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    Clinical Trial Results:
    A Two-Part Study to Assess the Safety and Preliminary Efficacy of Givinostat in Patients with JAK2V617F Positive Polycythemia Vera

    Summary
    EudraCT number
    		 2013-000860-27
    Trial protocol
    		 IT   FR   DE   GB   PL   HU  
    Global end of trial date
    25 Sep 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Jan 2019
    First version publication date
    25 Jan 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DSC/12/2357/45
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01901432
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    ITALFARMACO S.p.A.
    Sponsor organisation address
    Via dei Lavoratori, 54, Cinisello Balsamo (MI), Italy, 20092
    Public contact
    Medical Expert, ITALFARMACO S.p.A., 39 026443 258, p.bettica@italfarmaco.com
    Scientific contact
    Medical Expert, ITALFARMACO S.p.A., 39 026443 258, p.bettica@italfarmaco.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
    25 Sep 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Jun 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Sep 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Part A • To characterize the safety, tolerability and maximum tolerated dose (MTD) of givinostat in patients with Polycythemia Vera (PV). Part B • To evaluate the preliminary efficacy of givinostat at the MTD after 3 cycles. • To determine the safety and tolerability of givinostat at the MTD after 3 cycles. In Part A, all patients were to receive givinostat at an initial dose level (DL) of 100 milligrams (mg) twice daily (b.i.d.). In Part B, patients were to receive givinostat at the MTD determined in Part A.
    Protection of trial subjects
    The Investigator ensured that this study was conducted in full conformity with the principles of the “Declaration of Helsinki” or with the laws and regulations of the country in which the research was conducted, whichever afforded the greater protection to the individual. The study fully adhered to the principles outlined in “Guideline for Good Clinical Practice” International Council for Harmonisation Tripartite Guideline or with local law if it afforded greater protection to the patient.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Oct 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 7
    Country: Number of subjects enrolled
    Italy: 30
    Country: Number of subjects enrolled
    Poland: 3
    Country: Number of subjects enrolled
    United Kingdom: 6
    Worldwide total number of subjects
    48
    EEA total number of subjects
    48
    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)
    35
    From 65 to 84 years
    13
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a 2-part, multisite, open-label, non-randomized study to assess givinostat in patients with JAK2^V617F positive PV. Part A assessed safety and was the dose escalation portion of study, while Part B assessed preliminary efficacy. Patients were enrolled in 5 countries (France, Germany, Italy, Poland and the United Kingdom).

    Pre-assignment
    Screening details
    		 Patients were enrolled into either Part A or Part B, transition from 1 part to the other was not allowed. 48 patients were enrolled into the study overall: 12 patients in Part A to determine the MTD and 36 patients in Part B.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Givinostat DL0 (50 mg b.i.d.) (Part A)
    Arm description
    		 In Part A, 3 patients were assigned to receive givinostat by oral administration at Dose Level 0 (DL0) (50 milligrams [mg] b.i.d.). Patients were treated for up to 6 cycles (28 days in each cycle). Patients were treated for up to 6 cycles (28 days in each cycle). There were 3 DLs used during Part A; 50 mg b.i.d. (DL0) was the third DL to be administered.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Givinostat
    Investigational medicinal product code
    Other name
    Givinostat (ITF2357)
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    The product was supplied as hard gelatine capsules for oral administration at the strength of 50 mg, 75 mg and/or 100 mg each. In Part A, patients were assigned to receive the following DLs, progressively used: - DL1 (100 mg b.i.d.); - DL6 (2 capsules of 50 mg in the morning, AND one capsule of 50 mg in the evening); - DL0 (50 mg b.i.d.).

    Arm title
    		 Givinostat DL1 (100 mg b.i.d.) (Part A)
    Arm description
    		 In Part A, 3 patients were assigned to receive givinostat by oral administration at DL1 (100 mg b.i.d.). Patients were treated for up to 6 cycles (28 days in each cycle). There were 3 DLs used during Part A; 100 mg b.i.d. (DL1) was the initial DL to be administered.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Givinostat
    Investigational medicinal product code
    Other name
    Givinostat (ITF2357)
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    The product was supplied as hard gelatine capsules for oral administration at the strength of 50 mg, 75 mg and/or 100 mg each. In Part A, patients were assigned to receive the following DLs, progressively used: - DL1 (100 mg b.i.d.); - DL6 (2 capsules of 50 mg in the morning, AND one capsule of 50 mg in the evening); - DL0 (50 mg b.i.d.). In Part B, the starting dose of givinostat was the MTD determined in Part A (i.e. 100 mg b.i.d.).

    Arm title
    		 Givinostat DL1 expanded (100 mg b.i.d.) (Part A)
    Arm description
    		 Following initial assignment of 3 patients to DL1 in Part A, a further 3 patients were assigned to DL1 so this treatment group is referred to as “DL1 expanded” (patients received givinostat by oral administration at 100 mg b.i.d.). Patients were treated for up to 6 cycles (28 days in each cycle). There were 3 DLs used during Part A; 100 mg b.i.d. (DL1) was the initial DL to be administered.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Givinostat
    Investigational medicinal product code
    Other name
    Givinostat (ITF2357)
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    The product was supplied as hard gelatine capsules for oral administration at the strength of 50 mg, 75 mg and/or 100 mg each. In Part A, patients were assigned to receive the following DLs, progressively used: - DL1 (100 mg b.i.d.); - DL6 (2 capsules of 50 mg in the morning, AND one capsule of 50 mg in the evening); - DL0 (50 mg b.i.d.). In Part B, the starting dose of givinostat was the MTD determined in Part A (i.e. 100 mg b.i.d.).

    Arm title
    		 Givinostat DL6 (100 mg + 50 mg) (Part A)
    Arm description
    		 In Part A, 3 patients were assigned to receive givinostat by oral administration at DL6 (100 mg in the morning and 50 mg in the evening, i.e. 12 hours after). Patients were treated for up to 6 cycles in (28 days in each cycle). There were 3 DLs used during Part A; 100 mg + 50 mg (DL6) was the second DL to be administered.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Givinostat
    Investigational medicinal product code
    Other name
    Givinostat (ITF2357)
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    The product was supplied as hard gelatine capsules for oral administration at the strength of 50 mg, 75 mg and/or 100 mg each. In Part A, patients were assigned to receive the following DLs, progressively used: - DL1 (100 mg b.i.d.); - DL6 (2 capsules of 50 mg in the morning, AND one capsule of 50 mg in the evening); - DL0 (50 mg b.i.d.). In Part B, the starting dose of givinostat was the MTD determined in Part A (i.e. 100 mg b.i.d.).

    Arm title
    		 Givinostat at MTD (100 mg b.i.d.) (Part B)
    Arm description
    		 In Part B, patients were assigned to receive the starting dose of givinostat by oral administration at the MTD determined in Part A (i.e. 100 mg b.i.d.). Patients were treated for up to 6 cycles (28 days in each cycle). Based on evaluations performed as part of the visit procedures on Day 28 of each cycle up to Cycle 5 and/or in any necessary additional study visit, the givinostat dose was decreased if appropriate for any patients that met dose reduction criteria.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Givinostat
    Investigational medicinal product code
    Other name
    Givinostat (ITF2357)
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    The product was supplied as hard gelatine capsules for oral administration at the strength of 50 mg, 75 mg and/or 100 mg each. In Part B, the starting dose was the MTD determined in Part A, therefore all patients received givinostat at 100 mg b.i.d. during Cycle 1. During Part B Cycle 2 givinostat was administered at 100 mg, 75 mg and 50 mg b.i.d., since dose reductions were allowed from Cycle 2 onwards, as per protocol.

