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    Clinical Trial Results:
    A Phase II, Open-Label Study of Clofarabine in Paediatric Patients with Refractory / Relapsed Acute Lymphoblastic Leukaemia

    Summary
    EudraCT number
    2004-001853-27
    Trial protocol
    AT   IT  
    Global end of trial date
    26 Jul 2007

    Results information
    Results version number
    v1(current)
    This version publication date
    27 Apr 2016
    First version publication date
    18 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BIOV-111
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00930098
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    UKCCSG Number: NAG 2003 06
    Sponsors
    Sponsor organisation name
    Genzyme Corporation
    Sponsor organisation address
    500 Kendall Street, Cambridge, MA, United States, 02142
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    22 Jan 2008
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Jul 2007
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the overall response (OR) rate in paediatric subjects with refractory or relapsed acute lymphoblastic leukaemia (ALL) after 1 or more courses of clofarabine treatment.
    Protection of trial subjects
    Pediatric subjects: The study was conducted by investigators experienced in the treatment of pediatric subjects. The parent(s) or guardian(s) as well as the children were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time. In addition to the consent form for the parent(s)/guardian(s), an assent form in child-appropriate language was provided and explained to the child. Repeated invasive procedures were minimized. The number of blood samples as well as the amount of blood drawn were adjusted according to age and weight. A topical anesthesia may have been used to minimize distress and discomfort. Adult subjects: Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Dec 2003
    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: 29
    Country: Number of subjects enrolled
    Germany: 14
    Country: Number of subjects enrolled
    United Kingdom: 22
    Country: Number of subjects enrolled
    Netherlands: 7
    Country: Number of subjects enrolled
    Italy: 2
    Worldwide total number of subjects
    74
    EEA total number of subjects
    74
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    2
    Infants and toddlers (28 days-23 months)
    2
    Children (2-11 years)
    38
    Adolescents (12-17 years)
    21
    Adults (18-64 years)
    11
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 30 sites in 5 countries. A total of 74 subjects were enrolled between 1 December 2003 and 5 July 2007.

    Pre-assignment
    Screening details
    Of 74 enrolled subjects, 71 subjects were treated. 3 subjects were not treated due to death prior to first administration.

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

    Arms
    Arm title
    Clofarabine
    Arm description
    Clofarabine for 5 consecutive days and repeated every 21±7 days.
    Arm type
    Experimental

    Investigational medicinal product name
    Clofarabine
    Investigational medicinal product code
    Other name
    Clolar, Evoltra, 2-chloro-9-(2.-deoxy-2.-fluoro-ß-D-arabinofuranosyl)-9H-purine-6-amine
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Clofarabine 52 mg/m^2 or 1.7 mg/kg (for subjects under 1 year of age) over 2 hours.

    Number of subjects in period 1
    Clofarabine
    Started
    74
    Treated
    71
    Completed
    65
    Not completed
    9
         Investigator decision
             1
         Adverse event
             2
         Treatment not allowed by protocol
             1
         Disease relapse/progression
             2
         Death prior to first administration
             3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Clofarabine
    Reporting group description
    Clofarabine for 5 consecutive days and repeated every 21±7 days.

    Reporting group values
    Clofarabine Total
    Number of subjects
    74 74
    Age categorical
    Units: Subjects
        Newborns (0-27 days)
    2 2
        Infants and toddlers (28 days-23 months)
    2 2
        Children (2-11 years)
    38 38
        Adolescents (12-17 years)
    21 21
        Adults (18-64 years)
    11 11
    Gender categorical
    Units: Subjects
        Female
    26 26
        Male
    48 48

    End points

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    End points reporting groups
    Reporting group title
    Clofarabine
    Reporting group description
    Clofarabine for 5 consecutive days and repeated every 21±7 days.

