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    Clinical Trial Results:
    A phase I/II study evaluating the safety and activity of Pegylated recombinant human Arginase (BCT-100) in Relapsed/refractory cancers of Children and young adults

    Summary
    EudraCT number
    		 2017-002762-44
    Trial protocol
    		 GB   IE   NL  
    Global end of trial date
    22 Jul 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Feb 2023
    First version publication date
    08 Feb 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RG-16-040
    Additional study identifiers
    ISRCTN number
    		 ISRCTN21727048
    US NCT number
    		 NCT03455140
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 EudraCT Number : 2017-002762-44, ITCC: ITCC-062, CAS Number: MX1032
    Sponsors
    Sponsor organisation name
    University of Birmingham
    Sponsor organisation address
    Edgbaston, Birmingham , United Kingdom, B15 2TT
    Public contact
    Birgit Whitman , University of Birmingham , 0044 07814 650 003, researchgovernance@contacts.bham.ac.uk
    Scientific contact
    Birgit Whitman , University of Birmingham , 0044 07814 650 003, researchgovernance@contacts.bham.ac.uk
    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
    21 Sep 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Jun 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Jul 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objectives of this trial are to: - establish a safe and active dose of BCT-100 in children and young people - evaluate if BCT-100 is effective against acute leukaemias, neuroblastoma, sarcoma and high grade glioma which have come back (relapsed) or not responded to previous treatment (refractory)as measured by disease response at 8 weeks. In the first part, doctors will be looking for the dose of BCT-100 which is both safe and active in children and young adults. This will involve giving increasing doses of BCT-100 to patients to find the dose which does not cause significant side effects (known as dose-limiting toxicities) and completely depletes arginine levels. All the doses of BCT-100 used in this trial have found to be safe in adults. In the second part the trial, the final dose chosen in part 1 will then be given to all patients who take part. Disease response at 8 weeks will be measured to determine activity of BCT-100 against the four disease types.
    Protection of trial subjects
    The study was conducted by investigators experienced in the treatment of paediatric patients as well as patients lacking capacity to consent to research. The parent(s) or guardian(s) as well as the children were provided with sufficient information to allow patients/parents/legal guardians/legal representatives to make an informed decision about participation as well as the possibility to discontinue at any time. In addition to the consent form for the parent(s)/guardian(s), patient information in child-appropriate language (where appropriate) was provided and explained to the child and assent recorded. Repeated invasive procedures were minimised. The number of blood samples as well as the amount of blood drawn were adjusted according to a weight.
    Background therapy
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Aug 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    United Kingdom: 41
    Country: Number of subjects enrolled
    Australia: 4
    Worldwide total number of subjects
    49
    EEA total number of subjects
    4
    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)
    20
    Adolescents (12-17 years)
    22
    Adults (18-64 years)
    7
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial opened to recruitment on 28th August 2018 and closed to recruitment on 22nd July 2022. The trial recruited from Australia, the Netherlands and the UK.

    Pre-assignment
    Screening details
    		 Aged 1- <25 years old at registration Histologically confirmed disease in one of: Leukaemia, Neuroblastoma, High Grade Glioma or Sarcoma Radiological or laboratory evidence of disease progression Measurable bone marrow disease or at least one evaluable radiological site of disease Adequate liver function Negative pregnancy test

    Period 1
    Period 1 title
    Phase II
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Leukaemia
    Arm description
    		 Acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML)
    Arm type
    		 Experimental

    Investigational medicinal product name
    PEG-BCT-100
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1600U/kg BCT-100 administered as weekly intravenous infusion over one hour. Administered at 7 day intervals (+/- 1 day).

    Arm title
    		 Sarcoma
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    PEG-BCT-100
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1600U/kg BCT-100 administered as weekly intravenous infusion over one hour. Administered at 7 day intervals (+/- 1 day).