    Number of subjects in period 1
    		Givinostat DL0 (50 mg b.i.d.) (Part A) Givinostat DL1 (100 mg b.i.d.) (Part A) Givinostat DL1 expanded (100 mg b.i.d.) (Part A) Givinostat DL6 (100 mg + 50 mg) (Part A) Givinostat at MTD (100 mg b.i.d.) (Part B)
    Started
    3
    3
    3
    3
    36
    Received study drug
    3
    3
    3
    3
    35
    Completed
    3
    2
    1
    3
    27
    Not completed
    0
    1
    2
    0
    9
         Patient decision to stop study drug
    -
    -
    -
    -
    1
         Consent withdrawn by subject
    -
    -
    1
    -
    5
         Physician decision
    -
    -
    -
    -
    2
         Adverse event, non-fatal
    -
    1
    1
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Givinostat DL0 (50 mg b.i.d.) (Part A)
    Reporting group description
    		 In Part A, 3 patients were assigned to receive givinostat by oral administration at Dose Level 0 (DL0) (50 milligrams [mg] b.i.d.). Patients were treated for up to 6 cycles (28 days in each cycle). Patients were treated for up to 6 cycles (28 days in each cycle). There were 3 DLs used during Part A; 50 mg b.i.d. (DL0) was the third DL to be administered.

    Reporting group title
    Givinostat DL1 (100 mg b.i.d.) (Part A)
    Reporting group description
    		 In Part A, 3 patients were assigned to receive givinostat by oral administration at DL1 (100 mg b.i.d.). Patients were treated for up to 6 cycles (28 days in each cycle). There were 3 DLs used during Part A; 100 mg b.i.d. (DL1) was the initial DL to be administered.

    Reporting group title
    Givinostat DL1 expanded (100 mg b.i.d.) (Part A)
    Reporting group description
    		 Following initial assignment of 3 patients to DL1 in Part A, a further 3 patients were assigned to DL1 so this treatment group is referred to as “DL1 expanded” (patients received givinostat by oral administration at 100 mg b.i.d.). Patients were treated for up to 6 cycles (28 days in each cycle). There were 3 DLs used during Part A; 100 mg b.i.d. (DL1) was the initial DL to be administered.

    Reporting group title
    Givinostat DL6 (100 mg + 50 mg) (Part A)
    Reporting group description
    		 In Part A, 3 patients were assigned to receive givinostat by oral administration at DL6 (100 mg in the morning and 50 mg in the evening, i.e. 12 hours after). Patients were treated for up to 6 cycles in (28 days in each cycle). There were 3 DLs used during Part A; 100 mg + 50 mg (DL6) was the second DL to be administered.

    Reporting group title
    Givinostat at MTD (100 mg b.i.d.) (Part B)
    Reporting group description
    		 In Part B, patients were assigned to receive the starting dose of givinostat by oral administration at the MTD determined in Part A (i.e. 100 mg b.i.d.). Patients were treated for up to 6 cycles (28 days in each cycle). Based on evaluations performed as part of the visit procedures on Day 28 of each cycle up to Cycle 5 and/or in any necessary additional study visit, the givinostat dose was decreased if appropriate for any patients that met dose reduction criteria.

    Reporting group values
    		 Givinostat DL0 (50 mg b.i.d.) (Part A) Givinostat DL1 (100 mg b.i.d.) (Part A) Givinostat DL1 expanded (100 mg b.i.d.) (Part A) Givinostat DL6 (100 mg + 50 mg) (Part A) Givinostat at MTD (100 mg b.i.d.) (Part B) Total
    Number of subjects
    		 3 3 3 3 36 48
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0
        Adults (18-64 years)
    		 2 2 1 2 28 35
        From 65-84 years
    		 1 1 2 1 8 13
        85 years and over
    		 0 0 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 2 1 1 1 11 16
        Male
    		 1 2 2 2 25 32
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0 0
        Asian
    		 0 0 0 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0 0
        Black or African American
    		 0 0 0 0 0 0
        White
    		 3 3 3 3 36 48
        More than one race
    		 0 0 0 0 0 0
        Unknown or Not Reported
    		 0 0 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Givinostat DL0 (50 mg b.i.d.) (Part A)
    Reporting group description
    		 In Part A, 3 patients were assigned to receive givinostat by oral administration at Dose Level 0 (DL0) (50 milligrams [mg] b.i.d.). Patients were treated for up to 6 cycles (28 days in each cycle). Patients were treated for up to 6 cycles (28 days in each cycle). There were 3 DLs used during Part A; 50 mg b.i.d. (DL0) was the third DL to be administered.

    Reporting group title
    Givinostat DL1 (100 mg b.i.d.) (Part A)
    Reporting group description
    		 In Part A, 3 patients were assigned to receive givinostat by oral administration at DL1 (100 mg b.i.d.). Patients were treated for up to 6 cycles (28 days in each cycle). There were 3 DLs used during Part A; 100 mg b.i.d. (DL1) was the initial DL to be administered.

    Reporting group title
    Givinostat DL1 expanded (100 mg b.i.d.) (Part A)
    Reporting group description
    		 Following initial assignment of 3 patients to DL1 in Part A, a further 3 patients were assigned to DL1 so this treatment group is referred to as “DL1 expanded” (patients received givinostat by oral administration at 100 mg b.i.d.). Patients were treated for up to 6 cycles (28 days in each cycle). There were 3 DLs used during Part A; 100 mg b.i.d. (DL1) was the initial DL to be administered.

    Reporting group title
    Givinostat DL6 (100 mg + 50 mg) (Part A)
    Reporting group description
    		 In Part A, 3 patients were assigned to receive givinostat by oral administration at DL6 (100 mg in the morning and 50 mg in the evening, i.e. 12 hours after). Patients were treated for up to 6 cycles in (28 days in each cycle). There were 3 DLs used during Part A; 100 mg + 50 mg (DL6) was the second DL to be administered.

    Reporting group title
    Givinostat at MTD (100 mg b.i.d.) (Part B)
    Reporting group description
    		 In Part B, patients were assigned to receive the starting dose of givinostat by oral administration at the MTD determined in Part A (i.e. 100 mg b.i.d.). Patients were treated for up to 6 cycles (28 days in each cycle). Based on evaluations performed as part of the visit procedures on Day 28 of each cycle up to Cycle 5 and/or in any necessary additional study visit, the givinostat dose was decreased if appropriate for any patients that met dose reduction criteria.

    Subject analysis set title
    Givinostat Total (Part A)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    This dataset comprised all patients in the Intent-to-Treat (ITT) analysis set who received givinostat in Part A of the study. It represents the 4 Part A treatment arms and includes patients who received givinostat at DL0 (50 mg b.i.d.), DL1 (100 mg b.i.d. [i.e. including DL1 expanded] and DL6 (100 mg + 50 mg) in Part A. The ITT analysis set included all recruited patients who received 1 dose of study drug and from whom 1 post-baseline efficacy measurement was obtained.

    Subject analysis set title
    Givinostat DL0 (50 mg b.i.d.) (Part A PK analysis set)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    This dataset was used for pharmacokinetic (PK) analysis and included the patients who received givinostat at DL0 (50 mg b.i.d.) in Part A of the study and for whom PK data was available for analysis.

    Subject analysis set title
    Givinostat DL1 (100 mg b.i.d.) (Part A PK analysis set)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    This dataset was used for PK analysis and included the patients who received givinostat at DL1 (100 mg b.i.d. [i.e. including DL1 expanded]) in Part A of the study and for whom PK data was available for analysis.

    Subject analysis set title
    Givinostat DL6 (100 mg + 50 mg) (Part A PK analysis set)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    This dataset was used for PK analysis and included the patients who received givinostat at DL6 (100 mg in the morning and 50 mg in the evening) in Part A of the study and for whom PK data was available for analysis.

    Subject analysis set title
    Givinostat 100 mg b.i.d. (Part B PK analysis set)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    This dataset was used for PK analysis and included patients who received givinostat at the MTD (100 mg b.i.d.) in Part B of the study and for whom PK data was available for analysis. This dataset was used for PK analysis after Cycle 1 Day 1 (34 patients) and after Cycle 2 Day 28 (17 patients remaining at this dose).

