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    Clinical Trial Results:
    A phase 1/2a, dose escalation study of CHR-3996 in combination with tosedostat in subjects with relapsed, refractory multiple myeloma

    Summary
    EudraCT number
    		 2011-001914-33
    Trial protocol
    		 GB  
    Global end of trial date
    30 Oct 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Nov 2018
    First version publication date
    08 Nov 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    HM11/9825
    Additional study identifiers
    ISRCTN number
    		 ISRCTN24989786
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Leeds
    Sponsor organisation address
    CTRU, Leeds, United Kingdom, LS2 9JT
    Public contact
    Louise Flanagan, CTRU, University of Leeds , 44 1133431477, medctco@leeds.ac.uk
    Scientific contact
    Sarah Brown, CTRU, University of Leeds , 44 1133431477, medctco@leeds.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
    11 May 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 May 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Oct 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    During the dose escalation phase, the purpose of the study is to determine the maximum tolerated dose (MTD) of CHR-3996 and tosedostat administered in combination in subjects with relapsed or refractory multiple myeloma. In the dose expansion phase the purpose of the study is to determine the safety profile of CHR-3996 and tosedostat administered in combination and to estimate the response rate.
    Protection of trial subjects
    N/A
    Background therapy
    		 There are no comparators for this trial all participants received the trial drug.
    Evidence for comparator
    		 N/A
    Actual start date of recruitment
    01 Aug 2011
    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
    United Kingdom: 27
    Worldwide total number of subjects
    27
    EEA total number of subjects
    27
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    14
    From 65 to 84 years
    13
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were recruited from NHS Hospitals in the UK with ethical and regulatory approval. Participants were approached during their usual clinic visits by a doctor and consented if they were willing to take part. They were registered to the trial and eligibility checked. The recruitment period was July 2012 - December 2015.

    Pre-assignment
    Screening details
    		 Participants were screened for eligibility once consented and registered to the trial to ensure they met all criteria.

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

    Arms
    Arm title
    		 Safety analysis population
    Arm description
    		 The safety analysis population includes all participants who received at least one dose of trial treatment. Only participants, for whom written informed consent has not been received, are not included in this population.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CHR-3996
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    20mg/20mg/40mg/40mg once daily for 28 day cycle

    Investigational medicinal product name
    tosedostat
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    60mg/0mg/0mg/60mg once daily for 28 day cycle

    Number of subjects in period 1 [1]
    		Safety analysis population
    Started
    22
    Completed
    22
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: There were 27 patients recruited to the trial, but only 22 went on to receive treatment. This is why the number of patients in the safety analysis population (baseline period) does not match the number enrolled in the trial. This was agreed with the Scientific Lead.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall Trial Total
    Number of subjects
    		 22 22
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 11 11
        From 65-84 years
    		 11 11
        85 years and over
    		 0 0
    Age continuous
    Age at registration
    Units: years
        arithmetic mean (standard deviation)
    		 62.9 ( 8.7 ) -
    Gender categorical
    Units: Subjects
        Female
    		 9 9
        Male
    		 12 12
        Missing
    		 1 1
    ECOG status
    Units: Subjects
        Zero
    		 4 4
        One
    		 18 18
    Previous treatment lines
    Units: Subjects
        Two
    		 1 1
        Three
    		 3 3
        Four
    		 7 7
        Five
    		 4 4
        Six
    		 1 1
        Seven
    		 2 2
        Eight
    		 2 2
        Nine
    		 1 1
        Missing
    		 1 1
    Tumour Stage
    Units: Subjects
        One
    		 5 5
        Two
    		 11 11
        Three
    		 5 5
        Missing
    		 1 1
    Paraprotein type
    Units: Subjects
        IgG
    		 15 15
        IgA
    		 4 4
        Light chain only
    		 3 3
    Light chain type
    Units: Subjects
        Kappa
    		 13 13
        Lambda
    		 9 9
    Systolic BP
    Units: mmHg
        arithmetic mean (standard deviation)
    		 127.0 ( 17.21 ) -
    Diastolic BP
    Units: mmHg
        arithmetic mean (standard deviation)
    		 76.8 ( 7.58 ) -
    Pulse rate
    Units: bpm
        arithmetic mean (standard deviation)
    		 80.8 ( 11.22 ) -
    Temperature
    Units: degrees celcius
        arithmetic mean (standard deviation)
    		 36.5 ( 0.37 ) -
    QTcF interval
    Units: msec
        arithmetic mean (standard deviation)
    		 393.1 ( 82.03 ) -
    Time from most recent relapse to registration
    Time from most recent relapse to registration date
    Units: Months
        arithmetic mean (standard deviation)
    		 1.3 ( 1.2 ) -
    Time from last dose of systemic anti-myeloma treatment to registration
    Units: Months
        arithmetic mean (standard deviation)
    		 1.5 ( 1.81 ) -
    Subject analysis sets

    Subject analysis set title
    Primary analysis set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population is defined by all participants registered to receive the recommended dose (20mg CHR-3996 and 60mg tosedostat), and who received at least one dose of trial treatment.