    Primary: Overall Response Rate After 1 Course or More

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    End point title
    Overall Response Rate After 1 Course or More [1]
    End point description
    The overall response (OR) rate was defined as the sum of the number of subjects with complete response (CR) or complete response in the absence of total platelet recovery (CRp) with 1 or more courses of clofarabine treatment divided by the total number of subjects with 1 or more courses of clofarabine treatment. Analysis was carried out on one-course efficacy-evaluable (C1EE) population defined as all registered subjects whose diagnosis of ALL and best response was confirmed by independent response review panel (IRRP), who received at least 1 full course (5 consecutive daily infusions) of clofarabine treatment.
    End point type
    Primary
    End point timeframe
    Day 21 up to Day 203
    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: Due to EudraCT format constraint, the statistical analysis could not be provided for single arm study. 
    End point values
    Clofarabine
    Number of subjects analysed
    65
    Units: percentage of subjects
        number (confidence interval 95%)
    23.1 (13.5 to 35.2)
    No statistical analyses for this end point

    Secondary: Overall Response Rate After 2 Courses or More

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    End point title
    Overall Response Rate After 2 Courses or More
    End point description
    OR rate was defined as in primary endpoint. Analysis was carried out in two-course efficacy-evaluable (C2EE) population defined as all registered subjects whose diagnosis of ALL and best response was confirmed by IRRP, who received at least 2 full courses (each course consisting of 5 consecutive daily infusions) of clofarabine treatment.
    End point type
    Secondary
    End point timeframe
    Day 37 up to Day 203
    End point values
    Clofarabine
    Number of subjects analysed
    32
    Units: percentage of subjects
        number (confidence interval 95%)
    31.3 (16.1 to 50)
    No statistical analyses for this end point

    Secondary: Rate of Response After 1 Course or More

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    End point title
    Rate of Response After 1 Course or More
    End point description
    Analysis was carried out on C1EE population. In this section, -99999 and 99999 represent data not applicable as only one subject had partial response.
    End point type
    Secondary
    End point timeframe
    Day 21 up to Day 203
    End point values
    Clofarabine
    Number of subjects analysed
    65
    Units: percentage of subjects
    number (confidence interval 95%)
        CR
    4.6 (1 to 12.9)
        CRp
    18.5 (9.9 to 30)
        Partial Response (PR)
    1.5 (-99999 to 99999)
    No statistical analyses for this end point

    Secondary: Time-to-Event Parameters

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    End point title
    Time-to-Event Parameters
    End point description
    Time to event parameters included time to response (CR, CRp or PR) duration of remission (response) and survival. Analysis was carried out on C1EE population. In this section, 99999 represents data not applicable for upper limit of 95% CI. In this section, 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Up to death of subject or end of treatment (Day 203)
    End point values
    Clofarabine
    Number of subjects analysed
    65
    Units: days
    median (confidence interval 95%)
        Time to Response (n=47)
    68 (50 to 93)
        Duration of Response (n=16)
    108 (43 to 99999)
        Survival Time (n=65)
    85 (62 to 120)
    No statistical analyses for this end point

    Secondary: Time to Transplant Bone Marrow or Peripheral Blood Stem Cell Following Commencement of Clofarabine

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    End point title
    Time to Transplant Bone Marrow or Peripheral Blood Stem Cell Following Commencement of Clofarabine
    End point description
    Analysis was carried out on mITT population defined as all registered subjects with IRRP confirmed diagnosis of ALL who received at least one dose of clofarabine treatment. Here the number of subjects analyzed were those who received bone marrow or peripheral blood stem cell transplantation.
    End point type
    Secondary
    End point timeframe
    Up to death of subject or end of treatment (Day 203)
    End point values
    Clofarabine
    Number of subjects analysed
    7
    Units: days
        median (full range (min-max))
    40 (31 to 97)
    No statistical analyses for this end point

