose of 5-Azacytidine (5-Aza) at 75 mg/m2/day for 7 days in Week 1 of each cycle.

    Subject analysis set title
    Panobinostat + 5-Azacytidine (MDS-CMML)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    In phase II: Panobinostat : Rapid Phase II doses at 30 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15. In both phases, dose of 5-Azacytidine was 75 mg/m^2, subcutaneously Daily for Day 1 to Day 7.

    Subject analysis set title
    5-Azacytidine (MDS-CMML)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The dose of 5-Aza was fixed at 75 mg/m2/day for 7 days in Week 1 of each cycle. 5-Aza was sourced locally, except in 4 countries (Hungary, Switzerland, UK, and Spain, for which a central purchase was used by Novartis. Dose of 5-Azacytidine : 75 mg/m^2 subcutaneously daily from Day 1 to Day 7.

    Subject analysis set title
    Panobinostat + 5-Azacytidine (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    In phase II: Panobinostat : Rapid Phase II doses at 30 mg delivered orally at Day 3, Day5, Day 8, Day 10, Day 12, Day 15. In both phases, dose of 5-Azacytidine was 75 mg/m^2, subcutaneously Daily for Day 1 to Day 7.

    Subject analysis set title
    5-Azacytidine (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The dose of 5-Aza was fixed at 75 mg/m2/day for 7 days in Week 1 of each cycle. 5-Aza was sourced locally, except in 4 countries (Hungary, Switzerland, UK, and Spain, for which a central purchase was used by Novartis. Dose of 5-Azacytidine : 75 mg/m^2 subcutaneously daily from Day 1 to Day 7.

    Subject analysis set title
    Panobinostat + 5-Azacytidine (AML)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    In phase II: Panobinostat : Rapid Phase II doses at 30 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15. In both phases, dose of 5-Azacytidine was 75 mg/m^2, subcutaneously Daily for Day 1 to Day 7.

    Subject analysis set title
    5-Azacytidine (AML)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The dose of 5-Aza was fixed at 75 mg/m2/day for 7 days in Week 1 of each cycle. 5-Aza was sourced locally, except in 4 countries (Hungary, Switzerland, UK, and Spain, for which a central purchase was used by Novartis. Dose of 5-Azacytidine : 75 mg/m^2 subcutaneously daily from Day 1 to Day 7.

    Subject analysis sets values
    		 PAN + 5-Aza 20 mg PAN + 5-Aza 30 mg Panobinostat + 5-Azacytidine (MDS-CMML) 5-Azacytidine (MDS-CMML) Panobinostat + 5-Azacytidine (FAS) 5-Azacytidine (FAS) Panobinostat + 5-Azacytidine (AML) 5-Azacytidine (AML)
    Number of subjects
    5
    14
    31
    29
    40
    42
    9
    13
    Age Categorical
    Units: participants
        < 65
    0
    0
    0
    0
    14
    8
        >= 65
    0
    0
    0
    0
    26
    34
    Age continuous
    Units:
        
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    Sex: Female, Male
    Units: participants
        Female
    0
    0
    0
    0
    11
    17
        Male
    0
    0
    0
    0
    29
    25
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
        Black
        Asian
        Other

    End points

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    End points reporting groups
    Reporting group title
    PAN + 5-Aza 20 mg
    Reporting group description
    		 In this escalating phase, participants took panobinostat of 20 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15 and a fixed dose of 5-Azacytidine (5-Aza) at 75 mg/m2/day for 7 days in Week 1 of each cycle.

    Reporting group title
    PAN + 5-Aza 30 mg
    Reporting group description
    		 In this escalating phase, participants took panobinostat of 30 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15 and a fixed dose of 5-Azacytidine (5-Aza) at 75 mg/m2/day for 7 days in Week 1 of each cycle.

    Reporting group title
    PAN + 5-Aza 40 mg
    Reporting group description
    		 In this escalating phase, participants took panobinostat of 40 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15 and a fixed dose of 5-Azacytidine (5-Aza) at 75 mg/m2/day for 7 days in Week 1 of each cycle
    Reporting group title
    Panobinostat + 5-Azacytidine
    Reporting group description
    		 In phase II: Panobinostat : Rapid Phase II doses at 30 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15. In both phases, dose of 5-Azacytidine was 75 mg/m^2, subcutaneously Daily for Day 1 to Day 7.

    Reporting group title
    5-Azacytidine
    Reporting group description
    		 The dose of 5-Aza was fixed at 75 mg/m2/day for 7 days in Week 1 of each cycle. 5-Aza was sourced locally, except in 4 countries (Hungary, Switzerland, UK, and Spain, for which a central purchase was used by Novartis. Dose of 5-Azacytidine : 75 mg/m^2 subcutaneously daily from Day 1 to Day 7.

    Subject analysis set title
    PAN + 5-Aza 20 mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    ‌ In this escalating phase, participants took panobinostat of 20 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15 and a fixed dose of 5-Azacytidine (5-Aza) at 75 mg/m2/day for 7 days in Week 1 of each cycle.