    Arm title
    		 High Grade Glioma
    Arm description
    		 As defined by 2016 WHO CNS classification
    Arm type
    		 Experimental

    Investigational medicinal product name
    PEG-BCT-100
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1600U/kg BCT-100 administered as weekly intravenous infusion over one hour. Administered at 7 day intervals (+/- 1 day).

    Arm title
    		 Neuroblastoma
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    PEG-BCT-100
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1600U/kg BCT-100 administered as weekly intravenous infusion over one hour. Administered at 7 day intervals (+/- 1 day).

    Number of subjects in period 1
    		Leukaemia Sarcoma High Grade Glioma Neuroblastoma
    Started
    7
    13
    15
    14
    Completed
    7
    13
    13
    12
    Not completed
    0
    0
    2
    2
         Consent withdrawn by subject
    -
    -
    1
    1
         Progression
    -
    -
    1
    1
    Period 2
    Period 2 title
    Phase I
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Leukaemia
    Arm description
    		 Acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML)
    Arm type
    		 Experimental

    Investigational medicinal product name
    PEG-BCT-100
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1600U/kg BCT-100 administered as weekly intravenous infusion over one hour. Administered at 7 day intervals (+/- 1 day).

    Arm title
    		 Sarcoma
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    PEG-BCT-100
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1600U/kg BCT-100 administered as weekly intravenous infusion over one hour. Administered at 7 day intervals (+/- 1 day).

    Arm title
    		 High Grade Glioma
    Arm description
    		 As defined by 2016 WHO CNS classification
    Arm type
    		 Experimental

    Investigational medicinal product name
    PEG-BCT-100
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1600U/kg BCT-100 administered as weekly intravenous infusion over one hour. Administered at 7 day intervals (+/- 1 day).

    Number of subjects in period 2 [1]
    		Leukaemia Sarcoma High Grade Glioma
    Started
    1
    1
    3
    Completed
    0
    1
    2
    Not completed
    1
    0
    1
         Progression
    1
    -
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Period 1 was defined as Phase II and Period 2 was defined as Phase I as it was expected that Period 1 would be the period for which baseline characteristics were reported. It was also impossible to put Period 1 as Phase I due to lower numbers in Phase I than Phase II, the system would not allow the number of subjects in Period 2 to exceed the number in Period 1.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Leukaemia
    Reporting group description
    		 Acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML)

    Reporting group title
    Sarcoma
    Reporting group description
    		 -

    Reporting group title
    High Grade Glioma
    Reporting group description
    		 As defined by 2016 WHO CNS classification

    Reporting group title
    Neuroblastoma
    Reporting group description
    		 -

    Reporting group values
    		 Leukaemia Sarcoma High Grade Glioma Neuroblastoma Total
    Number of subjects
    		 7 13 15 14 49
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 7.9 (1.2 to 17.4) 12.2 (1.3 to 15.4) 12 (4.8 to 20) 10.3 (2.0 to 18.8) -
    Gender categorical
    Units: Subjects
        Female
    		 3 5 8 7 23
        Male
    		 4 8 7 7 26
    Weight
    Units: kilogram(s)
        median (full range (min-max))
    		 26.9 (9.9 to 70.5) 31.5 (10.7 to 58.0) 33.3 (19.4 to 94.4) 25.7 (12.0 to 86.1) -
    Bilirubin
    Units: umol/L
        median (full range (min-max))
    		 6.0 (3.0 to 17.0) 7.0 (4.0 to 12.0) 6.0 (3.0 to 10.0) 5.0 (3.0 to 11.0) -
    ALT
    Units: U/L
        median (full range (min-max))
    		 40.0 (12.0 to 110.0) 14.0 (9.0 to 25.0) 17.0 (7.0 to 64.0) 24.0 (13.0 to 115.0) -
    Latest Relapse
    Latest relapse: time from latest relapse to registration in days
    Units: Days
        arithmetic mean (standard deviation)
    		 15.4 ( 10.4 ) 71.8 ( 145.9 ) 12.3 ( 4.6 ) 65.7 ( 106.1 ) -
    Number of relapses
    Units: Number
        arithmetic mean (standard deviation)
    		 2.4 ( 0.9 ) 3.1 ( 2.3 ) 1.8 ( 0.5 ) 3.0 ( 1.4 ) -
    Progression
    Progression: time from progression to registration in days
    Units: Days
        arithmetic mean (standard deviation)
    		 2.5 ( 3.5 ) 130.7 ( 127.3 ) 47.4 ( 87.4 ) 65.3 ( 70.6 ) -