    Secondary: Plasma Clofarabine Concentration

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    End point title
    Plasma Clofarabine Concentration
    End point description
    In this section, 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    0 hour (pre-infusion); 2, 24, 26, 48, 50, 72, 74, 96, 98 hours post-infusion on Day 1
    End point values
    Clofarabine
    Number of subjects analysed
    29
    Units: uM
    arithmetic mean (standard deviation)
        0 h (n=28)
    0.02 ± 0.04
        2 h (n=29)
    1.75 ± 0.9
        24 h (n=27)
    0.06 ± 0.07
        26 h (n=28)
    2 ± 1.12
        48 h (n=27)
    0.07 ± 0.07
        50 h (n=27)
    2.28 ± 1.4
        72 h (n=21)
    0.06 ± 0.07
        74 h (n=20)
    2.08 ± 0.92
        96 h (n=16)
    0.07 ± 0.11
        98 h (n=16)
    2.25 ± 0.88
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AE) were collected from signature of the informed consent form up to the final visit (Day 203) regardless of seriousness or relationship to investigational product
    Adverse event reporting additional description
    Reported adverse events and deaths are treatment-emergent that is AEs that developed/worsened and deaths that occurred during the ‘on treatment period’ (time from first infusion of study drug up to 30 days after the last dose of study drug). Safety population included all registered subjects who received at least one infusion of study drug.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    Clofarabine
    Reporting group description
    Clofarabine for 5 consecutive days and repeated every 21±7 days.