    Subject analysis set title
    PAN + 5-Aza 30 mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    ‌ In this escalating phase, participants took panobinostat of 30 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15 and a fixed dose of 5-Azacytidine (5-Aza) at 75 mg/m2/day for 7 days in Week 1 of each cycle.

    Subject analysis set title
    Panobinostat + 5-Azacytidine (MDS-CMML)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    In phase II: Panobinostat : Rapid Phase II doses at 30 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15. In both phases, dose of 5-Azacytidine was 75 mg/m^2, subcutaneously Daily for Day 1 to Day 7.

    Subject analysis set title
    5-Azacytidine (MDS-CMML)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The dose of 5-Aza was fixed at 75 mg/m2/day for 7 days in Week 1 of each cycle. 5-Aza was sourced locally, except in 4 countries (Hungary, Switzerland, UK, and Spain, for which a central purchase was used by Novartis. Dose of 5-Azacytidine : 75 mg/m^2 subcutaneously daily from Day 1 to Day 7.

    Subject analysis set title
    Panobinostat + 5-Azacytidine (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    In phase II: Panobinostat : Rapid Phase II doses at 30 mg delivered orally at Day 3, Day5, Day 8, Day 10, Day 12, Day 15. In both phases, dose of 5-Azacytidine was 75 mg/m^2, subcutaneously Daily for Day 1 to Day 7.

    Subject analysis set title
    5-Azacytidine (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The dose of 5-Aza was fixed at 75 mg/m2/day for 7 days in Week 1 of each cycle. 5-Aza was sourced locally, except in 4 countries (Hungary, Switzerland, UK, and Spain, for which a central purchase was used by Novartis. Dose of 5-Azacytidine : 75 mg/m^2 subcutaneously daily from Day 1 to Day 7.

    Subject analysis set title
    Panobinostat + 5-Azacytidine (AML)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    In phase II: Panobinostat : Rapid Phase II doses at 30 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15. In both phases, dose of 5-Azacytidine was 75 mg/m^2, subcutaneously Daily for Day 1 to Day 7.

    Subject analysis set title
    5-Azacytidine (AML)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The dose of 5-Aza was fixed at 75 mg/m2/day for 7 days in Week 1 of each cycle. 5-Aza was sourced locally, except in 4 countries (Hungary, Switzerland, UK, and Spain, for which a central purchase was used by Novartis. Dose of 5-Azacytidine : 75 mg/m^2 subcutaneously daily from Day 1 to Day 7.

    Primary: Incidence of dose limiting toxicity (DLT) (Phase l)

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    End point title
    		 Incidence of dose limiting toxicity (DLT) (Phase l) [1]
    End point description
    Dose limiting toxicity (DLT) was defined as a toxicity requiring treatment withdrawal and included the following: Non-hematologic toxicity qualifying for DLT and Hematologic toxicity qualifying for DLT
    End point type
    Primary
    End point timeframe
    within the first 28 days (cycle 1)
    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: No Statistical analysis was planned for this endpoint
    End point values
    		 PAN + 5-Aza 20 mg PAN + 5-Aza 30 mg PAN + 5-Aza 40 mg
    Number of subjects analysed
    5
    14
    7
    Units: Participants
        Number of participants with DLTs
    1
    3
    2
        Number of DLTs
    2
    6
    4
    No statistical analyses for this end point

    Primary: Composite Complete Response(Phase llb)

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    End point title
    		 Composite Complete Response(Phase llb) [2]
    End point description
    Composite complete response is defined as complete response (CR), Complete response with incomplete blood count recovery (CRi) or bone marrow complete response (BM-CR).
    End point type
    Primary
    End point timeframe
    40 weeks
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No Statistical analysis was planned for this endpoint
    End point values
    		 Panobinostat + 5-Azacytidine 5-Azacytidine
    Number of subjects analysed
    40
    42
    Units: Percentage of participants
        number (confidence interval 95%)
    27.5 (14.60 to 43.89)
    14.3 (5.43 to 28.54)
    No statistical analyses for this end point

    Secondary: Clinical response other than Composite clinical response for myeloid dysplastic syndromes(MDS)/chronic myelomonocytic leukemia (CMML) patients per Investigator (Phase llb)

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    End point title
    		 Clinical response other than Composite clinical response for myeloid dysplastic syndromes(MDS)/chronic myelomonocytic leukemia (CMML) patients per Investigator (Phase llb)
    End point description
    This is the best overall response as measured by Clinical response. Clinical response is defined as having complete remission (CR), bone marrow complete remission (BM-CR), partial remission or hematologic improvement (HI).
    End point type
    Secondary
    End point timeframe
    40 weeks
    End point values
    		 Panobinostat + 5-Azacytidine (MDS-CMML) 5-Azacytidine (MDS-CMML)
    Number of subjects analysed
    31
    29
    Units: Percentage of subjects
        number (confidence interval 95%)
    41.9 (24.5 to 60.9)
    41.4 (23.5 to 61.1)
    No statistical analyses for this end point

    Secondary: Clinical response other than Composite clinical response for Acute myelogenous leukemia (AML) patients per Investigator (Phase llb)