    Subject analysis set title
    Givinostat 75 mg b.i.d. (Part B PK analysis set)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    This dataset was used for PK analysis and included patients who received givinostat at the reduced dose of 75 mg b.i.d. in Part B of the study and for whom PK data was available for analysis. This dataset only applied for PK analysis from Cycle 2 onwards (i.e. Cycle 2 Day 28).

    Subject analysis set title
    Givinostat 50 mg b.i.d. (Part B PK analysis set)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    This dataset was used for PK analysis and included patients who received givinostat at the reduced dose of 50 mg b.i.d. in Part B of the study and for whom PK data was available for analysis. This dataset only applied for PK analysis from Cycle 2 onwards (i.e. Cycle 2 Day 28).

    Primary: Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study

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    End point title
    		 Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study [1] [2]
    End point description
    Evaluations were performed on the type, incidence and severity of TEAEs, graded according to Common Terminology Criteria for Adverse Events (CTCAE) v. 4.03, following administration of givinostat for up to 6 cycles of treatment in Part A. Grades 1 through 5 were as follows: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe or medically significant but not immediately life threatening or requiring hospitalisation; Grade 4: Life threatening consequences; Grade 5: Death related to AE. Results are reported as number of patients with TEAEs for each of the indicated categories. Definitions: drug-related TEAE / treatment-emergent serious adverse event (TESAE) corresponded to reasonable suspicion that the TEAE / TESAE was associated with the use of the study drug, according to investigator assessment; discontinuation refers to discontinuation from treatment. Analysis performed on the Safety (SAF) analysis set, comprising all recruited patients who received 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    168 days (up to Cycle 6 Day 28 in Part A).
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analyses were performed as planned.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The treatment arm 'Givinostat at MTD (100 mg b.i.d.) (Part B)' is not applicable for this end point as only Part A study results are being presented.
    End point values
    		 Givinostat DL0 (50 mg b.i.d.) (Part A) Givinostat DL1 (100 mg b.i.d.) (Part A) Givinostat DL1 expanded (100 mg b.i.d.) (Part A) Givinostat DL6 (100 mg + 50 mg) (Part A)
    Number of subjects analysed
    3
    3
    3
    3
    Units: participants
        TEAE
    3
    3
    3
    3
        Drug-related TEAE
    1
    3
    3
    1
        TESAE
    0
    1
    0
    1
        Drug-related TESAE
    0
    0
    0
    0
        Death due to any cause
    0
    0
    0
    0
        Grade 3 TEAE
    0
    2
    1
    1
        Grade 3 drug-related TEAE
    0
    2
    1
    0
        Grade 4 TEAE
    0
    0
    1
    0
        Grade 4 drug-related TEAE
    0
    0
    1
    0
        Grade 5 TEAE
    0
    0
    0
    0
        Discontinuation due to TEAE
    0
    1
    1
    0
        Discontinuation due to drug-related TEAE
    0
    1
    1
    0
        Discontinuation due to TESAE
    0
    0
    0
    0
        Discontinuation due to drug-related TESAE
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Dose Limiting Toxicities (DLTs) After 1 Cycle in Part A of the Study

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    End point title
    		 Dose Limiting Toxicities (DLTs) After 1 Cycle in Part A of the Study [3] [4]
    End point description
    The MTD of givinostat was based only on Cycle 1 DLTs. A DLT was defined as the following drug-related toxicity: •Grade 4 hematological toxicity, or •Grade 3 febrile neutropenia, or •Grade ≥3 non-hematological toxicity (with the exception Grade 3 diarrhea without adequate supportive care lasting less than 3 days, and Grade 3 nausea or vomiting without adequate supportive care lasting less than 3 days), or •Any drug-related serious AE, or •Any toxicity clearly not related to disease progression or intercurrent illness requiring interruption of dosing for more than 3 days during first cycle. At end of Cycle 1, for the third patient in each DL, the safety of the 3 patients treated for 1 cycle was reviewed and it was decided if the dose should be escalated or not. Results are reported as the number of patients with DLT events for Cycle 1 in Part A. Analysis performed on MTD analysis set, comprising all patients who experienced a DLT or received ≥90% of study drug doses in Cycle 1.
    End point type
    Primary
    End point timeframe
    28 days (up to Cycle 1 Day 28 in Part A).
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analyses were performed as planned.
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The treatment arm 'Givinostat at MTD (100 mg b.i.d.) (Part B)' is not applicable for this end point as only Part A study results are being presented.
    End point values
    		 Givinostat DL0 (50 mg b.i.d.) (Part A) Givinostat DL1 (100 mg b.i.d.) (Part A) Givinostat DL1 expanded (100 mg b.i.d.) (Part A) Givinostat DL6 (100 mg + 50 mg) (Part A)
    Number of subjects analysed
    3
    3
    3
    3
    Units: participants
    0
    1
    0
    0
    No statistical analyses for this end point

    Primary: Number of Patients Experiencing TEAEs After 3 Cycles in Part B of the Study

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    End point title
    		 Number of Patients Experiencing TEAEs After 3 Cycles in Part B of the Study [5] [6]
    End point description
    Evaluations were performed on the type, incidence and severity of TEAEs, graded according to CTCAE v. 4.03, following administration of givinostat at the MTD for up to 3 cycles of treatment in Part B. Grades 1 through 5 were as follows: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe or medically significant but not immediately life threatening or requiring hospitalisation; Grade 4: Life threatening consequences; Grade 5: Death related to AE. Results are reported as number of patients with TEAEs for each of the indicated categories. Definitions: drug-related TEAE / TESAE corresponded to reasonable suspicion that the TEAE / TESAE was associated with the use of the study drug, according to investigator assessment; discontinuation refers to discontinuation from treatment. Analysis performed on the SAF analysis set.
    End point type
    Primary
    End point timeframe
    84 days (up to Cycle 3 Day 28 in Part B).
    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: Only descriptive analyses were performed as planned.
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The treatment arms 'Givinostat DL0 (50 mg b.i.d.) (Part A)', 'Givinostat DL1 (100 mg b.i.d.) (Part A)', 'Givinostat DL1 expanded (100 mg b.i.d.) (Part A)' and 'Givinostat DL6 (100 mg + 50 mg) (Part A)' ' are not applicable for this end point as only Part B study results are being presented.
    End point values
    		 Givinostat at MTD (100 mg b.i.d.) (Part B)
    Number of subjects analysed
    35
    Units: participants
        TEAE
    35
        Drug-related TEAE
    33
        TESAE
    2
        Drug-related TESAE
    1
        Death due to any cause
    0
        Grade 3 TEAE
    10
        Grade 3 drug-related TEAE
    7
        Grade 4 TEAE
    0
        Grade 4 drug-related TEAE
    0
        Grade 5 TEAE
    0
        Discontinuation due to TEAE
    2
        Discontinuation due to drug-related TEAE
    2
        Discontinuation due to TESAE
    0
        Discontinuation due to drug-related TESAE
    0
    No statistical analyses for this end point

    Primary: Overall Response Rate (ORR) (i.e. Complete Response [CR] and Partial Response [PR]) After 3 Cycles in Part B of the Study