    Serious adverse events
    Clofarabine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    59 / 71 (83.10%)
         number of deaths (all causes)
    59
         number of deaths resulting from adverse events
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Leukaemia
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Leukaemia Recurrent
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Malignant Neoplasm Progression
         subjects affected / exposed
    13 / 71 (18.31%)
         occurrences causally related to treatment / all
    0 / 14
         deaths causally related to treatment / all
    0 / 13
    Neoplasm Malignant
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    3 / 71 (4.23%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 71 (5.63%)
         occurrences causally related to treatment / all
    2 / 5
         deaths causally related to treatment / all
    1 / 1
    Mucosal Inflammation
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Necrosis
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Hepatic Enzyme Increased
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Hepatic Enzyme Abnormal
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Fibrin D Dimer Increased
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood Amylase Increased
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Alanine Aminotransferase Increased
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Cardiac Failure
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Pericardial Effusion
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Hypoxia
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary Oedema
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Febrile Bone Marrow Aplasia
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neutropenia
         subjects affected / exposed
    5 / 71 (7.04%)
         occurrences causally related to treatment / all
    7 / 7
         deaths causally related to treatment / all
    1 / 1
    Anaemia
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Leukopenia
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    1 / 1
    Febrile Neutropenia
         subjects affected / exposed
    34 / 71 (47.89%)
         occurrences causally related to treatment / all
    52 / 64
         deaths causally related to treatment / all
    1 / 2
    Thrombocytopenia
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Convulsion
         subjects affected / exposed
    5 / 71 (7.04%)
         occurrences causally related to treatment / all
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    Tremor
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    5 / 71 (7.04%)
         occurrences causally related to treatment / all
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Proctitis
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Renal Failure
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    1 / 2
    Renal Impairment
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal Failure Acute
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Palmar-Plantar Erythrodysaesthesia Syndrome
         subjects affected / exposed
    4 / 71 (5.63%)
         occurrences causally related to treatment / all
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    Vasculitic Rash
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone Pain
         subjects affected / exposed
    3 / 71 (4.23%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    1 / 1
    Pain In Extremity
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Back Pain
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Arthralgia
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyperuricaemia
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolic Acidosis
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Aspergillosis
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Bacteraemia
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Bacterial Sepsis
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    1 / 1
    Bronchopulmonary Aspergillosis
         subjects affected / exposed
    4 / 71 (5.63%)
         occurrences causally related to treatment / all
    6 / 7
         deaths causally related to treatment / all
    1 / 1
    Escherichia Sepsis
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Fungal Skin Infection
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Herpes Zoster
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Herpes Simplex
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung Infection
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Otitis Media
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neutropenic Sepsis
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Streptococcal Sepsis
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Staphylococcal Infection
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Staphylococcal Bacteraemia
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Septic Shock
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    1 / 1
    Pyelonephritis
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary Mycosis
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia Fungal
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    6 / 71 (8.45%)
         occurrences causally related to treatment / all
    3 / 6
         deaths causally related to treatment / all
    1 / 1
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Clofarabine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    71 / 71 (100.00%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    3 / 71 (4.23%)
         occurrences all number
    3
    Flushing
         subjects affected / exposed
    5 / 71 (7.04%)
         occurrences all number
    7
    Peripheral Circulatory Failure
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Pallor
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences all number
    2
    Haemorrhage
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences all number
    2
    Hypertension
         subjects affected / exposed
    7 / 71 (9.86%)
         occurrences all number
    9
    Hypotension
         subjects affected / exposed
    10 / 71 (14.08%)
         occurrences all number
    10
    Surgical and medical procedures
    Tooth Extraction
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour Lysis Syndrome
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences all number
    2
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    4 / 71 (5.63%)
         occurrences all number
    4
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    5 / 71 (7.04%)
         occurrences all number
    7
    Feeling Abnormal
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    3
    Crepitations
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Generalised Oedema
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Chills
         subjects affected / exposed
    5 / 71 (7.04%)
         occurrences all number
    6
    Chest Pain
         subjects affected / exposed
    3 / 71 (4.23%)
         occurrences all number
    3
    Catheter Site Rash
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Catheter Site Pain
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Face Oedema
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences all number
    2
    Fatigue
         subjects affected / exposed