    End points

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    End points reporting groups
    Reporting group title
    Leukaemia
    Reporting group description
    		 Acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML)

    Reporting group title
    Sarcoma
    Reporting group description
    		 -

    Reporting group title
    High Grade Glioma
    Reporting group description
    		 As defined by 2016 WHO CNS classification

    Reporting group title
    Neuroblastoma
    Reporting group description
    		 -
    Reporting group title
    Leukaemia
    Reporting group description
    		 Acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML)

    Reporting group title
    Sarcoma
    Reporting group description
    		 -

    Reporting group title
    High Grade Glioma
    Reporting group description
    		 As defined by 2016 WHO CNS classification

    Primary: Phase I Primary Endpoint - DLTs

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    End point title
    		 Phase I Primary Endpoint - DLTs [1]
    End point description
    End point type
    Primary
    End point timeframe
    3 evaluable patients were recruited to Phase I Cohort I of the PARC trial and received trial treatment (BCT-100) and monitored for 28 days following treatment for the occurrence of any dose-limiting toxicities (DLTs).
    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: Occurence of DLTs were assessed by Statistician and presented to DMC members to confirm if any DLTs had occured. No statistical analysis took place for this endpoint.
    End point values
    		 Leukaemia Sarcoma High Grade Glioma
    Number of subjects analysed
    0 [2]
    1
    2
    Units: Number of DLTs
    0
    0
    Notes
    [2] - Patient progressed and did not reach end point
    No statistical analyses for this end point

    Primary: Phase I Primary Endpoint - Successful Arginine Depletion

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    End point title
    		 Phase I Primary Endpoint - Successful Arginine Depletion [3]
    End point description
    End point type
    Primary
    End point timeframe
    3 evaluable patients were recruited to Phase I Cohort I of the trial. Optimal dose was measured by the complete depletion of arginine. This is defined as adequated arginine depltion (AAD) <8μM arginine in the blood after 4 doses of BCT-100.
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This primary endpoint was based on successful depletion of arginine in patients (<=8muM in blood). No formal statistical analysis took place.
    End point values
    		 Leukaemia Sarcoma High Grade Glioma
    Number of subjects analysed
    0 [4]
    1
    2
    Units: μM
        number (not applicable)
    5.25
    4.75
    Notes
    [4] - Patient progressed and did not reach endpoint
    No statistical analyses for this end point

    Primary: Phase II - Disease Response after 8 Weeks of treatment with BCT-100

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    End point title
    		 Phase II - Disease Response after 8 Weeks of treatment with BCT-100 [5]
    End point description
    Response assessment will be conducted as a Modified Intention-To-Treat (MITT) analysis, any patient who withdraws or dies prior to starting treatment will not be considered evaluable and will be replaced. A true response rate greater than 20% is of interest in any of the four disease groups. The trial will recruit 13 patients per group for the phase II component. Patients who were treated at the selected Phase II dose in the Phase I component will contribute to this 13 patient requirement. Response definitions are different for each disease group and are based on specific criteria related that disease e.g. Leukaemia, Solid tumours. Each group will have the response rate individually assessed using Bayesian posterior probability plots and 95% Credible Intervals. Posterior Probabilities will be calculated for the true response rate in each arm using a non-informative prior Beta(0.5, 0.5)
    End point type
    Primary
    End point timeframe
    Response for primary outcome is assessed at 8 weeks or potentially earlier in the case of progressive disease.
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analysis (Bayesian) is described in description of end point and plots are attached - could not add in the statistical analysis section as it would not allow a single arm analysis to be added and each disease group was assessed separately, no comparisons were made between arms.
    End point values
    		 Leukaemia Sarcoma High Grade Glioma Neuroblastoma
    Number of subjects analysed
    7
    13
    13
    12
    Units: Number of responses
    0
    0
    0
    0
    Attachments
    		 Leukaemia: Posterior Probability Plot
    Neuroblastoma: Posterior Probability Plot
    High Grade Glioma: Posterior Probability Plot
    Sarcoma: Posterior Probability Plot
    No statistical analyses for this end point