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    End point title
    		 Clinical response other than Composite clinical response for Acute myelogenous leukemia (AML) patients per Investigator (Phase llb)
    End point description
    This is the best overall response as measured by Clinical response. Clinical response is defined as having complete remission (CR), complete remission with incomplete blood count recovery (CRi) or partial remission.
    End point type
    Secondary
    End point timeframe
    40 weeks
    End point values
    		 Panobinostat + 5-Azacytidine (AML) 5-Azacytidine (AML)
    Number of subjects analysed
    9
    13
    Units: Percentage of participants
        number (confidence interval 95%)
    22.2 (2.8 to 60.0)
    30.8 (9.1 to 61.4)
    No statistical analyses for this end point

    Secondary: Overall response rate (ORR) assessed by Best overall response: Participants with MDS/CMML per Investigator (phase llb)

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    End point title
    		 Overall response rate (ORR) assessed by Best overall response: Participants with MDS/CMML per Investigator (phase llb)
    End point description
    Best overall response as measured by complete remission (CR) or bone marrow CR (BM-CR) or partial remission (PR) or hematologic improvement (HI).
    End point type
    Secondary
    End point timeframe
    40 weeks
    End point values
    		 Panobinostat + 5-Azacytidine (MDS-CMML) 5-Azacytidine (MDS-CMML)
    Number of subjects analysed
    31
    29
    Units: Percentage of participants
    number (not applicable)
        Clinical response (CR, BM-CR, PR, HI)
    41.9
    41.4
        Complete remission (CR)
    16.1
    6.9
        Bone marrow CR (BM-CR)
    12.9
    3.4
        Partial remission (PR)
    0.0
    6.9
    No statistical analyses for this end point

    Secondary: Overall response rate (ORR)assessed by Best overall response: Participants with AML per Investigator (phase llb)

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    End point title
    		 Overall response rate (ORR)assessed by Best overall response: Participants with AML per Investigator (phase llb)
    End point description
    Best overall response as measured by complete remission (CR) or complete response with incomplete blood count recovery (CRi )or partial remission (PR).
    End point type
    Secondary
    End point timeframe
    40 weeks
    End point values
    		 Panobinostat + 5-Azacytidine (AML) 5-Azacytidine (AML)
    Number of subjects analysed
    9
    13
    Units: Percentage of participants
    number (not applicable)
        Clinical response (CR, CRi, PR)
    22.2
    30.8
        Complete remission (CR)
    11.1
    15.4
        Compl remiss. with incompl blood cnt
    11.1
    7.7
        Partial remission (PR)
    0.0
    7.7
    No statistical analyses for this end point

    Secondary: Hematologic Improvement (HI) for myeloid dysplastic syndromes(MDS)/chronic myelomonocytic leukemia (CMML) patients per Investigator (Phase llb)

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    End point title
    		 Hematologic Improvement (HI) for myeloid dysplastic syndromes(MDS)/chronic myelomonocytic leukemia (CMML) patients per Investigator (Phase llb)
    End point description
    Hematologic response consists of Erythroid response (HI-E), Platelet response (HI-P) and Neutrophil response (HI-N). HI-E: Hgb increase by ≥ 1.5 g/dL over pretreatment & relevant reduction of units of RBC transfusions by an absolute number of at least 4 units of PRBCs/8 weeks compared with the pretreatment transfusion number in the previous 8 weeks. Only RBC transfusions given for a Hgb of ≤ 9.0 g/dL pretreatment will count in the RBC transfusion response evaluation. HI-P: Absolute increase of ≥ 30 x 109/L over pretreatment or patients starting with ≥ 20 x 109/L platelets OR increase from <20 x 109/L at pretreatment to > 20 x 109/L and by at least 100%. HI-N: At least 100% increase and an absolute increase > 0.5 x 109/L over pretreatment value.
    End point type
    Secondary
    End point timeframe
    40 weeks
    End point values
    		 Panobinostat + 5-Azacytidine (MDS-CMML) 5-Azacytidine (MDS-CMML)
    Number of subjects analysed
    31
    29
    Units: Percentage of participants
    number (confidence interval 95%)
        Erythroid response (HI-E)
    25.8 (11.9 to 44.6)
    31.0 (15.3 to 50.8)
        Platelet response (HI-P)
    35.5 (19.2 to 54.6)
    24.1 (10.3 to 43.5)
        Neutrophil response (HI-N)
    19.4 (7.5 to 37.5)
    13.8 (3.9 to 31.7)
    No statistical analyses for this end point

    Secondary: 1-year survival rate (Phase llb)

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    End point title
    		 1-year survival rate (Phase llb)
    End point description
    Overall survival was defined as the time from date of randomization to date of death due to any cause. If a patient was not known to have died, survival was censored at the date of last contact. Patients not known to have died were censored for ‘Lost to follow-up’ if the time between their last contact date and the analysis cut-off date was longer than 3 months and 2 weeks (104 days) during the first year after study evaluation completion, and longer than 6 months and 2 weeks (194 days), thereafter. The 1-year survival rate was obtained from the Kaplan-Meier analysis of overall survival, and its variance was estimated by Greenwood’s formula.
    End point type
    Secondary
    End point timeframe
    40 weeks
    End point values
    		 Panobinostat + 5-Azacytidine 5-Azacytidine
    Number of subjects analysed
    40
    42
    Units: months
        median (confidence interval 95%)
    14.9 (10.4 to 999)
    15.6 (11.4 to 999)
    No statistical analyses for this end point

