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    Clinical Trial Results:
    Phase I/II dose-escalation study of oral administration of the Pan-Histone Deacetylase (HDAC) Inhibitor S 78454 in Hodgkin’s Disease, non-Hodgkin Lymphoma and Chronic Lymphocytic Leukaemia

    Summary
    EudraCT number
    2009-013691-47
    Trial protocol
    FR   GB   BE   HU  
    Global end of trial date
    10 Feb 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    29 Jun 2017
    First version publication date
    29 Jun 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CL1-78454-001 / PCYC-1401-CA
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Pharmacyclics LLC
    Sponsor organisation address
    999 East Arques Avenue, Sunnyvale, United States, 94087
    Public contact
    Thorsten Graef, MD, PhD, Pharmacyclics LLC, + 1 408 408-774-0330,
    Scientific contact
    Thorsten Graef, MD, PhD, Pharmacyclics LLC, + 1 408 408-774-0330,
    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
    10 Feb 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Feb 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Feb 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Phase I part:­ - To assess the MTD and the dose-limiting toxicities (DLTs).­ Phase II part: - To assess the objective response rate at the recommended dose defined in the phase I part.­ - To assess the safety and tolerability.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements, with the exception of known instances of non-conformance (Appendix 14) which were not considered to have an impact on the overall conclusions of this study.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    08 Feb 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    France: 81
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Hungary: 15
    Country: Number of subjects enrolled
    Singapore: 9
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 17
    Country: Number of subjects enrolled
    Canada: 4
    Worldwide total number of subjects
    135
    EEA total number of subjects
    105
    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)
    67
    From 65 to 84 years
    67
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    This was a Phase 1/2, multicenter, open-label, non-randomized, non-comparative dose-escalation and efficacy evaluation of abexinostat conducted at multiple sites in Canada, Europe, and Asia conducted in 2 parts, Phase 1 and Phase 2.

    Pre-assignment
    Screening details
    In Phase 1, eligible subjects were adult men or women with any measurable or evaluable histologically confirmed HD and NHL, and with any evaluable CLL.treated/relapsed In Phase 2, eligible subjects were adult men or women with any measurable hist. confirmed and previously treated NHL in relapse or refractory to conventional, standard therapy

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

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Phase 1
    Arm description
    Phase 1 (Dose Escalation)Assess the safety and tolerability of the oral capsule form of abexinostat given orally bid 4 hours apart during a 3-week cycle in patients with HD, non-Hodgkin’s lymphoma (NHL), and chronic lymphocytic leukemia (CLL) in terms of the maximum tolerated dose (MTD) and the dose-limiting toxicities (DLTs) for each dosing schedule tested.  Determine the optimal dosing schedule and the associated recommended Phase 2 dose of the oral capsule form of abexinostat given orally bid 4 hours apart during a 3-week cycle.Secondary Objectives:  Determine the pharmacokinetic (PK) profile of the oral capsule form of abexinostat, its main metabolites, and its dose exposure relationship.  Determine the pharmacodynamic (PD) profile of the oral capsule form of abexinostat
    Arm type
    Experimental

    Investigational medicinal product name
    Abexinostat
    Investigational medicinal product code
    S 78454
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    In Schedule 1, 6 subjects were enrolled in the 30 mg/m2 cohort, 12 subjects (3 initial subjects + 9 additional subjects for the confirmatory phase) in the 45 mg/m2 cohort, and 3 subjects in the 60 mg/m2 cohort (Section 7.2). In Schedule 2, 3 subjects were enrolled in the 45 mg/m2 cohort, and 3 subjects in the 60 mg/m2 cohort. In Schedule 3, 3 subjects were enrolled in the 45 mg/m2 cohort, and 5 subjects in the 60 mg/m2 cohort.