    Secondary: Progression-Free Survival

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    End point title
    		 Progression-Free Survival
    End point description
    Measured from the date of registration, an event here is defined as either progression or death, patients are followed up until they have either experienced an event or are censored at date last seen. Kaplan-Meier plots will be produced, estimates of median PFS and PFS at 6 and 12 months will be reported along with associated confidence intervals (where they can be calculated).
    End point type
    Secondary
    End point timeframe
    Measured from the date of registration, an event here is defined as either progression or death, patients are followed up until they have either experienced an event or are censored at date last seen.
    End point values
    		 Leukaemia Sarcoma High Grade Glioma Neuroblastoma
    Number of subjects analysed
    7
    13
    13
    12
    Units: Months
        median (confidence interval 95%)
    1.1 (0.5 to 1.7)
    1.8 (0.9 to 1.9)
    1.5 (0.7 to 2.0)
    1.8 (0.6 to 2.1)
    Attachments
    		 Progression-Free Survival: Kaplan-Meier Plot
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Kaplan-Meier plots will be produced, estimates of median survival and survival at 6 and 12 months will be reported along with associated confidence intervals (where they can be calculated).
    End point type
    Secondary
    End point timeframe
    Measured from the date of registration, an event here is defined as death, patients are followed up until they have either died or are censored at date last seen.
    End point values
    		 Leukaemia Sarcoma High Grade Glioma Neuroblastoma
    Number of subjects analysed
    7
    13
    13
    12
    Units: Months
        median (standard error)
    1.28 ( 0.043 )
    3.5 ( 0.985 )
    2.2 ( 0.315 )
    2.9 ( 5.042 )
    Attachments
    		 Overall Survival: Kaplan-Meier Plot
    No statistical analyses for this end point

    Other pre-specified: Disease response ( CR / PR) at any time during treatment with BCT-100

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    End point title
    		 Disease response ( CR / PR) at any time during treatment with BCT-100
    End point description
    The outcome will be tabulated as best disease response by response categories Complete Response/Partial Response/Stable Disease/Progressive Disease (CR/PR/SD/PD) for each patient in each disease group, at any time during treatment with BCT-100, with CR/PR equal to disease response.
    End point type
    Other pre-specified
    End point timeframe
    For this exploratory end point, the best response at any time while on treatment is reported for each patient.
    End point values
    		 Leukaemia Sarcoma High Grade Glioma Neuroblastoma
    Number of subjects analysed
    7
    13
    13
    12
    Units: Number of responses
        CR
    0
    0
    0
    0
        PR
    0
    0
    1
    0
        SD
    1
    3
    1
    3
        PD
    1
    4
    3
    4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Details of all AEs will be documented and reported from the date of informed consent until 28 days after the administration of the last dose of trial treatment.
    Adverse event reporting additional description
    AEs will be reviewed using the Common Terminology Criteria for Adverse Events (CTCAE), version 4
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    Leukaemia
    Reporting group description
    		 Acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML)

    Reporting group title
    Neuroblastoma
    Reporting group description
    		 -

    Reporting group title
    Sarcoma
    Reporting group description
    		 -

    Reporting group title
    High Grade Glioma
    Reporting group description
    		 As defined by 2016 WHO CNS classification