    Subject analysis set title
    Non-recommended dose analysis set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population is defined by all participants who were not registered to receive the recommended dose (20mg CHR-3996 and 60mg tosedostat), and who received at least one dose of trial treatment.

    Subject analysis sets values
    		 Primary analysis set Non-recommended dose analysis set
    Number of subjects
    10
    12
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    6
    5
        From 65-84 years
    4
    7
        85 years and over
    0
    0
    Age continuous
    Age at registration
    Units: years
        arithmetic mean (standard deviation)
    61.2 ( 9.34 )
    64.2 ( 8.38 )
    Gender categorical
    Units: Subjects
        Female
    4
    5
        Male
    5
    7
        Missing
    1
    0
    ECOG status
    Units: Subjects
        Zero
    2
    2
        One
    8
    10
    Previous treatment lines
    Units: Subjects
        Two
    1
    0
        Three
    0
    3
        Four
    6
    1
        Five
    0
    4
        Six
    0
    1
        Seven
    1
    1
        Eight
    0
    2
        Nine
    1
    0
        Missing
    1
    0
    Tumour Stage
    Units: Subjects
        One
    2
    3
        Two
    5
    6
        Three
    3
    2
        Missing
    0
    1
    Paraprotein type
    Units: Subjects
        IgG
    7
    8
        IgA
    2
    2
        Light chain only
    1
    2
    Light chain type
    Units: Subjects
        Kappa
    6
    7
        Lambda
    4
    5
    Systolic BP
    Units: mmHg
        arithmetic mean (standard deviation)
    117.5 ( 13.71 )
    134.8 ( 16.21 )
    Diastolic BP
    Units: mmHg
        arithmetic mean (standard deviation)
    75.4 ( 9.18 )
    77.9 ( 6.13 )
    Pulse rate
    Units: bpm
        arithmetic mean (standard deviation)
    84.6 ( 9.50 )
    77.6 ( 11.91 )
    Temperature
    Units: degrees celcius
        arithmetic mean (standard deviation)
    36.6 ( 0.20 )
    36.5 ( 0.47 )
    QTcF interval
    Units: msec
        arithmetic mean (standard deviation)
    409.4 ( 18.15 )
    379.6 ( 110.16 )
    Time from most recent relapse to registration
    Time from most recent relapse to registration date
    Units: Months
        arithmetic mean (standard deviation)
    0.7 ( 0.46 )
    1.7 ( 1.38 )
    Time from last dose of systemic anti-myeloma treatment to registration
    Units: Months
        arithmetic mean (standard deviation)
    0.5 ( 0.24 )
    2.3 ( 2.17 )

    End points

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    End points reporting groups
    Reporting group title
    Safety analysis population
    Reporting group description
    		 The safety analysis population includes all participants who received at least one dose of trial treatment. Only participants, for whom written informed consent has not been received, are not included in this population.

    Subject analysis set title
    Primary analysis set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population is defined by all participants registered to receive the recommended dose (20mg CHR-3996 and 60mg tosedostat), and who received at least one dose of trial treatment.

    Subject analysis set title
    Non-recommended dose analysis set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population is defined by all participants who were not registered to receive the recommended dose (20mg CHR-3996 and 60mg tosedostat), and who received at least one dose of trial treatment.

    Primary: Dose escalation phase: Dose limiting toxicity (DLT)