    Secondary: Time to progression (TTP) (Phase llb)

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    End point title
    		 Time to progression (TTP) (Phase llb)
    End point description
    Time to progression (TTP) was defined as the time from the date of randomization to the date of the first documented PD per investigator’s assessment or death due to study indication. Time to progression was analyzed by the Kaplan Meier method. Based on the Guidelines for Implementation of international working group (IWG) response criteria in AML, MDS and CMML according to Cheson 2003 and 2006.
    End point type
    Secondary
    End point timeframe
    40 weeks
    End point values
    		 Panobinostat + 5-Azacytidine 5-Azacytidine
    Number of subjects analysed
    40
    42
    Units: months
        median (confidence interval 95%)
    99 (11.1 to 999)
    15.2 (11.0 to 999)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All Adverse events are reported in this record from First Patient First Treatment until Last Patient Last Visit.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    PAN + 5-Aza
    Reporting group description
    		 In phase II: Panobinostat : Rapid Phase II doses at 30 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15. In both phases, dose of 5-Azacytidine was 75 mg/m^2, subcutaneously Daily for Day 1 to Day 7.

    Reporting group title
    All Patients
    Reporting group description
    		 Patients in the Panobinostat + 5-Azacytidine arm and in the 5-Azacytidine arm.

    Reporting group title
    5-Aza
    Reporting group description
    		 The dose of 5-Aza was fixed at 75 mg/m2/day for 7 days in Week 1 of each cycle. 5-Aza was sourced locally, except in 4 countries (Hungary, Switzerland, UK, and Spain, for which a central purchase was used by Novartis. Dose of 5-Azacytidine : 75 mg/m^2 subcutaneously daily from Day 1 to Day