    Serious adverse events
    		 Leukaemia Neuroblastoma Sarcoma High Grade Glioma
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 7 (85.71%)
    6 / 12 (50.00%)
    7 / 13 (53.85%)
    7 / 13 (53.85%)
         number of deaths (all causes)
    7
    10
    13
    12
         number of deaths resulting from adverse events
    1
    0
    0
    0
    Cardiac disorders
    Atrial Ectopics
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    2 / 13 (15.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    1 / 7 (14.29%)
    3 / 12 (25.00%)
    5 / 13 (38.46%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    infusion related infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Allergic reaction
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    distress due to fluid overload
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    dyspnea
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    2 / 13 (15.38%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Polyuria Polydispsia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    upper respiratory infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterienie
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Leukaemia Neuroblastoma Sarcoma High Grade Glioma
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 7 (100.00%)
    12 / 12 (100.00%)
    13 / 13 (100.00%)
    13 / 13 (100.00%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Thromboembolic event
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Hypertension
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    3 / 13 (23.08%)
         occurrences all number
    1
    0
    1
    4
    Hypotension
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 12 (16.67%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    2
    0
    0
    General disorders and administration site conditions
    fever
         subjects affected / exposed
    2 / 7 (28.57%)
    5 / 12 (41.67%)
    6 / 13 (46.15%)
    3 / 13 (23.08%)
         occurrences all number
    2
    15
    9
    7
    Pain
         subjects affected / exposed
    4 / 7 (57.14%)
    4 / 12 (33.33%)
    7 / 13 (53.85%)
    2 / 13 (15.38%)
         occurrences all number
    4
    7
    10
    2
    Fatigue
         subjects affected / exposed
    0 / 7 (0.00%)
    3 / 12 (25.00%)
    1 / 13 (7.69%)
    2 / 13 (15.38%)
         occurrences all number
    0
    5
    1
    3
    Runny nose
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    2 / 13 (15.38%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Weakness
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hypothermia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Common cold
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Chills
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Coryzal symptoms
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Night sweats
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Excess transpiration
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Localised oedema
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Oedema trunk
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Immune system disorders
    Allergic reaction
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    1
    0
    1
    Reproductive system and breast disorders
    Vaginal pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Apnea
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Epistaxis
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Pulmonary oedema
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Respiratory distress
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Respiratory failure
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Runny nose
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Cough
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 12 (16.67%)
    3 / 13 (23.08%)
    1 / 13 (7.69%)
         occurrences all number
    0
    2
    5
    1
    Dyspnea
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 12 (8.33%)
    4 / 13 (30.77%)
    2 / 13 (15.38%)
         occurrences all number
    1
    1
    6
    4
    Hypoxia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 12 (8.33%)
    1 / 13 (7.69%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    1
    2
    Pleural effusion
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    2 / 13 (15.38%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Sore throat
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    2 / 13 (15.38%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Psychiatric disorders
    Confusion
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    1 / 13 (7.69%)
         occurrences all number
    1
    0
    1
    1
    Euphoria
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Libido decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Low mood
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Restlessness
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Anxiety
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    3 / 13 (23.08%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    4
    1
    Insomnia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    2
    0
    0
    2
    Investigations
    Lymphocyte count decreased
         subjects affected / exposed
    5 / 7 (71.43%)
    5 / 12 (41.67%)
    6 / 13 (46.15%)
    10 / 13 (76.92%)
         occurrences all number
    13
    12
    11
    17
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 7 (57.14%)
    7 / 12 (58.33%)
    2 / 13 (15.38%)
    3 / 13 (23.08%)
         occurrences all number
    8
    11
    2
    5
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 7 (42.86%)
    6 / 12 (50.00%)
    0 / 13 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    5
    14
    0
    2
    Creatinine decreased
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 12 (16.67%)
    2 / 13 (15.38%)
    3 / 13 (23.08%)
         occurrences all number
    2
    6
    7
    4
    Chloride high
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    0
    0
    13
    Bicarbonate low
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    3
    0
    0
    5
    Creatinine increased
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 12 (0.00%)
    2 / 13 (15.38%)
    0 / 13 (0.00%)