    11 / 71 (15.49%)
         occurrences all number
    14
    Mucosal Inflammation
         subjects affected / exposed
    12 / 71 (16.90%)
         occurrences all number
    15
    Oedema
         subjects affected / exposed
    3 / 71 (4.23%)
         occurrences all number
    4
    Oedema Peripheral
         subjects affected / exposed
    3 / 71 (4.23%)
         occurrences all number
    3
    Pain
         subjects affected / exposed
    7 / 71 (9.86%)
         occurrences all number
    7
    Malaise
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Localised Oedema
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences all number
    4
    Irritability
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Hypothermia
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Pyrexia
         subjects affected / exposed
    35 / 71 (49.30%)
         occurrences all number
    72
    Psychiatric disorders
    Personality Change
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    2
    Mood Altered
         subjects affected / exposed
    7 / 71 (9.86%)
         occurrences all number
    11
    Insomnia
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Emotional Distress
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Agitation
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences all number
    2
    Depressed Mood
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Confusional State
         subjects affected / exposed
    3 / 71 (4.23%)
         occurrences all number
    3
    Anxiety
         subjects affected / exposed
    7 / 71 (9.86%)
         occurrences all number
    7
    Depression
         subjects affected / exposed
    6 / 71 (8.45%)
         occurrences all number
    7
    Psychotic Disorder
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences all number
    2
    Reproductive system and breast disorders
    Vaginal Discharge
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Procedural Pain
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences all number
    2
    Post Procedural Haemorrhage
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences all number
    3
    Periorbital Haematoma
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Chemical Eye Injury
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    5 / 71 (7.04%)
         occurrences all number
    10
    Alanine Aminotransferase
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Blood Urine Present
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Blood Potassium Decreased
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences all number
    5
    Blood Magnesium Decreased
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences all number
    4
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    4 / 71 (5.63%)
         occurrences all number
    12
    Blood Bilirubin Increased
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences all number
    2
    Blood Amylase
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Blood Alkaline Phosphatase Increased
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    2
    Blood Creatinine Increased
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Weight Increased
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences all number
    2
    Weight Decreased
         subjects affected / exposed
    6 / 71 (8.45%)
         occurrences all number
    7
    Platelet Count Decreased
         subjects affected / exposed
    5 / 71 (7.04%)
         occurrences all number
    6
    Body Temperature Increased
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Neutrophil Count
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Haemoglobin Decreased
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    4
    Haemoglobin
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences all number
    2
    Oxygen Consumption
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    White Blood Cell Count Decreased
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    2
    Cardiac disorders
    Arrhythmia Supraventricular
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Bradycardia
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Left Ventricular Dysfunction
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    2
    Palpitations
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Sinus Arrhythmia
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Tachycardia
         subjects affected / exposed
    5 / 71 (7.04%)
         occurrences all number
    5
    Respiratory, thoracic and mediastinal disorders
    Pulmonary Oedema
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    2
    Pleuritic Pain
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Pharyngolaryngeal Pain
         subjects affected / exposed
    5 / 71 (7.04%)
         occurrences all number
    7
    Bradypnoea
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Epistaxis
         subjects affected / exposed
    10 / 71 (14.08%)
         occurrences all number
    13
    Dyspnoea
         subjects affected / exposed
    4 / 71 (5.63%)
         occurrences all number
    4
    Cough
         subjects affected / exposed
    13 / 71 (18.31%)
         occurrences all number
    18
    Hypoxia
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    2
    Respiratory Distress
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Wheezing
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Pancytopenia
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Anaemia
         subjects affected / exposed
    4 / 71 (5.63%)
         occurrences all number
    4
    Febrile Bone Marrow Aplasia
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Febrile Neutropenia
         subjects affected / exposed
    11 / 71 (15.49%)
         occurrences all number
    17
    Leukopenia
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Neutropenia
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences all number
    4
    Thrombocytopenia
         subjects affected / exposed
    4 / 71 (5.63%)
         occurrences all number
    4
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Headache
         subjects affected / exposed
    38 / 71 (53.52%)
         occurrences all number
    71
    Dizziness
         subjects affected / exposed
    3 / 71 (4.23%)
         occurrences all number
    3
    Convulsion
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Trigeminal Nerve Disorder
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    2
    Speech Disorder
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Sinus Headache
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    3
    Hyperaesthesia
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Paraesthesia
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Lethargy
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Hypoaesthesia
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Peripheral Sensory Neuropathy
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Eye disorders
    Diplopia
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Conjunctivitis
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Conjunctival Haemorrhage
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Abnormal Sensation In Eye
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Eye Swelling
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Eye Oedema