    Serious adverse events
    		 PAN + 5-Aza All Patients 5-Aza
    Total subjects affected by serious adverse events
         subjects affected / exposed
    28 / 38 (73.68%)
    56 / 80 (70.00%)
    28 / 42 (66.67%)
         number of deaths (all causes)
    6
    9
    3
         number of deaths resulting from adverse events
    2
    2
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Benign anorectal neoplasm
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 80 (1.25%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large cell lung cancer metastatic
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 80 (1.25%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 80 (1.25%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 80 (1.25%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 80 (1.25%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 80 (1.25%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 38 (7.89%)
    3 / 80 (3.75%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 80 (2.50%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 80 (1.25%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 80 (1.25%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 80 (1.25%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 80 (1.25%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 80 (2.50%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 80 (1.25%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 80 (1.25%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 80 (1.25%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram ST segment depression
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 80 (1.25%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram T wave inversion
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 80 (1.25%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 80 (1.25%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 80 (1.25%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 80 (1.25%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 80 (1.25%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transfusion reaction
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 80 (1.25%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 80 (1.25%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 80 (1.25%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 80 (1.25%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 80 (1.25%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 80 (1.25%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 80 (1.25%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Coronary artery disease
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 80 (1.25%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Left ventricular hypertrophy
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 80 (1.25%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Dysarthria
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 80 (1.25%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 80 (1.25%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 80 (2.50%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 80 (1.25%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 38 (5.26%)
    2 / 80 (2.50%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaemia of malignant disease
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 80 (1.25%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    10 / 38 (26.32%)
    16 / 80 (20.00%)
    6 / 42 (14.29%)
         occurrences causally related to treatment / all
    8 / 17
    9 / 24
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemolytic anaemia
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 80 (1.25%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 80 (1.25%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 38 (5.26%)
    4 / 80 (5.00%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 80 (2.50%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    3 / 38 (7.89%)
    6 / 80 (7.50%)
    3 / 42 (7.14%)
         occurrences causally related to treatment / all
    2 / 3
    3 / 6
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Diplopia
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 80 (1.25%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uveitis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 80 (1.25%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vision blurred
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 80 (1.25%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 80 (1.25%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 80 (1.25%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 80 (2.50%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 80 (2.50%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestinal haemorrhage
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 80 (1.25%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 80 (2.50%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 80 (1.25%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 80 (1.25%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tongue haematoma
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 80 (1.25%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Volvulus
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 80 (1.25%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 80 (1.25%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 80 (1.25%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prerenal failure
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 80 (1.25%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 80 (1.25%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 80 (1.25%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 80 (1.25%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 80 (1.25%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess soft tissue
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 80 (1.25%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 80 (1.25%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 80 (1.25%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast cellulitis
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 80 (1.25%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 80 (1.25%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 38 (2.63%)
    3 / 80 (3.75%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 80 (1.25%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 80 (1.25%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 80 (1.25%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia infection