         occurrences all number
    6
    0
    2
    0
    GGT increased
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    4
    1
    0
    2
    Monocyte count increased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    2 / 13 (15.38%)
    2 / 13 (15.38%)
         occurrences all number
    1
    0
    3
    3
    MCV decrease
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    2 / 13 (15.38%)
    3 / 13 (23.08%)
         occurrences all number
    0
    0
    2
    4
    MCV increase
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    3 / 13 (23.08%)
    0 / 13 (0.00%)
         occurrences all number
    2
    0
    4
    0
    CRP increased
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    4
    0
    0
    0
    Eosinophils decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    3 / 13 (23.08%)
         occurrences all number
    0
    0
    0
    4
    Alkaline phosphatase increased
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 12 (8.33%)
    2 / 13 (15.38%)
    0 / 13 (0.00%)
         occurrences all number
    1
    1
    2
    0
    Lymphocyte count increased
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Phosphate high
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    2
    0
    1
    0
    ALT decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    2
    Creatinine decrease
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Weight loss
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 12 (8.33%)
    2 / 13 (15.38%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Elevated Bicarbonate Levels
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    2
    Mean Corpuscular Volume Decrease
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    2
    Monocytes low
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Haemoglobin increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    2
    MCHC High
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    2
    0
    0
    0
    C-reactive protein increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    2
    0
    alkaline phosphatase decrease
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    cholesterol high
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    INR increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Basophils high
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Urine output decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Lactate dehydrogenase increase
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Haemoglobin low
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Weight gain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Mean cell haemoglobin decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Mean cell haemoglobin increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Chloride increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    High ferritine
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Thrombin time increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Increased urine output
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood prolactin abnormal
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Bruising
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    4
    0
    1
    Sinus tachycardia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 12 (8.33%)
    1 / 13 (7.69%)
    2 / 13 (15.38%)
         occurrences all number
    1
    1
    1
    2
    Cardiac arrest
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    5 / 13 (38.46%)
    5 / 13 (38.46%)
         occurrences all number
    0
    0
    8
    9
    Lethargy
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 12 (16.67%)
    2 / 13 (15.38%)
    4 / 13 (30.77%)
         occurrences all number
    1
    3
    3
    4
    Dysarthria
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    2
    1
    0
    4
    Seizure
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    4 / 13 (30.77%)
         occurrences all number
    0
    1
    0
    5
    Hydrocephalus
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    3 / 13 (23.08%)
         occurrences all number
    0
    0
    0
    3
    Ataxia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Facial muscle weakness
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    0
    0
    2
    Paresthesia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    1
    Hemiplegia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Spasticity
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Sleep disturbance - wakes early
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Paraplegia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Bladder emptying disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Memory impairment
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Dysaesthesia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Tremor
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Imbalance
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Somnolence
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Spinal cord injury
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Polydipsia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Dysphagia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Hypersomnia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Bowel emptying disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Dysgeusia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Intratumoural haemorrage and surrounding cerebral oedema
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Dizziness
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    7 / 7 (100.00%)
    9 / 12 (75.00%)
    8 / 13 (61.54%)
    7 / 13 (53.85%)
         occurrences all number
    24
    18
    14
    20
    Platelet count decreased
         subjects affected / exposed
    6 / 7 (85.71%)
    7 / 12 (58.33%)
    0 / 13 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    49
    9
    0
    2
    White blood cell count decreased
         subjects affected / exposed
    5 / 7 (71.43%)
    5 / 12 (41.67%)
    3 / 13 (23.08%)
    6 / 13 (46.15%)
         occurrences all number
    15
    7
    5
    29
    Neutrophil count decreased
         subjects affected / exposed
    6 / 7 (85.71%)
    5 / 12 (41.67%)
    1 / 13 (7.69%)