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    End point title
    		 Overall Response Rate (ORR) (i.e. Complete Response [CR] and Partial Response [PR]) After 3 Cycles in Part B of the Study [7] [8]
    End point description
    ORR, CR and PR following administration of givinostat at MTD for 3 cycles in Part B, reported as percentage of patients with a response. Response was evaluated according to the clinico-hematological European LeukemiaNet (ELN) response criteria. If Investigator's clinical response assessment (taking into account the overall medical judgment of the specific patient's case) was not in agreement with exact application of the ELN response criteria, the Investigator's assessment superseded the mathematical application of these criteria and was used for analysis. Analysis performed on ITT analysis set. CR defined as: 1.Hematocrit (HCT) <45% without phlebotomy, and 2.Platelets ≤400 x10^9/litre (L), and 3.White Blood Cell count ≤10 x10^9/L, and 4.Normal spleen size, and 5.No disease-related systemic symptoms (i.e. pruritus, headache, microvascular disturbances). PR defined as: Patients not fulfilling CR and 1.HCT <45% without phlebotomy, or 2.Response in ≥3 other criteria.
    End point type
    Primary
    End point timeframe
    84 days (up to cycle 3 Day 28 in Part B).
    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: Only descriptive analyses were performed as planned.
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The treatment arms 'Givinostat DL0 (50 mg b.i.d.) (Part A)', 'Givinostat DL1 (100 mg b.i.d.) (Part A)', 'Givinostat DL1 expanded (100 mg b.i.d.) (Part A)' and 'Givinostat DL6 (100 mg + 50 mg) (Part A)' ' are not applicable for this end point as only Part B study results are being presented.
    End point values
    		 Givinostat at MTD (100 mg b.i.d.) (Part B)
    Number of subjects analysed
    31
    Units: percentage of participants
    number (confidence interval 95%)
        ORR (CR + PR)
    80.6 (62.53 to 92.55)
        CR
    9.7 (2.04 to 25.75)
        PR
    71.0 (51.96 to 85.78)
    No statistical analyses for this end point

    Secondary: ORR After 3 Cycles and After 6 Cycles in Part A of the Study

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    End point title
    		 ORR After 3 Cycles and After 6 Cycles in Part A of the Study
    End point description
    ORR following administration of givinostat after 3 cycles and after 6 cycles in Part A, reported as percentage of patients with a response. Response was evaluated according to the clinico-hematological ELN response criteria. If Investigator's clinical response assessment (taking into account the overall medical judgment of the specific patient's case) was not in agreement with exact application of the ELN response criteria, the Investigator's assessment superseded the mathematical application of these criteria and was used for analysis. Analysis performed on ITT analysis set using the dataset for all Part A patients combined.
    End point type
    Secondary
    End point timeframe
    84 and 168 days (up to Cycle 3 Day 28 and Cycle 6 Day 28 in Part A).
    End point values
    		 Givinostat Total (Part A)
    Number of subjects analysed
    11
    Units: percentage of participants
    number (confidence interval 95%)
        Cycle 3 Day 28
    72.7 (39.03 to 93.98)
        Cycle 6 Day 28
    72.7 (39.03 to 93.98)
    No statistical analyses for this end point

    Secondary: ORR After 6 Cycles in Part B of the Study

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    End point title
    		 ORR After 6 Cycles in Part B of the Study [9]
    End point description
    ORR following administration of givinostat at the MTD for 6 cycles in Part B, reported as percentage of patients with a response. Response was evaluated according to the clinico-hematological ELN response criteria. If Investigator's clinical response assessment (taking into account the overall medical judgment of the specific patient's case) was not in agreement with exact application of the ELN response criteria, the Investigator's assessment superseded the mathematical application of these criteria and was used for analysis. Analysis performed on ITT analysis set.
    End point type
    Secondary
    End point timeframe
    168 days (up to Cycle 6 Day 28 in Part B).
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The treatment arms 'Givinostat DL0 (50 mg b.i.d.) (Part A)', 'Givinostat DL1 (100 mg b.i.d.) (Part A)', 'Givinostat DL1 expanded (100 mg b.i.d.) (Part A)' and 'Givinostat DL6 (100 mg + 50 mg) (Part A)' ' are not applicable for this end point as only Part B study results are being presented.
    End point values
    		 Givinostat at MTD (100 mg b.i.d.) (Part B)
    Number of subjects analysed
    31
    Units: percentage of participants
        number (confidence interval 95%)
    80.6 (62.53 to 92.55)
    No statistical analyses for this end point

    Secondary: Number of Patients Experiencing TEAEs After 6 Cycles in Part B of the Study

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    End point title
    		 Number of Patients Experiencing TEAEs After 6 Cycles in Part B of the Study [10]
    End point description
    Evaluations were performed on the type, incidence and severity of TEAEs, graded according to CTCAE v. 4.03, following administration of givinostat at the MTD for up to 6 cycles of treatment in Part B. Grades 1 through 5 were as follows: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe or medically significant but not immediately life threatening or requiring hospitalisation; Grade 4: Life threatening consequences; Grade 5: Death related to AE. Results are reported as number of patients with TEAEs for each of the indicated categories. Definitions: drug-related TEAE / TESAE corresponded to reasonable suspicion that the TEAE / TESAE was associated with the use of the study drug, according to investigator assessment; discontinuation refers to discontinuation from treatment. Results are reported as number of patients with TEAEs for each of the indicated categories. Analysis performed on the SAF analysis set.
    End point type
    Secondary
    End point timeframe
    168 days (up to Cycle 6 Day 28 in Part B).
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The treatment arms 'Givinostat DL0 (50 mg b.i.d.) (Part A)', 'Givinostat DL1 (100 mg b.i.d.) (Part A)', 'Givinostat DL1 expanded (100 mg b.i.d.) (Part A)' and 'Givinostat DL6 (100 mg + 50 mg) (Part A)' ' are not applicable for this end point as only Part B study results are being presented.
    End point values
    		 Givinostat at MTD (100 mg b.i.d.) (Part B)
    Number of subjects analysed
    35
    Units: participants
        TEAE
    35
        Drug-related TEAE
    33
        TESAE
    1
        Drug-related TESAE
    1
        Death due to any cause
    0
        Grade 3 TEAE
    12
        Grade 3 drug-related TEAE
    10
        Grade 4 TEAE
    0
        Grade 4 drug-related TEAE
    0
        Grade 5 TEAE
    0
        Discontinuation due to TEAE
    2
        Discontinuation due to drug-related TEAE
    2
        Discontinuation due to TESAE
    0
        Discontinuation due to drug-related TESAE
    0
    No statistical analyses for this end point

    Secondary: Assessment of Maximum Plasma Concentration (Cmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study

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    End point title
    		 Assessment of Maximum Plasma Concentration (Cmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study
    End point description
    PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of Cmax following administration of givinostat for 1 cycle in Part A. PK calculations were performed by standard non-compartmental analysis. Results are reported for Cycle 1 Day 1 and Cycle 1 Day 28.. Analysis performed on PK analysis set. Only patients with data available for analysis are presented (n in the category title indicates number of patients analyzed for each parameter).
    End point type
    Secondary
    End point timeframe
    Blood samples were collected in Part A on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 1 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.
    End point values
    		 Givinostat DL0 (50 mg b.i.d.) (Part A PK analysis set) Givinostat DL1 (100 mg b.i.d.) (Part A PK analysis set) Givinostat DL6 (100 mg + 50 mg) (Part A PK analysis set)
    Number of subjects analysed
    3 [11]
    6
    3
    Units: nanograms per millilitre (ng/mL)
    arithmetic mean (standard deviation)
        Givinostat Cycle 1 Day 1 (n=3, 5, 3)
    60.2 ( 43.1 )
    54.3 ( 17.2 )
    82.5 ( 24.4 )
        ITF2374 Cycle 1 Day 1 (n=0, 5, 3)
    9999999 ( 9999999 )
    3.74 ( 4.09 )
    5.69 ( 2.87 )
        ITF2375 Cycle 1 Day 1 (n=0, 5, 2)
    9999999 ( 9999999 )
    68.6 ( 21.2 )
    101 ( 24.5 )
        Givinostat Cycle 1 Day 28 (n=3, 4, 3)
    22.4 ( 8.92 )
    73.3 ( 31.9 )
    290 ( 330 )
        ITF2374 Cycle 1 Day 28 (n=0, 4, 3)
    9999999 ( 9999999 )
    19.7 ( 7.24 )
    31.3 ( 4.95 )
        ITF2375 Cycle 1 Day 28 (n=2, 4, 3)
    110 ( 22.8 )
    259 ( 75.9 )
    376 ( 215 )
    Notes
    [11] - 9999999=not calculated. For certain parameters, concentration data not available for PK analysis.
    No statistical analyses for this end point