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 80 (1.25%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 80 (1.25%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes simplex
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 80 (1.25%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 80 (1.25%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 80 (1.25%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 38 (0.00%)
    3 / 80 (3.75%)
    3 / 42 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oral bacterial infection
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 80 (1.25%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Parotitis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 80 (1.25%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pharyngeal abscess
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 80 (1.25%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    8 / 38 (21.05%)
    12 / 80 (15.00%)
    4 / 42 (9.52%)
         occurrences causally related to treatment / all
    4 / 9
    5 / 13
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 80 (1.25%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    4 / 38 (10.53%)
    8 / 80 (10.00%)
    4 / 42 (9.52%)
         occurrences causally related to treatment / all
    2 / 5
    2 / 9
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    Septic shock
         subjects affected / exposed
    2 / 38 (5.26%)
    2 / 80 (2.50%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    Tooth infection
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 80 (1.25%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 80 (1.25%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 80 (1.25%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 80 (1.25%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 80 (1.25%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 PAN + 5-Aza All Patients 5-Aza
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    38 / 38 (100.00%)
    76 / 80 (95.00%)
    38 / 42 (90.48%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    2 / 38 (5.26%)
    7 / 80 (8.75%)
    5 / 42 (11.90%)
         occurrences all number
    2
    9
    7
    Hypotension
         subjects affected / exposed
    2 / 38 (5.26%)
    4 / 80 (5.00%)
    2 / 42 (4.76%)
         occurrences all number
    3
    5
    2
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    10 / 38 (26.32%)
    16 / 80 (20.00%)
    6 / 42 (14.29%)
         occurrences all number
    12
    24
    12
    Chills
         subjects affected / exposed
    3 / 38 (7.89%)
    6 / 80 (7.50%)
    3 / 42 (7.14%)
         occurrences all number
    4
    7
    3
    Fatigue
         subjects affected / exposed
    10 / 38 (26.32%)
    26 / 80 (32.50%)
    16 / 42 (38.10%)
         occurrences all number
    25
    44
    19
    Injection site erythema
         subjects affected / exposed
    3 / 38 (7.89%)
    6 / 80 (7.50%)
    3 / 42 (7.14%)
         occurrences all number
    4
    10
    6
    Injection site rash
         subjects affected / exposed
    2 / 38 (5.26%)
    3 / 80 (3.75%)
    1 / 42 (2.38%)
         occurrences all number
    2
    4
    2
    Injection site pain
         subjects affected / exposed
    2 / 38 (5.26%)
    5 / 80 (6.25%)
    3 / 42 (7.14%)
         occurrences all number
    2
    5
    3
    Malaise
         subjects affected / exposed
    1 / 38 (2.63%)
    5 / 80 (6.25%)
    4 / 42 (9.52%)
         occurrences all number
    1
    6
    5
    Injection site reaction
         subjects affected / exposed
    3 / 38 (7.89%)
    5 / 80 (6.25%)
    2 / 42 (4.76%)
         occurrences all number
    23
    26
    3
    Non-cardiac chest pain
         subjects affected / exposed
    4 / 38 (10.53%)
    6 / 80 (7.50%)
    2 / 42 (4.76%)
         occurrences all number
    5
    7
    2
    Oedema peripheral
         subjects affected / exposed
    8 / 38 (21.05%)
    17 / 80 (21.25%)
    9 / 42 (21.43%)
         occurrences all number
    10
    20
    10
    Pain
         subjects affected / exposed
    2 / 38 (5.26%)
    3 / 80 (3.75%)
    1 / 42 (2.38%)
         occurrences all number
    3
    4
    1
    Pyrexia
         subjects affected / exposed
    18 / 38 (47.37%)
    27 / 80 (33.75%)
    9 / 42 (21.43%)
         occurrences all number
    26
    47
    21
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    2 / 38 (5.26%)
    2 / 80 (2.50%)
    0 / 42 (0.00%)
         occurrences all number
    2
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    7 / 38 (18.42%)
    13 / 80 (16.25%)
    6 / 42 (14.29%)
         occurrences all number
    9
    17
    8
    Dyspnoea
         subjects affected / exposed
    2 / 38 (5.26%)
    6 / 80 (7.50%)
    4 / 42 (9.52%)
         occurrences all number
    2
    7
    5
    Epistaxis
         subjects affected / exposed
    5 / 38 (13.16%)
    11 / 80 (13.75%)
    6 / 42 (14.29%)
         occurrences all number
    7
    13
    6
    Oropharyngeal pain
         subjects affected / exposed
    0 / 38 (0.00%)
    5 / 80 (6.25%)
    5 / 42 (11.90%)
         occurrences all number
    0
    7
    7
    Productive cough
         subjects affected / exposed
    0 / 38 (0.00%)
    3 / 80 (3.75%)
    3 / 42 (7.14%)
         occurrences all number
    0
    3
    3
    Rhinorrhoea
         subjects affected / exposed
    2 / 38 (5.26%)
    3 / 80 (3.75%)
    1 / 42 (2.38%)
         occurrences all number
    2
    3
    1
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    2 / 38 (5.26%)
    2 / 80 (2.50%)
    0 / 42 (0.00%)
         occurrences all number
    2
    2
    0
    Insomnia
         subjects affected / exposed
    5 / 38 (13.16%)
    8 / 80 (10.00%)
    3 / 42 (7.14%)
         occurrences all number
    9
    12
    3
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 38 (7.89%)
    5 / 80 (6.25%)
    2 / 42 (4.76%)
         occurrences all number
    7
    10
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 38 (10.53%)
    5 / 80 (6.25%)
    1 / 42 (2.38%)
         occurrences all number
    8
    10
    2
    Blood albumin decreased
         subjects affected / exposed
    2 / 38 (5.26%)
    3 / 80 (3.75%)
    1 / 42 (2.38%)
         occurrences all number
    2
    3
    1
    C-reactive protein increased
         subjects affected / exposed
    2 / 38 (5.26%)
    3 / 80 (3.75%)
    1 / 42 (2.38%)
         occurrences all number
    2
    3