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    2
    Eyelid Oedema
         subjects affected / exposed
    3 / 71 (4.23%)
         occurrences all number
    3
    Photophobia
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Ear Pain
         subjects affected / exposed
    4 / 71 (5.63%)
         occurrences all number
    4
    Ear Haemorrhage
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Hypoacusis
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Hearing Impaired
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    2
    Gastrointestinal disorders
    Abdominal Distension
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Abdominal Pain
         subjects affected / exposed
    26 / 71 (36.62%)
         occurrences all number
    37
    Abdominal Pain Upper
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences all number
    3
    Anal Fissure
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences all number
    3
    Anal Haemorrhage
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Anorectal Disorder
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Gastrointestinal Pain
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Gastrointestinal Oedema
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Gastrointestinal Haemorrhage
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    2
    Dysphagia
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Dyspepsia
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Dry Mouth
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Diarrhoea
         subjects affected / exposed
    25 / 71 (35.21%)
         occurrences all number
    40
    Colitis
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Constipation
         subjects affected / exposed
    10 / 71 (14.08%)
         occurrences all number
    12
    Lip Swelling
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    37 / 71 (52.11%)
         occurrences all number
    66
    Pancreatitis
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Proctalgia
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Stomatitis
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Toothache
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    52 / 71 (73.24%)
         occurrences all number
    100
    Renal and urinary disorders
    Urinary Tract Inflammation
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Urinary Retention
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences all number
    2
    Haemorrhage Urinary Tract
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences all number
    2
    Renal Impairment
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Pollakiuria
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Urinary Bladder Haemorrhage
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Hepatobiliary disorders
    Cytolytic Hepatitis
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    6
    Hepatotoxicity
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Hepatomegaly
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences all number
    2
    Generalised Erythema
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Exfoliative Rash
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences all number
    2
    Erythema Multiforme
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Ecchymosis
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Dry Skin
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    2
    Erythema
         subjects affected / exposed
    4 / 71 (5.63%)
         occurrences all number
    4
    Rash Macular
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Rash
         subjects affected / exposed
    27 / 71 (38.03%)
         occurrences all number
    37
    Pruritus
         subjects affected / exposed
    20 / 71 (28.17%)
         occurrences all number
    28
    Petechiae
         subjects affected / exposed
    4 / 71 (5.63%)
         occurrences all number
    4
    Melanodermia
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Palmar-Plantar Erythrodysaesthesia Syndrome
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Night Sweats
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Nail Disorder
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Periorbital Oedema
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Rash Maculo-Papular
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Skin Lesion
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences all number
    2
    Skin Exfoliation
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Rash Pruritic
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Urticaria
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences all number
    3
    Musculoskeletal and connective tissue disorders
    Musculoskeletal Pain
         subjects affected / exposed
    5 / 71 (7.04%)
         occurrences all number
    16
    Muscular Weakness
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Muscle Spasms
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Arthralgia
         subjects affected / exposed
    5 / 71 (7.04%)
         occurrences all number
    7
    Bone Pain
         subjects affected / exposed
    9 / 71 (12.68%)
         occurrences all number
    11
    Back Pain
         subjects affected / exposed
    8 / 71 (11.27%)
         occurrences all number
    10
    Lower Extremity Mass
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Pain In Extremity
         subjects affected / exposed
    17 / 71 (23.94%)
         occurrences all number
    22
    Neck Pain
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences all number
    2
    Myalgia
         subjects affected / exposed
    3 / 71 (4.23%)
         occurrences all number
    3
    Musculoskeletal Stiffness
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences all number
    2
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences all number
    2
    Hypomagnesaemia
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Hypokalaemia
         subjects affected / exposed
    3 / 71 (4.23%)
         occurrences all number
    4
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    2
    Dehydration
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Decreased Appetite
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Anorexia
         subjects affected / exposed
    11 / 71 (15.49%)
         occurrences all number
    12
    Hypernatraemia
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    2
    Infections and infestations
    Abscess
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Catheter Related Infection
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Cellulitis
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Central Line Infection
         subjects affected / exposed
    3 / 71 (4.23%)
         occurrences all number
    4
    Enterococcal Infection
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Gastrointestinal Candidiasis
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Herpes Simplex
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Herpes Zoster
         subjects affected / exposed
    3 / 71 (4.23%)
         occurrences all number
    5
    Infection
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences all number
    2
    Nasopharyngitis
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Cystitis