    4 / 13 (30.77%)
         occurrences all number
    18
    9
    1
    10
    Haematocrit decreased
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 12 (16.67%)
    5 / 13 (38.46%)
    6 / 13 (46.15%)
         occurrences all number
    1
    2
    11
    8
    Neutrophil count increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    3 / 13 (23.08%)
    5 / 13 (38.46%)
         occurrences all number
    0
    0
    10
    7
    Red blood cell count decreased
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 12 (8.33%)
    3 / 13 (23.08%)
    4 / 13 (30.77%)
         occurrences all number
    1
    1
    7
    7
    Platelet count increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 12 (8.33%)
    3 / 13 (23.08%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    5
    2
    White blood cell count increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    2 / 13 (15.38%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    5
    1
    Febrile neutropenia
         subjects affected / exposed
    2 / 7 (28.57%)
    2 / 12 (16.67%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    2
    2
    1
    0
    Hypertension
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    3 / 13 (23.08%)
         occurrences all number
    1
    0
    1
    4
    Red blood cell count increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Leukocytosis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Enlarged lymph node
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Haematocrit increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Buzzing in left ear
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Eye disorders
    Optic nerve disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    blurred vision
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Papilledema
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    2 / 7 (28.57%)
    3 / 12 (25.00%)
    6 / 13 (46.15%)
    5 / 13 (38.46%)
         occurrences all number
    2
    10
    12
    9
    Constipation
         subjects affected / exposed
    3 / 7 (42.86%)
    3 / 12 (25.00%)
    4 / 13 (30.77%)
    4 / 13 (30.77%)
         occurrences all number
    4
    3
    4
    8
    Nausea
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 12 (8.33%)
    6 / 13 (46.15%)
    3 / 13 (23.08%)
         occurrences all number
    1
    5
    8
    3
    Diarrhoea
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 12 (8.33%)
    2 / 13 (15.38%)
    2 / 13 (15.38%)
         occurrences all number
    1
    1
    4
    2
    Dysphagia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    3 / 13 (23.08%)
         occurrences all number
    1
    0
    0
    6
    Abdominal pain
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 12 (16.67%)
    2 / 13 (15.38%)
    0 / 13 (0.00%)
         occurrences all number
    0
    3
    2
    0
    stomach pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 12 (8.33%)
    2 / 13 (15.38%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Oral pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Dyspepsia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    0
    0
    1
    Dry mouth
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    blood in stool
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dental caries
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    bloating
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Enterocolitis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Soft stool
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Crohn's disease
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    hypersalivation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Gait disturbance
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    0
    0
    2
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Blister on abdomen
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dry skin
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Itching
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Photosensitivity
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pruritus
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    0
    0
    1
    Rash-Graft Versus Host Disease
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Shingles
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin atrophy
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Skin ulceration
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Urticaria
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Alopecia
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 12 (16.67%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    3
    0
    0
    Rash maculo-papular
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 12 (8.33%)
    1 / 13 (7.69%)
    1 / 13 (7.69%)
         occurrences all number
    2
    1
    1
    1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Bladder perforation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Bladder spasm
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Cystitis noninfective
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Polyuria
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Urea high
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Urinary incontinence
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Urinary retention
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Urate low
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Urea decreased
         subjects affected / exposed
    2 / 7 (28.57%)
    4 / 12 (33.33%)
    0 / 13 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    2
    9
    0
    2
    Urea increased
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 12 (16.67%)
    1 / 13 (7.69%)
    3 / 13 (23.08%)
         occurrences all number
    2
    4
    3
    6
    Endocrine disorders
    Cushingoid
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    TSH level decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    FSH level decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Adrenal insufficiency
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    LH level decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Hypoparathyroidism