    Secondary: Assessment of Time to Maximum Plasma Concentration (Tmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study

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    End point title
    		 Assessment of Time to Maximum Plasma Concentration (Tmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study
    End point description
    PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of Tmax following administration of givinostat for 1 cycle in Part A. PK calculations were performed by standard non-compartmental analysis. Results are reported for Cycle 1 Day 1 and Cycle 1 Day 28. Analysis performed on PK analysis set. Only patients with data available for analysis are presented (n in the category title indicates number of patients analyzed for each parameter).
    End point type
    Secondary
    End point timeframe
    Blood samples were collected in Part A on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 1 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.
    End point values
    		 Givinostat DL0 (50 mg b.i.d.) (Part A PK analysis set) Givinostat DL1 (100 mg b.i.d.) (Part A PK analysis set) Givinostat DL6 (100 mg + 50 mg) (Part A PK analysis set)
    Number of subjects analysed
    3 [12]
    6
    3
    Units: nanograms per millilitre (ng/ml)
    median (full range (min-max))
        Givinostat Cycle 1 Day 1 (n=3, 5, 3)
    2.00 (1.92 to 3.00)
    2.00 (2.00 to 2.00)
    3.00 (2.00 to 3.00)
        ITF2374 Cycle 1 Day 1 (n=0, 4, 3)
    9999999 (9999999 to 9999999)
    8.00 (8.00 to 8.00)
    8.00 (3.00 to 8.00)
        ITF2375 Cycle 1 Day 1 (n=0, 5, 2)
    9999999 (9999999 to 9999999)
    3.00 (2.00 to 3.00)
    2.50 (2.00 to 3.00)
        Givinostat Cycle 1 Day 28 (n=3, 4 3)
    3.90 (3.83 to 4.00)
    1.50 (1.00 to 3.98)
    2.05 (1.05 to 4.00)
        ITF2374 Cycle 1 Day 28 (n=0, 4, 3)
    9999999 (9999999 to 9999999)
    8.00 (0.00 to 8.00)
    2.00 (1.05 to 4.05)
        ITF2375 Cycle 1 Day 28 (n=2, 4, 3)
    2.00 (2.00 to 2.00)
    1.99 (1.00 to 3.98)
    4.00 (0.00 to 4.05)
    Notes
    [12] - 9999999=not calculated. For certain parameters, concentration data not available for PK analysis.
    No statistical analyses for this end point

    Secondary: Assessment of Time of the Last Detectable Concentration (Tlast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study

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    End point title
    		 Assessment of Time of the Last Detectable Concentration (Tlast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study
    End point description
    PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of Tlast following administration of givinostat for 1 cycle in Part A. PK calculations were performed by standard non-compartmental analysis. Results are reported for Cycle 1 Day 1 and Cycle 1 Day 28. Analysis performed on PK analysis set. Only patients with data available for analysis are presented (n in the category title indicates number of patients analyzed for each parameter).
    End point type
    Secondary
    End point timeframe
    Blood samples were collected in Part A on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 1 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.
    End point values
    		 Givinostat DL0 (50 mg b.i.d.) (Part A PK analysis set) Givinostat DL1 (100 mg b.i.d.) (Part A PK analysis set) Givinostat DL6 (100 mg + 50 mg) (Part A PK analysis set)
    Number of subjects analysed
    3 [13]
    6
    3
    Units: hours
    arithmetic mean (standard deviation)
        Givinostat Cycle 1 Day 1 (n=3, 5, 3)
    7.97 ( 0.0462 )
    8.00 ( 0.00 )
    8.00 ( 0.00 )
        ITF2374 Cycle 1 Day 1 (n=0, 4, 3)
    9999999 ( 9999999 )
    8.00 ( 0.00 )
    8.00 ( 0.00 )
        ITF2375 Cycle 1 Day 1 (n=0, 5, 2)
    9999999 ( 9999999 )
    8.00 ( 0.00 )
    8.00 ( 0.00 )
        Givinostat Cycle 1 Day 28 (n=3, 4, 3)
    8.05 ( 0.249 )
    7.00 ( 2.01 )
    8.02 ( 0.0252 )
        ITF2374 Cycle 1 Day 28 (n=0, 4, 3)
    9999999 ( 9999999 )
    7.00 ( 2.01 )
    8.02 ( 0.0252 )
        ITF2375 Cycle 1 Day 28 (n=2, 4, 3)
    3.00 ( 1.41 )
    7.00 ( 2.01 )
    6.70 ( 2.30 )
    Notes
    [13] - 9999999=not calculated. For certain parameters, concentration data not available for PK analysis.
    No statistical analyses for this end point

    Secondary: Assessment of Area Under Plasma Concentration Versus the Time Curve up to the Last Detectable Concentration (AUClast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study

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    End point title
    		 Assessment of Area Under Plasma Concentration Versus the Time Curve up to the Last Detectable Concentration (AUClast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study
    End point description
    PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of AUClast following administration of givinostat for 1 cycle in Part A. PK calculations were performed by standard non-compartmental analysis and AUClast was calculated using the linear trapezoidal rule. Results are reported for Cycle 1 Day 1 and Cycle 1 Day 28. Analysis performed on PK analysis set. Only patients with data available for analysis are presented (n in the category title indicates number of patients analyzed for each parameter).
    End point type
    Secondary
    End point timeframe
    Blood samples were collected in Part A on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 1 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.
    End point values
    		 Givinostat DL0 (50 mg b.i.d.) (Part A PK analysis set) Givinostat DL1 (100 mg b.i.d.) (Part A PK analysis set) Givinostat DL6 (100 mg + 50 mg) (Part A PK analysis set)
    Number of subjects analysed
    3 [14]
    6
    3
    Units: ng*h/mL
    arithmetic mean (standard deviation)
        Givinostat Cycle 1 Day 1 (n=3, 5, 3)
    208 ( 136 )
    238 ( 55.6 )
    429 ( 109 )
        ITF2374 Cycle 1 Day 1 (n=0, 5, 3)
    9999999 ( 9999999 )
    14.4 ( 19.0 )
    29.6 ( 9.64 )
        ITF2375 Cycle 1 Day 1 (n=0, 5, 2)
    9999999 ( 9999999 )
    416 ( 153 )
    611 ( 146 )
        Givinostat Cycle 1 Day 28 (n=3, 4, 3)
    132 ( 45.1 )
    359 ( 203 )
    1100 ( 1050 )
        ITF2374 Cycle 1 Day 28 (n=0, 4, 3)
    9999999 ( 9999999 )
    102 ( 11.7 )
    158 ( 42.6 )
        ITF2375 Cycle 1 Day 28 (n=2, 4, 3)
    263 ( 192 )
    1390 ( 675 )
    1780 ( 1190 )
    Notes
    [14] - 9999999=not calculated. For certain parameters, concentration data not available for PK analysis.
    No statistical analyses for this end point

    Secondary: Assessment of Area Under Plasma Concentration Versus the Time Curve in the Dosing Interval (0-12 Hours) (AUC0-12) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study