    Arm title
    Phase 2
    Arm description
    All 100 subjects were to receive a fixed dose of 80 mg bid.The aim of Phase 2 was exploratory
    Arm type
    Experimental

    Investigational medicinal product name
    abexinostat
    Investigational medicinal product code
    S 78454
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects in Phase 2 were to receive abexinostat bid 4 hours apart during a 3-week cycle at the RD and optimal dosing schedule defined in Phase 1. De-escalation to a lower dose and switching to a different schedule were permitted in cases of toxicity. Phase 2 subjects received abexinostat orally bid, 4 hours apart for 14 consecutive days during a 3-week cycle (Dosing Schedule 1) at a fixed dose of 80 mg bid

    Arm title
    Efficacy Set Phase 1
    Arm description
    Subjects who received at least one dose of study medication and who had at least one baseline and one post-baseline assessment.
    Arm type
    Experimental

    Investigational medicinal product name
    Abexinostat
    Investigational medicinal product code
    S 78454
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    In Schedule 1, 6 subjects were enrolled in the 30 mg/sqm cohort, 12 subjects (3 initial subjects + 9 additional subjects for the confirmatory phase) in the 45 mg/sqm cohort, and 3 subjects in the 60 mg/sqm cohort (Section 7.2). In Schedule 2, 3 subjects were enrolled in the 45 mg/sqm cohort, and 3 subjects in the 60 mg/sqm cohort. In Schedule 3, 3 subjects were enrolled in the 45 mg/sqm cohort, and 5 subjects in the 60 mg/sqm cohort.

    Arm title
    Efficacy Set Phase 2
    Arm description
    Subjects who received at least one dose of study medication and who had at least one baseline and one post-baseline assessment.
    Arm type
    Experimental

    Investigational medicinal product name
    abexinostat
    Investigational medicinal product code
    S 78454
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects in Phase 2 were to receive abexinostat bid 4 hours apart during a 3-week cycle at the RD and optimal dosing schedule defined in Phase 1. De-escalation to a lower dose and switching to a different schedule were permitted in cases of toxicity. Phase 2 subjects received abexinostat orally bid, 4 hours apart for 14 consecutive days during a 3-week cycle (Dosing Schedule 1) at a fixed dose of 80 mg bid

    Number of subjects in period 1
    Phase 1 Phase 2 Efficacy Set Phase 1 Efficacy Set Phase 2
    Started
    35
    100
    32
    87
    Completed
    35
    100
    32
    87

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase 1
    Reporting group description
    Phase 1 (Dose Escalation)Assess the safety and tolerability of the oral capsule form of abexinostat given orally bid 4 hours apart during a 3-week cycle in patients with HD, non-Hodgkin’s lymphoma (NHL), and chronic lymphocytic leukemia (CLL) in terms of the maximum tolerated dose (MTD) and the dose-limiting toxicities (DLTs) for each dosing schedule tested.  Determine the optimal dosing schedule and the associated recommended Phase 2 dose of the oral capsule form of abexinostat given orally bid 4 hours apart during a 3-week cycle.Secondary Objectives:  Determine the pharmacokinetic (PK) profile of the oral capsule form of abexinostat, its main metabolites, and its dose exposure relationship.  Determine the pharmacodynamic (PD) profile of the oral capsule form of abexinostat

    Reporting group title
    Phase 2
    Reporting group description
    All 100 subjects were to receive a fixed dose of 80 mg bid.The aim of Phase 2 was exploratory

    Reporting group title
    Efficacy Set Phase 1
    Reporting group description
    Subjects who received at least one dose of study medication and who had at least one baseline and one post-baseline assessment.

    Reporting group title
    Efficacy Set Phase 2
    Reporting group description
    Subjects who received at least one dose of study medication and who had at least one baseline and one post-baseline assessment.

    Reporting group values
    Phase 1 Phase 2 Efficacy Set Phase 1 Efficacy Set Phase 2 Total
    Number of subjects
    35 100 32 87 135
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0 0
        Newborns (0-27 days)
    0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0 0
        Children (2-11 years)
    0 0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0 0
        Adults (18-64 years)
    22 48 20 41 70
        From 65-84 years
    13 51 12 46 64
        85 years and over
    0 1 0 0 1
    Age continuous
    Units: years
        median (full range (min-max))
    61 (21 to 83) 66.5 (32 to 85) 61 (21 to 83) 66 (32 to 85) -
    Gender categorical
    Units: Subjects
        Female
    13 45 13 38 58
        Male
    22 55 19 49 77