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    End point title
    		 Dose escalation phase: Dose limiting toxicity (DLT) [1]
    End point description
    The number of participants recruited to the dose escalation phase of the study, experiencing DLTs within the first 28-day cycle of CHR-3996 and tosedostat. DLT was defined by any of the following events: - Any non haematological toxicity ≥ Grade 3 according to NCI CTCAE Version 4 which fails to return to ≤Grade 1 or baseline after 7 days. Nausea, vomiting, diarrhoea and electrolyte imbalances will be considered DLTs only if they reach ≥ Grade 3 severity despite adequate supportive care measures. - Grade 4 neutropenia with sepsis or Grade 4 neutropenia lasting >7 days despite adequate supportive care measures. - Any grade 4 thrombocytopenia which fails to return to baseline after 7 days with platelet support - Omission of > 7 days for resumption of treatment due to toxicity (i.e an inability to commence cycle 2 until after day 8) - Treatment related death
    End point type
    Primary
    End point timeframe
    DLTs were assessed during the first cycle of treatment, up to the administration of cycle 2 day 1 of dose escalation patients.
    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: As this is a phase I study, the primary endpoint related to data summaries only.
    End point values
    		 Safety analysis population
    Number of subjects analysed
    15 [2]
    Units: Number of DLTs
        20mg CHR-3996, 0mg Tosedostat - DLT
    0
        20mg CHR-3996, 0mg Tosedostat - no DLT
    3
        40mg CHR-3996, 0mg Tosedostat - DLT
    0
        40mg CHR-3996, 0mg Tosedostat - no DLT
    3
        40mg CHR-3996, 60mg Tosedostat - DLT
    1
        40mg CHR-3996, 60mg Tosedostat - no DLT
    2
        20mg CHR-3996, 60mg Tosedostat - DLT
    0
        20mg CHR-3996, 60mg Tosedostat - no DLT
    6
    Notes
    [2] - 15 participants were recruited to the dose escalation phase and were evaluable for DLTs
    No statistical analyses for this end point

    Primary: Expansion phase: Stable disease

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    End point title
    		 Expansion phase: Stable disease [3]
    End point description
    The proportion of participants achieving at least stable disease (SD) after 4 cycles of CHR-3996 and tosedostat. Response to treatment is assessed after a participant has received 4 cycles of treatment. If a participant stops treatment within 4 months of registration for reasons other than disease progression, response will be assessed every 4 weeks until 4 months post-registration or disease progression, whichever is earlier. If a participant progresses within 4 cycles of treatment, the participant will be classed as not achieving at least stable disease after 4 cycles of treatment.
    End point type
    Primary
    End point timeframe
    after 4 cycles of CHR-3996 and tosedostat
    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: As this is a phase I study, the primary endpoint related to data summaries only.
    End point values
    		 Primary analysis set Non-recommended dose analysis set
    Number of subjects analysed
    10
    12
    Units: Proportion
        number (confidence interval 95%)
    30 (6.7 to 65.2)
    16.7 (2.1 to 48.4)
    No statistical analyses for this end point

    Secondary: Maximum response (6 cycles)

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    End point title
    		 Maximum response (6 cycles)
    End point description
    The proportion of participants with each maximum response category within 6 cycles of therapy. Maximum response is defined as the maximum response category achieved within the corresponding assessment period, for each participant. The response categories are: stringent complete response (sCR); complete response (CR); very good partial response (VGPR); partial response (PR); minimal response (MR); stable disease (SD)/no change (NC).
    End point type
    Secondary
    End point timeframe
    within 6 cycles
    End point values
    		 Primary analysis set Non-recommended dose analysis set
    Number of subjects analysed
    10
    12
    Units: Subjects
        PR
    1
    0
        SD or NC
    4
    9
        PD
    4
    3
        Participant died within first cycle of treatment
    1
    0
    No statistical analyses for this end point

    Secondary: Maximum response (overall)

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    End point title
    		 Maximum response (overall)
    End point description
    The proportion of participants with each maximum response category to therapy overall. Maximum response is defined as the maximum response category achieved within the corresponding assessment period, for each participant. The response categories are: stringent complete response (sCR); complete response (CR); very good partial response (VGPR); partial response (PR); minimal response (MR); stable disease (SD)/no change (NC).
    End point type
    Secondary
    End point timeframe
    over the whole trial
    End point values
    		 Primary analysis set Non-recommended dose analysis set
    Number of subjects analysed
    10
    12
    Units: Subjects
        PR
    1
    0
        MR
    1
    0
        SD or NC
    3
    9
        PD
    4
    3
        Participant died within first cycle of treatment
    1
    0
    No statistical analyses for this end point

    Secondary: Time to maximum response

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    End point title
    		 Time to maximum response
    End point description
    Time to maximum response was defined as the time from registration until the patient achieved their maximum response. Those who did not achieve maximum response, are censored at the date of disease progression.
    End point type
    Secondary
    End point timeframe
    registration until patient achieved their maximum response
    End point values
    		 Primary analysis set Non-recommended dose analysis set
    Number of subjects analysed
    5 [4]
    9 [5]
    Units: Months
        median (confidence interval 95%)
    1.84 (1.09 to 8.65)
    1.45 (1.22 to 1.81)
    Notes
    [4] - Of the 10 participants in the primary analysis set, only 5 achieved a maximum response.
    [5] - Of the 12 participants in the non-RD analysis set, only 9 achieved a maximum response.
    No statistical analyses for this end point