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences all number
    2
    Staphylococcal Infection
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Skin Infection
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Sepsis
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Oral Herpes
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences all number
    2
    Pyelonephritis
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Otitis Media
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Respiratory Tract Infection Viral
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Urinary Tract Infection
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    2
    Upper Respiratory Tract Infection
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Oct 2003
    - The criterion for evaluability was changed from having received a minimum of 4 courses to having received a minimum of 2 courses. - The following secondary endpoint was added: Bone marrow transplant (BMT)/ peripheral blood stem cell transplant (PBSCT) rate was to be determined by dividing the number of subjects receiving BMT/PBSCT by the total number of subjects evaluable for response. - The following was added to the preamble to the inclusion criteria: The trial would recruit subjects who had failed to achieve remission by standard first line therapy or following first relapse, failed to achieve remission by standard relapse therapy. Subjects with multiple relapses would be eligible provided their prior salvage therapy did not include BMT or PBSCT. - Following Inclusion criterion was removed: National and local ethical approval for the protocol. - The criterion for subject discontinuation was changed from “lead investigator’s discretion” to “investigator’s discretion”. - It was specified that off-study (end of study) assessments were to be performed within 14 days of the last dose of clofarabine. No time-frame had been specified in version 1 of the protocol. - A definition of “end of study” for analysis purposes was added, being the completion of course 4 of clofarabine treatment, including the bone marrow aspirate (BMA) taken at the end of course 4 to assess disease status and response to clofarabine treatments. - The confidence interval for characterising the overall response (OR) was changed from 99% to 95%.
    28 Oct 2003
    - The lead Clinical Research Organization (Tessman Technology Limited) was removed. - The preamble to the inclusion criteria was amended to specify that: Children who had received an allogeneic progenitor cell transplant must be at least 6 months post-transplant. - Following inclusion criterion was amended to: Subjects with 2 or more relapses of acute lymphoblastic leukaemia (ALL) Children who had received an allogeneic progenitor cell transplant, must be a. At least 6-months post transplant b. Had good organ function c. Stable with no major complications. - The requirement that subjects’ prior salvage therapy did not include BMT or PBSCT was deleted from inclusion criterion. - Exclusion criterion was amended to allow the inclusion of subjects with prior BMT or PBSCT provided this happened more than 6 months previously. As a result, a new exclusion criterion was added, with all subsequent criteria being renumbered, to exclude subjects with prior BMT or PBSCT and poor organ function.
    08 Mar 2005
    - Overall remission, complete remission, partial remission, etc were changed to OR, etc. However the term “duration of remission” was not changed. - Secondary objective “To document an OR rate of ≥ 20% in children with refractory or relapsed ALL” was removed. - The following new secondary objective was inserted with all subsequent secondary objectives being renumbered; the modified overall response (MOR) rate was also defined as a secondary endpoint. To document the MOR rate in paediatric subjects with refractory or relapsed ALL. The MOR rate was defined as the sum of the number of subjects with either complete response (CR), complete response in the absence of platelet recovery (CRp) or partial response (PR) divided by the total number of subjects evaluable for response. - The option to reduce the dose in the event of “significant haematological toxicity” was introduced. - Exclusion criterion was amended to read: Had an active or uncontrolled systemic infection considered opportunistic, life threatening, or clinically significant at the time of treatment. Subjects who had a recent (< 30 days) history of fungal or bacterial infection or who were receiving therapeutic doses of antibiotics or antifungals. - A new exclusion criterion was introduced: Had recent history of significant renal, hepatic or pulmonary dysfunction, or cardiac dysfunction, or on treatment to support cardiac function. - A new criterion for subject discontinuation was introduced: No MOR after 4 courses of clofarabine treatment. - Metabolism studies (urine sampling) were added for the subset of subjects that consented to these investigations. - The definition of serious adverse events (SAEs) was changed to include “any medically important event” and all National Cancer Institute common toxicity criteria (NCI-CTC) grade 4 events. - Information on capillary leak syndrome and instructions to the investigators in the event of such a case occurring were added.
    30 Nov 2006
    - The primary objective was amended to determine OR only in subjects that had completed at least one full course of clofarabine treatment. -Determination of OR after 2 or more courses, which was the primary objective in the previous versions, was changed to secondary objective. - Secondary endpoint was amended to: The OR rate after 2 courses or more will be determined by the sum of the number of subjects with either a CR or CRp with 2 courses or more of clofarabine divided by the total number of subjects who received 2 courses or more of clofarabine. - The inclusion of subjects without primary refractory disease was permitted if they had relapsed or refractory disease after a minimum of 2 prior blocks of treatment.- Inclusion criterion was reworded to include definitions of adequate cardiac function. - The definition of adequate hepatic function for inclusion were amended to specify AST and ALT of ≤ 5 x ULN. - Reasons for discontinuation were amended to remove the option for discontinuation at the investigator’s discretion, and to remove the exclusion from discontinuation due to non-haematological toxicities for elevated liver function tests.- Dosage, Administration, and Storage section was amended to state that the diluted clofarabine was to be used immediately or that if not used immediately, would normally not exceed 24 hours at 2 to 8°C unless reconstitution/dilution (etc) had taken place in controlled and validated aseptic conditions.- Repetition of clofarabine courses was to be at 21 ± 7 day intervals, and that subjects were to receive a minimum of 1 course and a maximum of 12 courses.- Criteria for dose reduction in subjects experiencing haematological toxicities were introduced.- The requirement for absolute neutrophil count (ANC) recovery to 0.75 × 10 9 /L for the third and subsequent courses of treatment was removed.- Criteria for bone marrow or blood sampling for molecular pharmacology studies were 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.
    None reported
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