    End points

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    End points reporting groups
    Reporting group title
    Phase 1
    Reporting group description
    Phase 1 (Dose Escalation)Assess the safety and tolerability of the oral capsule form of abexinostat given orally bid 4 hours apart during a 3-week cycle in patients with HD, non-Hodgkin’s lymphoma (NHL), and chronic lymphocytic leukemia (CLL) in terms of the maximum tolerated dose (MTD) and the dose-limiting toxicities (DLTs) for each dosing schedule tested.  Determine the optimal dosing schedule and the associated recommended Phase 2 dose of the oral capsule form of abexinostat given orally bid 4 hours apart during a 3-week cycle.Secondary Objectives:  Determine the pharmacokinetic (PK) profile of the oral capsule form of abexinostat, its main metabolites, and its dose exposure relationship.  Determine the pharmacodynamic (PD) profile of the oral capsule form of abexinostat

    Reporting group title
    Phase 2
    Reporting group description
    All 100 subjects were to receive a fixed dose of 80 mg bid.The aim of Phase 2 was exploratory

    Reporting group title
    Efficacy Set Phase 1
    Reporting group description
    Subjects who received at least one dose of study medication and who had at least one baseline and one post-baseline assessment.

    Reporting group title
    Efficacy Set Phase 2
    Reporting group description
    Subjects who received at least one dose of study medication and who had at least one baseline and one post-baseline assessment.

    Primary: Objective Response Rate (ORR)

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    End point title
    Objective Response Rate (ORR) [1] [2]
    End point description
    End point type
    Primary
    End point timeframe
    From first dose in a subject until subject left the study.
    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: This was a Phase 1/2, multicenter, open-label, non-randomized, non-comparative study evaluating subjects with several different types of B-cell malignancies. In this context a strict statistical analysis did not appear meaningful.
    [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 objective of the Part 1 of this study was to assess the safety of increasing doses of abexinostat in subjects with hematological malignancies. Therefore, no formal statistical analysis has been conducted for these 35 subjects.
    End point values
    Efficacy Set Phase 1 Efficacy Set Phase 2
    Number of subjects analysed
    32
    87
    Units: percent
        number (confidence interval 95%)
    34.4 (20 to 50)
    27.6 (20 to 40)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of study drug up to 30 days after the last dose of study drug
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Overall trial Phase 1 and Phase 2
    Reporting group description
    -