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Flank pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Joint range of motion decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Muscle weakness lower limb
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Muscle weakness right-sided
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Muscle weakness trunk
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Myalgia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Neck pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    0
    1
    Pain in right shoulder
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Back pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    2 / 13 (15.38%)
         occurrences all number
    0
    0
    1
    2
    Generalised muscle weakness
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    2
    0
    0
    1
    Muscle weakness left-sided
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    5 / 13 (38.46%)
         occurrences all number
    0
    0
    0
    5
    Pain in extremity
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 12 (16.67%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    0
    2
    2
    0
    Infections and infestations
    Bacillus Cereus
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Bacteraemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    staphylococcus epidermis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Common cold? No virology done
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Common cold? Virus unknown
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Conjunctivitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    COVID-19
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    0
    1
    Hand-foot-and-mouth disease
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Herpetic lip lesions
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nail infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Oral fungal infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    2
    Rhinovirus infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Sepsis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Unknown viral cough
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Upper respiratory infection
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 12 (8.33%)
    1 / 13 (7.69%)
    1 / 13 (7.69%)
         occurrences all number
    1
    1
    1
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Metabolism and nutrition disorders
    Chloride levels decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Dehydration
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    1
    hyperglycemia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    hyperkalemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Hyperuricaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    1
    Hypocalcaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Increased thirst
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    weight gain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Anorexia nervosa
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    2
    Blood glucose increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    2
    Hypernatraemia
         subjects affected / exposed
    1 / 7 (14.29%)
    3 / 12 (25.00%)
    1 / 13 (7.69%)
    2 / 13 (15.38%)
         occurrences all number
    1
    3
    1
    2
    Hyperphosphataemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Hypoalbuminaemia
         subjects affected / exposed
    4 / 7 (57.14%)
    3 / 12 (25.00%)
    2 / 13 (15.38%)
    0 / 13 (0.00%)
         occurrences all number
    9
    5
    2
    0
    Hypokalaemia
         subjects affected / exposed
    5 / 7 (71.43%)
    0 / 12 (0.00%)
    4 / 13 (30.77%)
    2 / 13 (15.38%)
         occurrences all number
    14
    0
    12
    4
    Hypomagnesaemia
         subjects affected / exposed
    3 / 7 (42.86%)
    2 / 12 (16.67%)
    0 / 13 (0.00%)
    3 / 13 (23.08%)
         occurrences all number
    6
    5
    0
    3
    Hyponatraemia
         subjects affected / exposed
    2 / 7 (28.57%)
    3 / 12 (25.00%)
    1 / 13 (7.69%)
    1 / 13 (7.69%)
         occurrences all number
    3
    5
    1
    2
    Hypophosphataemia
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 12 (8.33%)
    2 / 13 (15.38%)
    0 / 13 (0.00%)
         occurrences all number
    4
    2
    2
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 May 2020
    Update of Senior Trial Coordinator and Trial Coordinator, NCC for France updated, Added email address for DLT & SAE forms, Removed the word international from title in Trial Synopsis, Clarification of timepoints at which to collect PD’s/PK’s, Section 12.1.2 spelling error corrected (Events), To add that monitoring for Dose Limiting Toxicities will also be completed for the first 28 days of treatment in Phase II, Updated pregnancy frequency for Republic of Ireland, Updated age inclusion criteria for patients in the Republic of Ireland, Removal of the following statement “Comparatively arginase appeared more effective than asparaginase – the only current metabolic enzyme therapy in upfront clinical protocols for leukaemia”, Added the following in section 16.1; ” Any patient who withdraws or dies prior to starting treatment will not be considered evaluable and will be replaced.”, Exclusion criteria added: History of an anaphylactic reaction to kanamycin, Updated section 12.2.4.5: Details of all SUSARs and any other safety issue which arises during the course of the trial will be reported to Principal Investigator within 3 days. A copy should be filed in the ISF, Added to section 17.4: The Sponsor will ensure that any potential signal for lack of efficacy that the TMG are aware of in the PARC study is brought to the attention of the DMC and is appropriately investigated. Subsequently, the DMC can make recommendations to the TMG/sponsor regarding any concerns for lack of efficacy, Addition of note to the following sections: Trial Schema, section 3.2 and section 7.2.1 (Note: Phase I reported in Jan 2019 with 1600U/kg BCT-100 defined as the recommended Phase II dose. Phase II opened to recruitment on 16th January 2019), Added section: 7.5.7 GCSF to table of contents.

    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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