    1
    Electrocardiogram QT prolonged
         subjects affected / exposed
    3 / 38 (7.89%)
    3 / 80 (3.75%)
    0 / 42 (0.00%)
         occurrences all number
    3
    3
    0
    Blood creatinine increased
         subjects affected / exposed
    4 / 38 (10.53%)
    4 / 80 (5.00%)
    0 / 42 (0.00%)
         occurrences all number
    5
    5
    0
    Haemoglobin decreased
         subjects affected / exposed
    2 / 38 (5.26%)
    3 / 80 (3.75%)
    1 / 42 (2.38%)
         occurrences all number
    6
    7
    1
    Neutrophil count decreased
         subjects affected / exposed
    6 / 38 (15.79%)
    9 / 80 (11.25%)
    3 / 42 (7.14%)
         occurrences all number
    31
    34
    3
    Platelet count decreased
         subjects affected / exposed
    8 / 38 (21.05%)
    10 / 80 (12.50%)
    2 / 42 (4.76%)
         occurrences all number
    36
    38
    2
    Weight decreased
         subjects affected / exposed
    7 / 38 (18.42%)
    13 / 80 (16.25%)
    6 / 42 (14.29%)
         occurrences all number
    8
    15
    7
    White blood cell count decreased
         subjects affected / exposed
    4 / 38 (10.53%)
    4 / 80 (5.00%)
    0 / 42 (0.00%)
         occurrences all number
    4
    4
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    3 / 38 (7.89%)
    5 / 80 (6.25%)
    2 / 42 (4.76%)
         occurrences all number
    3
    5
    2
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    3 / 38 (7.89%)
    4 / 80 (5.00%)
    1 / 42 (2.38%)
         occurrences all number
    3
    4
    1
    Sinus tachycardia
         subjects affected / exposed
    2 / 38 (5.26%)
    2 / 80 (2.50%)
    0 / 42 (0.00%)
         occurrences all number
    2
    2
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    5 / 38 (13.16%)
    8 / 80 (10.00%)
    3 / 42 (7.14%)
         occurrences all number
    7
    10
    3
    Dysgeusia
         subjects affected / exposed
    3 / 38 (7.89%)
    5 / 80 (6.25%)
    2 / 42 (4.76%)
         occurrences all number
    3
    5
    2
    Headache
         subjects affected / exposed
    7 / 38 (18.42%)
    14 / 80 (17.50%)
    7 / 42 (16.67%)
         occurrences all number
    14
    22
    8
    Syncope
         subjects affected / exposed
    2 / 38 (5.26%)
    4 / 80 (5.00%)
    2 / 42 (4.76%)
         occurrences all number
    2
    4
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    12 / 38 (31.58%)
    26 / 80 (32.50%)
    14 / 42 (33.33%)
         occurrences all number
    39
    55
    16
    Febrile neutropenia
         subjects affected / exposed
    6 / 38 (15.79%)
    8 / 80 (10.00%)
    2 / 42 (4.76%)
         occurrences all number
    6
    8
    2
    Leukopenia
         subjects affected / exposed
    4 / 38 (10.53%)
    5 / 80 (6.25%)
    1 / 42 (2.38%)
         occurrences all number
    8
    9
    1
    Lymphopenia
         subjects affected / exposed
    2 / 38 (5.26%)
    2 / 80 (2.50%)
    0 / 42 (0.00%)
         occurrences all number
    2
    2
    0
    Neutropenia
         subjects affected / exposed
    16 / 38 (42.11%)
    26 / 80 (32.50%)
    10 / 42 (23.81%)
         occurrences all number
    40
    72
    32
    Pancytopenia
         subjects affected / exposed
    3 / 38 (7.89%)
    4 / 80 (5.00%)
    1 / 42 (2.38%)
         occurrences all number
    4
    5
    1
    Thrombocytopenia
         subjects affected / exposed
    18 / 38 (47.37%)
    28 / 80 (35.00%)
    10 / 42 (23.81%)
         occurrences all number
    86
    110
    24
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    6 / 38 (15.79%)
    8 / 80 (10.00%)
    2 / 42 (4.76%)
         occurrences all number
    6
    9
    3
    Abdominal pain upper
         subjects affected / exposed
    2 / 38 (5.26%)
    4 / 80 (5.00%)
    2 / 42 (4.76%)
         occurrences all number
    2
    4
    2
    Constipation
         subjects affected / exposed
    10 / 38 (26.32%)
    26 / 80 (32.50%)
    16 / 42 (38.10%)
         occurrences all number
    26
    51
    25
    Diarrhoea
         subjects affected / exposed
    22 / 38 (57.89%)
    31 / 80 (38.75%)
    9 / 42 (21.43%)
         occurrences all number
    41
    56
    15
    Dry mouth
         subjects affected / exposed
    3 / 38 (7.89%)
    3 / 80 (3.75%)
    0 / 42 (0.00%)
         occurrences all number
    3
    3
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 38 (5.26%)
    3 / 80 (3.75%)
    1 / 42 (2.38%)
         occurrences all number
    3
    4
    1
    Haemorrhoids
         subjects affected / exposed
    5 / 38 (13.16%)
    6 / 80 (7.50%)
    1 / 42 (2.38%)
         occurrences all number
    5
    6
    1
    Nausea
         subjects affected / exposed
    23 / 38 (60.53%)
    41 / 80 (51.25%)
    18 / 42 (42.86%)
         occurrences all number
    57
    97
    40
    Stomatitis
         subjects affected / exposed
    2 / 38 (5.26%)
    6 / 80 (7.50%)
    4 / 42 (9.52%)
         occurrences all number
    2
    17
    15
    Toothache
         subjects affected / exposed
    1 / 38 (2.63%)
    4 / 80 (5.00%)
    3 / 42 (7.14%)
         occurrences all number
    1
    4
    3
    Vomiting
         subjects affected / exposed
    16 / 38 (42.11%)
    28 / 80 (35.00%)
    12 / 42 (28.57%)
         occurrences all number
    29
    46
    17
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    2 / 38 (5.26%)
    2 / 80 (2.50%)
    0 / 42 (0.00%)
         occurrences all number
    2
    2
    0
    Ecchymosis
         subjects affected / exposed
    2 / 38 (5.26%)
    3 / 80 (3.75%)
    1 / 42 (2.38%)
         occurrences all number
    4
    5
    1
    Erythema
         subjects affected / exposed
    1 / 38 (2.63%)
    5 / 80 (6.25%)
    4 / 42 (9.52%)
         occurrences all number
    1
    5
    4
    Pain of skin
         subjects affected / exposed
    2 / 38 (5.26%)
    2 / 80 (2.50%)
    0 / 42 (0.00%)
         occurrences all number
    2
    2
    0
    Petechiae
         subjects affected / exposed
    3 / 38 (7.89%)
    4 / 80 (5.00%)
    1 / 42 (2.38%)
         occurrences all number
    4
    5
    1
    Pruritus
         subjects affected / exposed
    4 / 38 (10.53%)
    7 / 80 (8.75%)
    3 / 42 (7.14%)
         occurrences all number
    4
    7
    3
    Rash
         subjects affected / exposed
    6 / 38 (15.79%)
    10 / 80 (12.50%)
    4 / 42 (9.52%)
         occurrences all number
    7
    11
    4
    Rash maculo-papular
         subjects affected / exposed
    2 / 38 (5.26%)
    3 / 80 (3.75%)
    1 / 42 (2.38%)
         occurrences all number