    Serious adverse events
    Overall trial Phase 1 and Phase 2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    93 / 135 (68.89%)
         number of deaths (all causes)
    14
         number of deaths resulting from adverse events
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma
         subjects affected / exposed
    2 / 135 (1.48%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    6 / 135 (4.44%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 5
    Tumour compression
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Coma
         subjects affected / exposed
    2 / 135 (1.48%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Syncope
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cervical cord compression
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Balance disorder
         subjects affected / exposed
    2 / 135 (1.48%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 135 (2.22%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    2 / 135 (1.48%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Asthenia
         subjects affected / exposed
    2 / 135 (1.48%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Thrombosis in device
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Performance status decreased
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Anaphylactic shock
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Genital haemorrhage
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    2 / 135 (1.48%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chylothorax
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Productive cough
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    2 / 135 (1.48%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Platelet aggregation decreased
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Colonoscopy
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood creatine increased
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Muscle strain
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Multiple fractures
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Foreign body
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    62 / 135 (45.93%)
         occurrences causally related to treatment / all
    131 / 132
         deaths causally related to treatment / all
    0 / 0
    Neutropenia
         subjects affected / exposed
    14 / 135 (10.37%)
         occurrences causally related to treatment / all
    14 / 17
         deaths causally related to treatment / all
    0 / 0
    Anaemia
         subjects affected / exposed
    10 / 135 (7.41%)
         occurrences causally related to treatment / all
    7 / 16
         deaths causally related to treatment / all
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    5 / 135 (3.70%)
         occurrences causally related to treatment / all
    5 / 6
         deaths causally related to treatment / all
    1 / 1
    Febrile bone marrow aplasia
         subjects affected / exposed
    3 / 135 (2.22%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 1
    Pancytopenia
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Abdominal pain
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abdominal mass
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal failure
         subjects affected / exposed
    2 / 135 (1.48%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Urinary tract obstruction
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    6 / 135 (4.44%)
         occurrences causally related to treatment / all
    1 / 6
         deaths causally related to treatment / all
    0 / 1
    Lung infection
         subjects affected / exposed
    3 / 135 (2.22%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Cellulitis
         subjects affected / exposed
    3 / 135 (2.22%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia streptococcal
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Otitis externa
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ear infection
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    bronchopneumonia
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchitis haemophilus
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Biliary tract infection
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    2 / 135 (1.48%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gout
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Overall trial Phase 1 and Phase 2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    134 / 135 (99.26%)
    Investigations
    Weight decreased
         subjects affected / exposed
    14 / 135 (10.37%)
         occurrences all number
    15
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    7 / 135 (5.19%)
         occurrences all number
    9
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 135 (5.93%)
         occurrences all number
    11
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    78 / 135 (57.78%)
         occurrences all number
    394
    Anaemia
         subjects affected / exposed
    41 / 135 (30.37%)
         occurrences all number
    83
    Neutropenia
         subjects affected / exposed
    35 / 135 (25.93%)
         occurrences all number
    124
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    55 / 135 (40.74%)
         occurrences all number
    77
    Fatigue
         subjects affected / exposed
    16 / 135 (11.85%)
         occurrences all number
    17
    Pyrexia
         subjects affected / exposed
    14 / 135 (10.37%)
         occurrences all number
    17
    Oedema peripheral
         subjects affected / exposed
    8 / 135 (5.93%)
         occurrences all number
    8
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    65 / 135 (48.15%)
         occurrences all number
    119
    Nausea
         subjects affected / exposed
    48 / 135 (35.56%)
         occurrences all number
    56
    Vomiting
         subjects affected / exposed
    28 / 135 (20.74%)
         occurrences all number
    35
    Constipation
         subjects affected / exposed
    17 / 135 (12.59%)
         occurrences all number
    19
    Abdominal pain
         subjects affected / exposed
    11 / 135 (8.15%)
         occurrences all number
    13
    Abdominal pain upper
         subjects affected / exposed
    8 / 135 (5.93%)
         occurrences all number
    9
    Dry mouth
         subjects affected / exposed
    8 / 135 (5.93%)
         occurrences all number
    8
    Abdominal distension
         subjects affected / exposed
    7 / 135 (5.19%)
         occurrences all number
    7
    Dyspepsia
         subjects affected / exposed
    7 / 135 (5.19%)
         occurrences all number
    9
    Gastrooesophageal reflux disease
         subjects affected / exposed
    7 / 135 (5.19%)
         occurrences all number
    8
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    14 / 135 (10.37%)
         occurrences all number
    17
    Dyspnoea
         subjects affected / exposed
    9 / 135 (6.67%)
         occurrences all number
    9
    Epistaxis
         subjects affected / exposed
    9 / 135 (6.67%)
         occurrences all number
    10
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    14 / 135 (10.37%)
         occurrences all number
    16
    Pruritus
         subjects affected / exposed
    10 / 135 (7.41%)
         occurrences all number
    11
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    7 / 135 (5.19%)
         occurrences all number
    7
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    19 / 135 (14.07%)
         occurrences all number
    24
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    11 / 135 (8.15%)
         occurrences all number
    13
    Influenza
         subjects affected / exposed
    10 / 135 (7.41%)
         occurrences all number
    11
    Rhinitis
         subjects affected / exposed
    10 / 135 (7.41%)
         occurrences all number
    10
    Bronchitis
         subjects affected / exposed
    9 / 135 (6.67%)
         occurrences all number
    11
    Urinary tract infection
         subjects affected / exposed
    9 / 135 (6.67%)
         occurrences all number
    14
    Upper respiratory tract infection
         subjects affected / exposed
    8 / 135 (5.93%)
         occurrences all number
    14
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    41 / 135 (30.37%)
         occurrences all number
    45
    Hyperkalaemia
         subjects affected / exposed
    13 / 135 (9.63%)
         occurrences all number
    15
    Hypokalaemia
         subjects affected / exposed
    8 / 135 (5.93%)
         occurrences all number
    11

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Sep 2009
    Original Protocol
    01 Dec 2009
    Amendment 1
    29 Jun 2010
    Amendment 2
    23 May 2011
    Amendment 3
    19 Jul 2011
    Amendment 5
    29 May 2012
    Amendment 6
    20 Jun 2012
    Amendment 7
    28 Mar 2013
    Amendment 9
    10 Jul 2014
    Amendment 10
    13 Apr 2015
    Amendment 14
    15 Oct 2015
    Amendment 15

    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.
    None reported
    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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