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    End point title
    		 Assessment of Area Under Plasma Concentration Versus the Time Curve in the Dosing Interval (0-12 Hours) (AUC0-12) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study
    End point description
    PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of AUC0-12 following administration of givinostat for 1 cycle in Part A. PK calculations were performed by standard non-compartmental analysis and AUC0-12 was calculated using the linear trapezoidal rule. Results are reported for Cycle 1 Day 1 and Cycle 1 Day 28. Analysis performed on PK analysis set. Only patients with data available for analysis are presented (n in the category title indicates number of patients analyzed for each parameter).
    End point type
    Secondary
    End point timeframe
    Blood samples were collected in Part A on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 1 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.
    End point values
    		 Givinostat DL0 (50 mg b.i.d.) (Part A PK analysis set) Givinostat DL1 (100 mg b.i.d.) (Part A PK analysis set) Givinostat DL6 (100 mg + 50 mg) (Part A PK analysis set)
    Number of subjects analysed
    3 [15]
    6 [16]
    3 [17]
    Units: ng*h/mL
    arithmetic mean (standard deviation)
        Givinostat Cycle 1 Day 1 (n=3, 5, 3)
    235 ( 146 )
    289 ( 68.9 )
    508 ( 107 )
        ITF2374 Cycle 1 Day 1 (n=0, 0, 0)
    9999999 ( 9999999 )
    9999999 ( 9999999 )
    9999999 ( 9999999 )
        ITF2375 Cycle 1 Day 1 (n=0, 5, 2)
    9999999 ( 9999999 )
    598 ( 259 )
    870 ( 182 )
        Givinostat Cycle 1 Day 28 (n=3, 3, 3)
    161 ( 51.8 )
    533 ( 223 )
    1180 ( 1050 )
        ITF2374 Cycle 1 Day 28 (n=0, 0, 0)
    9999999 ( 9999999 )
    9999999 ( 9999999 )
    9999999 ( 9999999 )
        ITF2375 Cycle 1 Day 28 (n=1, 3, 3)
    863 ( 999999 )
    2020 ( 1000 )
    2340 ( 970 )
    Notes
    [15] - 9999999=not calculated. For certain parameters, concentration data not available for PK analysis.
    [16] - 9999999=not calculated. For certain parameters, concentration data not available for PK analysis.
    [17] - 9999999=not calculated. For certain parameters, concentration data not available for PK analysis.
    No statistical analyses for this end point

    Secondary: Assessment of Cmax of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study

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    End point title
    		 Assessment of Cmax of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study
    End point description
    PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of Cmax following administration of givinostat for 2 cycles in Part B. PK calculations were performed by standard non-compartmental analysis. Following definition of the MTD in Part A, during Part B Cycle 1, givinostat was administered at 100 mg b.i.d. and during Part B Cycle 2 was administered at 100 mg, 75 mg and 50 mg b.i.d. (since dose reductions due to TEAEs were allowed from Cycle 2 onwards, as per protocol). Results are reported for Cycle 1 Day 1 and Cycle 2 Day 28 for the doses administered during Part B. Analysis performed on PK analysis set. Only patients with data available for analysis are presented (n in the category title indicates number of patients analyzed for each parameter). PK evaluation of givinostat 75 mg and 50 mg b.i.d. dose groups for Cycle 1 Day 1 not applicable (since all received 100 mg b.i.d.).
    End point type
    Secondary
    End point timeframe
    Blood samples were collected in Part B on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 2 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.
    End point values
    		 Givinostat 100 mg b.i.d. (Part B PK analysis set) Givinostat 75 mg b.i.d. (Part B PK analysis set) Givinostat 50 mg b.i.d. (Part B PK analysis set)
    Number of subjects analysed
    34
    12 [18]
    2 [19]
    Units: ng/mL
    arithmetic mean (standard deviation)
        Givinostat Cycle 1 Day 1 (n=34, 0, 0)
    71.5 ( 34.4 )
    9999999 ( 9999999 )
    9999999 ( 9999999 )
        ITF2374 Cycle 1 Day 1 (n=34, 0, 0)
    7.85 ( 4.89 )
    9999999 ( 9999999 )
    9999999 ( 9999999 )
        ITF2375 Cycle 1 Day 1 (n=29, 0, 0)
    161 ( 72.9 )
    9999999 ( 9999999 )
    9999999 ( 9999999 )
        Givinostat Cycle 2 Day 28 (n=17, 12, 2)
    90.8 ( 33.5 )
    64.0 ( 22.6 )
    62.6 ( 21.8 )
        ITF2374 Cycle 2 Day 28 (n=17, 12, 2)
    32.3 ( 21.0 )
    22.6 ( 11.2 )
    21.4 ( 0.424 )
        ITF2375 Cycle 2 Day 28 (n=16, 9, 0)
    320 ( 238 )
    203 ( 78.7 )
    9999999 ( 9999999 )
    Notes
    [18] - 9999999=not calculated. For certain parameters, concentration data not available for PK analysis.
    [19] - 9999999=not calculated. For certain parameters, concentration data not available for PK analysis.
    No statistical analyses for this end point

    Secondary: Assessment of Tmax of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study

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    End point title
    		 Assessment of Tmax of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study
    End point description
    PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of Tmax following administration of givinostat for 2 cycles in Part B. PK calculations were performed by standard non-compartmental analysis. Following definition of the MTD in Part A, during Part B Cycle 1, givinostat was administered at 100 mg b.i.d. and during Part B Cycle 2 was administered at 100 mg, 75 mg and 50 mg b.i.d. (since dose reductions due to TEAEs were allowed from Cycle 2 onwards, as per protocol). Results are reported for Cycle 1 Day 1 and Cycle 2 Day 28 for the doses administered during Part B. Analysis performed on PK analysis set. Only patients with data available for analysis are presented (n in the category title indicates number of patients analyzed for each parameter). PK evaluation of givinostat 75 mg and 50 mg b.i.d. dose groups for Cycle 1 Day 1 not applicable (since all received 100 mg b.i.d.).
    End point type
    Secondary
    End point timeframe
    Blood samples were collected in Part B on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 2 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.
    End point values
    		 Givinostat 100 mg b.i.d. (Part B PK analysis set) Givinostat 75 mg b.i.d. (Part B PK analysis set) Givinostat 50 mg b.i.d. (Part B PK analysis set)
    Number of subjects analysed
    34
    12 [20]
    2 [21]
    Units: ng/mL
    median (full range (min-max))
        Givinostat Cycle 1 Day 1 (n=34, 0, 0)
    2.00 (0.00 to 8.00)
    9999999 (9999999 to 9999999)
    9999999 (9999999 to 9999999)
        ITF2374 Cycle 1 Day 1 (n=34, 0, 0)
    8.00 (2.08 to 8.17)
    9999999 (9999999 to 9999999)
    9999999 (9999999 to 9999999)
        ITF2375 Cycle 1 Day 1 (n=29, 0, 0)
    3.00 (1.83 to 8.00)
    9999999 (9999999 to 9999999)
    9999999 (9999999 to 9999999)
        Givinostat Cycle 2 Day 28 (n=17, 12, 2)
    2.00 (0.00 to 4.07)
    2.00 (1.00 to 8.00)
    0.985 (0.00 to 1.97)
        ITF2374 Cycle 2 Day 28 (n=17, 12, 2)
    4.00 (0.00 to 8.00)
    3.04 (1.00 to 8.00)
    5.99 (3.97 to 8.00)
        ITF2375 Cycle 2 Day 28 (n=16, 9, 0)
    2.00 (0.00 to 4.00)
    2.00 (1.00 to 8.00)
    9999999 (9999999 to 9999999)
    Notes
    [20] - 9999999=not calculated. For certain parameters, concentration data not available for PK analysis.
    [21] - 9999999=not calculated. For certain parameters, concentration data not available for PK analysis.
    No statistical analyses for this end point

    Secondary: Assessment of Tlast of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study