    2
    3
    1
    Urticaria
         subjects affected / exposed
    4 / 38 (10.53%)
    4 / 80 (5.00%)
    0 / 42 (0.00%)
         occurrences all number
    5
    5
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    2 / 38 (5.26%)
    2 / 80 (2.50%)
    0 / 42 (0.00%)
         occurrences all number
    4
    4
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 38 (7.89%)
    7 / 80 (8.75%)
    4 / 42 (9.52%)
         occurrences all number
    4
    10
    6
    Back pain
         subjects affected / exposed
    5 / 38 (13.16%)
    9 / 80 (11.25%)
    4 / 42 (9.52%)
         occurrences all number
    9
    14
    5
    Myalgia
         subjects affected / exposed
    3 / 38 (7.89%)
    5 / 80 (6.25%)
    2 / 42 (4.76%)
         occurrences all number
    3
    8
    5
    Musculoskeletal pain
         subjects affected / exposed
    2 / 38 (5.26%)
    5 / 80 (6.25%)
    3 / 42 (7.14%)
         occurrences all number
    2
    7
    5
    Pain in extremity
         subjects affected / exposed
    4 / 38 (10.53%)
    6 / 80 (7.50%)
    2 / 42 (4.76%)
         occurrences all number
    5
    10
    5
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 38 (5.26%)
    4 / 80 (5.00%)
    2 / 42 (4.76%)
         occurrences all number
    4
    6
    2
    Cellulitis
         subjects affected / exposed
    1 / 38 (2.63%)
    5 / 80 (6.25%)
    4 / 42 (9.52%)
         occurrences all number
    2
    7
    5
    Herpes simplex
         subjects affected / exposed
    2 / 38 (5.26%)
    4 / 80 (5.00%)
    2 / 42 (4.76%)
         occurrences all number
    2
    5
    3
    Conjunctivitis
         subjects affected / exposed
    3 / 38 (7.89%)
    3 / 80 (3.75%)
    0 / 42 (0.00%)
         occurrences all number
    4
    4
    0
    Rhinitis
         subjects affected / exposed
    2 / 38 (5.26%)
    2 / 80 (2.50%)
    0 / 42 (0.00%)
         occurrences all number
    2
    2
    0
    Pneumonia
         subjects affected / exposed
    1 / 38 (2.63%)
    4 / 80 (5.00%)
    3 / 42 (7.14%)
         occurrences all number
    1
    4
    3
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 38 (7.89%)
    6 / 80 (7.50%)
    3 / 42 (7.14%)
         occurrences all number
    3
    10
    7
    Skin infection
         subjects affected / exposed
    2 / 38 (5.26%)
    3 / 80 (3.75%)
    1 / 42 (2.38%)
         occurrences all number
    2
    3
    1
    Urinary tract infection
         subjects affected / exposed
    3 / 38 (7.89%)
    7 / 80 (8.75%)
    4 / 42 (9.52%)
         occurrences all number
    10
    15
    5
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    9 / 38 (23.68%)
    15 / 80 (18.75%)
    6 / 42 (14.29%)
         occurrences all number
    18
    25
    7
    Dehydration
         subjects affected / exposed
    3 / 38 (7.89%)
    4 / 80 (5.00%)
    1 / 42 (2.38%)
         occurrences all number
    4
    5
    1
    Fluid overload
         subjects affected / exposed
    0 / 38 (0.00%)
    3 / 80 (3.75%)
    3 / 42 (7.14%)
         occurrences all number
    0
    4
    4
    Hyperglycaemia
         subjects affected / exposed
    2 / 38 (5.26%)
    2 / 80 (2.50%)
    0 / 42 (0.00%)
         occurrences all number
    2
    2
    0
    Hyperkalaemia
         subjects affected / exposed
    1 / 38 (2.63%)
    4 / 80 (5.00%)
    3 / 42 (7.14%)
         occurrences all number
    1
    4
    3
    Hyperuricaemia
         subjects affected / exposed
    2 / 38 (5.26%)
    3 / 80 (3.75%)
    1 / 42 (2.38%)
         occurrences all number
    2
    5
    3
    Hypokalaemia
         subjects affected / exposed
    7 / 38 (18.42%)
    13 / 80 (16.25%)
    6 / 42 (14.29%)
         occurrences all number
    10
    16
    6
    Hypocalcaemia
         subjects affected / exposed
    2 / 38 (5.26%)
    4 / 80 (5.00%)
    2 / 42 (4.76%)
         occurrences all number
    2
    4
    2
    Hypomagnesaemia
         subjects affected / exposed
    2 / 38 (5.26%)
    4 / 80 (5.00%)
    2 / 42 (4.76%)
         occurrences all number
    2
    4
    2
    Hyponatraemia
         subjects affected / exposed
    2 / 38 (5.26%)
    3 / 80 (3.75%)
    1 / 42 (2.38%)
         occurrences all number
    2
    3
    1
    Hypophosphataemia
         subjects affected / exposed
    4 / 38 (10.53%)
    5 / 80 (6.25%)
    1 / 42 (2.38%)
         occurrences all number
    4
    5
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Apr 2010
    The rationale for this amendment was to correct inconsistencies within the protocol and to provide clarifications on timing of study procedures. Moreover, the amendment was intended to provide clarification on exclusion criterion number 8 and to provide further details on study procedures.
    24 Oct 2011
    Collect preliminary efficacy data of panobinostat at the recommended phase II dose (RPIID) level in conjunction with azacytidine (5-Aza/) by introducing a randomized, two-arm, open-label expansion phase, which determines the Phase IIb part of the study.
    29 May 2012
    Global amendment to provide guidance on dose adjustments for panobinostat and/or 5-Aza in the event of hematological toxicity, in particular thrombocytopenia and neutropenia as well as in the event of non-hematological toxicity for subjects enrolled in the Phase IIb part.
    31 Aug 2012
    Country-specific, non-substantial amendment for the Republic of Korea to clarify that the dose adjustment recommendations are for panobinostat and 5-Aza. The Korean Health Authority had given full approval for amendment 3, however requested to make the above mentioned changes prior to starting enrollment in Korea.
    18 Nov 2016
    The rationale of this amendment was to ensure treatment access for the patients that were still on treatment after the interim CSR data cut-off with a limited data collection. Therefore, for the patients ongoing treatment the study focused on collecting continuously Adverse Events, Serious Adverse Events, Concomitant Medications, and Dose Administration Records information. In addition, information (date and reason) related to End of Treatment and Study Evaluation Completion, date of disease progression as well as Survival information was to be provided. All other assessments were performed at the discretion of the investigators.

    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.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.nov for complete trial results.
    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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