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    End point title
    		 Assessment of Tlast of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study
    End point description
    PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of Tlast following administration of givinostat for 2 cycles in Part B. PK calculations were performed by standard non-compartmental analysis. Following definition of the MTD in Part A, during Part B Cycle 1, givinostat was administered at 100 mg b.i.d. and during Part B Cycle 2 was administered at 100 mg, 75 mg and 50 mg b.i.d. (since dose reductions due to TEAEs were allowed from Cycle 2 onwards, as per protocol). Results are reported for Cycle 1 Day 1 and Cycle 2 Day 28 for the doses administered during Part B. Analysis performed on PK analysis set. Only patients with data available for analysis are presented (n in the category title indicates number of patients analyzed for each parameter). PK evaluation of givinostat 75 mg and 50 mg b.i.d. dose groups for Cycle 1 Day 1 not applicable (since all received 100 mg b.i.d.).
    End point type
    Secondary
    End point timeframe
    Blood samples were collected in Part B on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 2 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.
    End point values
    		 Givinostat 100 mg b.i.d. (Part B PK analysis set) Givinostat 75 mg b.i.d. (Part B PK analysis set) Givinostat 50 mg b.i.d. (Part B PK analysis set)
    Number of subjects analysed
    34
    12 [22]
    2 [23]
    Units: hours
    arithmetic mean (standard deviation)
        Givinostat Cycle 1 Day 1 (n=34, 0, 0)
    7.42 ( 1.61 )
    9999999 ( 9999999 )
    9999999 ( 9999999 )
        ITF2374 Cycle 1 Day 1 (n=34, 0, 0)
    7.42 ( 1.61 )
    9999999 ( 9999999 )
    9999999 ( 9999999 )
        ITF2375 Cycle 1 Day 1 (n=29, 0, 0)
    8.00 ( 0.0505 )
    9999999 ( 9999999 )
    9999999 ( 9999999 )
        Givinostat Cycle 2 Day 28 (n=17, 12, 2)
    8.00 ( 0.0340 )
    7.98 ( 0.0753 )
    7.99 ( 0.0212 )
        ITF2374 Cycle 2 Day 28 (n=17, 12, 2)
    8.00 ( 0.0340 )
    7.98 ( 0.0753 )
    7.99 ( 0.0212 )
        ITF2375 Cycle 2 Day 28 (n=16, 9, 0)
    7.75 ( 1.00 )
    8.00 ( 0.00 )
    9999999 ( 9999999 )
    Notes
    [22] - 9999999=not calculated. For certain parameters, concentration data not available for PK analysis.
    [23] - 9999999=not calculated. For certain parameters, concentration data not available for PK analysis.
    No statistical analyses for this end point

    Secondary: Assessment of AUClast of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study

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    End point title
    		 Assessment of AUClast of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study
    End point description
    PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of AUClast following administration of givinostat for 2 cycles in Part B. PK calculations were performed by standard non-compartmental analysis and AUClast was calculated using the linear trapezoidal rule. Following definition of the MTD in Part A, during Part B Cycle 1, givinostat was administered at 100 mg b.i.d. and during Part B Cycle 2 was administered at 100 mg, 75 mg and 50 mg b.i.d. (since dose reductions due to TEAEs were allowed from Cycle 2 onwards, as per protocol). Results are reported for Cycle 1 Day 1 and Cycle 2 Day 28 for the for the doses administered during Part B. Analysis performed on PK analysis set. Only patients with data available for analysis are presented (n in the category title indicates number of patients analyzed for each parameter). PK evaluation of givinostat 75 mg and 50 mg b.i.d. dose groups for Cycle 1 Day 1 not applicable (since all received 100 mg b.i.d.).
    End point type
    Secondary
    End point timeframe
    Blood samples were collected in Part B on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 2 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.
    End point values
    		 Givinostat 100 mg b.i.d. (Part B PK analysis set) Givinostat 75 mg b.i.d. (Part B PK analysis set) Givinostat 50 mg b.i.d. (Part B PK analysis set)
    Number of subjects analysed
    34
    12 [24]
    2 [25]
    Units: ng*h/mL
    arithmetic mean (standard deviation)
        Givinostat Cycle 1 Day 1 (n=34, 0, 0)
    289 ( 130 )
    99999999 ( 99999999 )
    99999999 ( 99999999 )
        ITF2374 Cycle 1 Day 1 (n=34, 0, 0)
    28.5 ( 14.0 )
    99999999 ( 99999999 )
    99999999 ( 99999999 )
        ITF2375 Cycle 1 Day 1 (n=29, 0, 0)
    888 ( 439 )
    99999999 ( 99999999 )
    99999999 ( 99999999 )
        Givinostat Cycle 2 Day 28 (n=17, 12, 2)
    459 ( 145 )
    323 ( 107 )
    269 ( 78.5 )
        ITF2374 Cycle 2 Day 28 (n=17, 12, 2)
    216 ( 127 )
    161 ( 83.5 )
    145 ( 20.9 )
        ITF2375 Cycle 2 Day 28 (n=16, 9, 0)
    1830 ( 1660 )
    1210 ( 585 )
    99999999 ( 99999999 )
    Notes
    [24] - 9999999=not calculated. For certain parameters, concentration data not available for PK analysis.
    [25] - 9999999=not calculated. For certain parameters, concentration data not available for PK analysis.
    No statistical analyses for this end point

    Secondary: Assessment of AUC0-12 of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study

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    End point title
    		 Assessment of AUC0-12 of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study
    End point description
    PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of AUC0-12 following administration of givinostat for 2 cycles in Part B. PK calculations were performed by standard non-compartmental analysis and AUClast was calculated using the linear trapezoidal rule. Following definition of the MTD in Part A, during Part B Cycle 1, givinostat was administered at 100 mg b.i.d. and during Part B Cycle 2 was administered at 100 mg, 75 mg and 50 mg b.i.d. (since dose reductions due to TEAEs were allowed from Cycle 2 onwards, as per protocol). Results are reported for Cycle 1 Day 1 and Cycle 2 Day 28 for the doses administered during Part B. Analysis performed on PK analysis set. Only patients with data available for analysis are presented (n in category title indicates number of patients analyzed for each parameter). PK evaluation of givinostat 75 mg and 50 mg b.i.d. dose groups for Cycle 1 Day 1 not applicable (since all received 100 mg b.i.d.).
    End point type
    Secondary
    End point timeframe
    Blood samples were collected in Part B on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 2 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.
    End point values
    		 Givinostat 100 mg b.i.d. (Part B PK analysis set) Givinostat 75 mg b.i.d. (Part B PK analysis set) Givinostat 50 mg b.i.d. (Part B PK analysis set)
    Number of subjects analysed
    34 [26]
    12 [27]
    2 [28]
    Units: ng*h/mL
    arithmetic mean (standard deviation)
        Givinostat Cycle 1 Day 1 (n=29, 0, 0)
    372 ( 137 )
    9999999 ( 9999999 )
    9999999 ( 9999999 )
        ITF2374 Cycle 1 Day 1 (n=0, 0, 0)
    9999999 ( 9999999 )
    9999999 ( 9999999 )
    9999999 ( 9999999 )
        ITF2375 Cycle 1 Day 1 (n=22, 0, 0)
    1080 ( 619 )
    9999999 ( 9999999 )
    9999999 ( 9999999 )
        Givinostat Cycle 2 Day 28 (n=17, 11, 2)
    561 ( 176 )
    410 ( 129 )
    326 ( 54.0 )
        ITF2374 Cycle 2 Day 28 (n=0, 0, 0)
    9999999 ( 9999999 )
    9999999 ( 9999999 )
    9999999 ( 9999999 )
        ITF2375 Cycle 2 Day 28 (n=14, 7, 0)
    2460 ( 2450 )
    1460 ( 608 )
    9999999 ( 9999999 )
    Notes
    [26] - 9999999=not calculated. For certain parameters, concentration data not available for PK analysis.
    [27] - 9999999=not calculated. For certain parameters, concentration data not available for PK analysis.
    [28] - 9999999=not calculated. For certain parameters, concentration data not available for PK analysis.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days).
    Adverse event reporting additional description
    TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Givinostat DL0 (50 mg b.i.d.) (Part A)
    Reporting group description
    		 In Part A, 3 patients were assigned to receive givinostat by oral administration at DL0 (50 mg b.i.d.). Patients were treated for up to 6 cycles (28 days in each cycle).

    Reporting group title
    Givinostat DL1 (100 mg b.i.d.) (Part A)
    Reporting group description
    		 In Part A, 3 patients were assigned to receive givinostat by oral administration at DL1 (100 mg b.i.d.). Patients were treated for up to 6 cycles (28 days in each cycle).

    Reporting group title
    Givinostat DL1 expanded (100 mg b.i.d.) (Part A)
    Reporting group description
    		 Following initial assignment of 3 patients to DL1 in Part A, a further 3 patients were assigned to DL1 so this treatment group is referred to as “DL1 expanded” (patients received givinostat by oral administration at 100 mg b.i.d.). Patients were treated for up to 6 cycles (28 days in each cycle).

    Reporting group title
    Givinostat DL6 (100 mg + 50 mg) (Part A)
    Reporting group description
    		 In Part A, 3 patients were assigned to receive givinostat by oral administration at DL 6 (100 mg in the morning and 50 mg in the evening, i.e. 12 hours after). Patients were treated for up to 6 cycles in (28 days in each cycle).

    Reporting group title
    Givinostat at MTD (100 mg b.i.d.) (Part B)
    Reporting group description
    		 In Part B, patients were assigned to receive the starting dose of givinostat by oral administration at the MTD determined in Part A (i.e. 100 mg b.i.d.). Patients were treated for up to 6 cycles (28 days in each cycle). Based on evaluations performed as part of the visit procedures on Day 28 of each cycle up to Cycle 5 and/or in any necessary additional study visit, the givinostat doses could be decreased for any patients that met dose reduction criteria.

    Serious adverse events
    		 Givinostat DL0 (50 mg b.i.d.) (Part A) Givinostat DL1 (100 mg b.i.d.) (Part A) Givinostat DL1 expanded (100 mg b.i.d.) (Part A) Givinostat DL6 (100 mg + 50 mg) (Part A) Givinostat at MTD (100 mg b.i.d.) (Part B)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    2 / 35 (5.71%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Vascular disorders
    Thrombophlebitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    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
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Givinostat DL0 (50 mg b.i.d.) (Part A) Givinostat DL1 (100 mg b.i.d.) (Part A) Givinostat DL1 expanded (100 mg b.i.d.) (Part A) Givinostat DL6 (100 mg + 50 mg) (Part A) Givinostat at MTD (100 mg b.i.d.) (Part B)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    35 / 35 (100.00%)
    Vascular disorders
    Erythromelalgia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Flushing
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 35 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Hypertension
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    1
    0
    0
    0
    2
    Lymphoedema
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Thrombosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    0
    0
    0
    2
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    10 / 35 (28.57%)
         occurrences all number
    0
    1
    1
    1
    22
    Chest pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Early satiety
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    Fatigue
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    2 / 35 (5.71%)
         occurrences all number
    0
    0
    1
    1
    3
    Oedema peripheral
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    1
    0
    0
    0
    2
    Pyrexia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    4 / 35 (11.43%)
         occurrences all number
    0
    0
    1
    0
    4
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    3 / 35 (8.57%)
         occurrences all number
    0
    0
    0
    0
    3
    Dyspnoea
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    1
    0
    1
    0
    2
    Dyspnoea exertional
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    0
    0
    0
    3
    Oropharyngeal pain
         subjects affected / exposed
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    2
    0
    0
    0
    3
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Irritability
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    0
    1
    0
    2
    Blood creatinine increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    14 / 35 (40.00%)
         occurrences all number
    0
    0
    0
    1
    21
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Electrocardiogram qt prolonged
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Weight decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    0
    1
    0
    2
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    3 / 35 (8.57%)
         occurrences all number
    0
    1
    0
    0
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    0
    0
    0
    2
    Dysgeusia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    3 / 35 (8.57%)
         occurrences all number
    0
    2
    1
    2
    3
    Head discomfort
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Headache
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    1
    0
    1
    Hypoaesthesia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    0
    0
    0
    2
    Memory impairment
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    6 / 35 (17.14%)
         occurrences all number
    0
    0
    0
    0
    14
    Haemolytic anaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Neutropenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    0
    0
    0
    2
    Thrombocytopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    16 / 35 (45.71%)
         occurrences all number
    0
    2
    4
    0
    22
    Thrombocytosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    0
    0
    0
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    8 / 35 (22.86%)
         occurrences all number
    0
    0
    0
    3
    9
    Abdominal pain upper
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    4 / 35 (11.43%)
         occurrences all number
    0
    0
    0
    0
    5
    Constipation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    3 / 35 (8.57%)
         occurrences all number
    0
    0
    0
    0
    3
    Diarrhoea
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    2 / 3 (66.67%)
    2 / 3 (66.67%)
    20 / 35 (57.14%)
         occurrences all number
    2
    4
    3
    5
    39
    Dry mouth
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Dyspepsia
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    5 / 35 (14.29%)
         occurrences all number
    1
    6
    0
    0
    5
    Faeces soft
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Flatulence
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    2 / 35 (5.71%)
         occurrences all number
    0
    0
    0
    1
    3
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 35 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Nausea
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    10 / 35 (28.57%)
         occurrences all number
    1
    0
    0
    0
    13
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    4 / 35 (11.43%)
         occurrences all number
    0
    0
    0
    1
    4
    Pruritus
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    3 / 35 (8.57%)
         occurrences all number
    0
    0
    1
    0
    3
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    2
    0
    0
    0
    2
    Chromaturia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 35 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Chronic kidney disease
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 35 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    0
    0
    0
    2
    Chondrocalcinosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Rheumatoid arthritis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Infections and infestations
    Localised infection
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Parainfluenzae virus infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    0
    0
    0
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    4 / 35 (11.43%)
         occurrences all number
    0
    0
    1
    0
    4
    Hyperglycaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 35 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Hyperkalaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 35 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Hypocalcaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    5 / 35 (14.29%)
         occurrences all number
    0
    0
    0
    0
    6
    Iron deficiency
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    0
    0
    0
    2

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Jul 2013
    1.Inclusion criterion regarding contraception and contraceptive methods updated, as requested by French Regulatory Authority. 2.Patient numbering sections updated as per study electronic Case Report Form. 3.Exploratory endpoint of Part B added, in order to also evaluate preliminary efficacy of givinostat according to the revised ELN Response Criteria.
    29 Jul 2015
    1.Preclinical rationale wording amended. 2.Approved drugs for treatment of PV and Myelofibrosis updated. 3.Neuromuscular disorders added as an indication. 4.Necessity to receive all approvals before starting long-term study DSC/11/2357/44 clarified. 5.Contract Manufacturing Organization as possible delegate for management of the study drug added. 6.Exclusion criterion updated to clarify “any other investigational drug or device”. 7.Instructions for study drug administration and dispensing were specified. 8.Spleen evaluations in Part B clarified. 9.Explanation that in case patient completes the study (i.e. performs all evaluations at Cycle 6 Day 28), these evaluations also counted for end of study visit. 10.Specification that in case patient completes the study (i.e. performs all evaluations requested at Cycle 6 Day 28) and is eligible to continue study drug treatment in DSC/11/2357/44, these evaluations could also count for the pre-treatment evaluations of DSC/11/2357/44. 11.Population for all efficacy analyses was clarified. 12.The SAE Form, AEs definition and details of Sponsor’s Drug Safety Unit were updated in the safety section. 13.Sections related to Part B were updated based on definition of the MTD of givinostat as chronic treatment in PV patients (relating to tolerability data for patients enrolled in Part A). 14.Dose modification rules to be applied in Part B (and in Part A) were updated. 15.75 mg strength added. 16.Pharmacodynamic evaluations added. 17.Calculation of estimated Glomerular Filtration Rate clarified, as agreed with German Regulatory Authority. 18.Evaluation of Urea updated. 19.Performing additional electrocardiogram evaluations (if first evaluation demonstrates a prolonged QTc interval) was clarified. 20.In Part B, recommendation that patients should arrive after an overnight fast at all study visits requiring a blood test was clarified. 21.Collection of blood sample for mutational status analysis during Part B added.

    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.
    No limitations or caveats are applicable to this summary of the results.
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