    Secondary: Progression-free survival

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    End point title
    		 Progression-free survival
    End point description
    Progression free survival is defined as the time from registration to first documented evidence of disease progression or death. Participants who, at the time of analysis, have not progressed will be censored at the last date they were known to be alive and progression free. Calculated using the Kaplan-Meier method.
    End point type
    Secondary
    End point timeframe
    registration until first documented evidence of disease progression or death.
    End point values
    		 Primary analysis set
    Number of subjects analysed
    10
    Units: Month
        median (confidence interval 95%)
    1.8 (0.92 to 4.61)
    No statistical analyses for this end point

    Secondary: CHR-3996 dose reduction (toxicity)

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    End point title
    		 CHR-3996 dose reduction (toxicity)
    End point description
    Number of dose reductions, is defined as the number of participants experiencing at least 1 CHR-3996 dose reduction due to toxicity.
    End point type
    Secondary
    End point timeframe
    whilst receiving trial treatment
    End point values
    		 Primary analysis set Non-recommended dose analysis set
    Number of subjects analysed
    10
    12
    Units: Subjects
        No reduction
    8
    10
        Reduction
    2
    2
    No statistical analyses for this end point

    Secondary: Tosedostat dose reduction (toxicity)

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    End point title
    		 Tosedostat dose reduction (toxicity)
    End point description
    Number of dose reductions, is defined as the number of participants experiencing at least 1 tosedostat dose reduction due to toxicity.
    End point type
    Secondary
    End point timeframe
    whilst receiving trial treatment
    End point values
    		 Primary analysis set Non-recommended dose analysis set
    Number of subjects analysed
    10
    12
    Units: Subject
        No reduction
    9
    12
        Reduction
    1
    0
    No statistical analyses for this end point

    Secondary: Treatment compliance

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    End point title
    		 Treatment compliance
    End point description
    Participants will be regarded as compliant to treatment where treatment is received as per protocol until withdrawal from trial treatment, without missing >5 days of either CHR-3996 or tosedostat in the first cycle for reasons other than toxicity, or >5 days of either treatment in any subsequent cycle.
    End point type
    Secondary
    End point timeframe
    until withdrawal from trial treatment
    End point values
    		 Primary analysis set Non-recommended dose analysis set
    Number of subjects analysed
    10
    12
    Units: Subjects
        Missed more than 5 days dosing
    6
    8
        Did not miss more than 5 days dosing
    4
    4
    No statistical analyses for this end point

    Secondary: Safety: number of patients with 1 or more SAEs

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    End point title
    		 Safety: number of patients with 1 or more SAEs
    End point description
    The number of patients with one or more serious adverse reaction (SAR)/serious adverse event (SAE).
    End point type
    Secondary
    End point timeframe
    time of written informed consent until 30 days post cessation of trial therapy.
    End point values
    		 Primary analysis set Non-recommended dose analysis set
    Number of subjects analysed
    10
    12
    Units: Subjects
        Yes: SAR
    2
    3
        Yes: SAE
    7
    4
        No
    1
    5
    No statistical analyses for this end point

    Secondary: Safety: SAEs

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    End point title
    		 Safety: SAEs
    End point description
    Summary statistics of the number of serious adverse events (SAEs) reported
    End point type
    Secondary
    End point timeframe
    time of written informed consent until 30 days post cessation of trial therapy.
    End point values
    		 Primary analysis set Non-recommended dose analysis set
    Number of subjects analysed
    10
    12
    Units: Subjects/SAEs
        Number of patients with one of more SAE
    9
    7
        Number of SAEs reported
    14
    8
    No statistical analyses for this end point

    Secondary: Safety: number of SAEs per patient

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    End point title
    		 Safety: number of SAEs per patient
    End point description
    Summary statistics of the number of serious adverse events (SAEs) per patient.
    End point type
    Secondary
    End point timeframe
    time of written informed consent until 30 days post cessation of trial therapy.
    End point values
    		 Primary analysis set Non-recommended dose analysis set
    Number of subjects analysed
    9 [6]
    7 [7]
    Units: SAEs
    arithmetic mean (standard deviation)
        Number of SAEs per patient
    1.6 ( 0.88 )
    1.1 ( 0.38 )
    Notes
    [6] - 9 out of the 10 participants in the primary population experienced an SAE
    [7] - 7 out of the 12 participants in the non-RD population experienced an SAE
    No statistical analyses for this end point

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    Overall survival is defined as the time from registration to date of death from any cause. Participants who were still alive at the time of analysis were censored at the last date they were known to be alive.
    End point type
    Secondary
    End point timeframe
    registration until date of death or final analysis, which was sooner.
    End point values
    		 Primary analysis set Non-recommended dose analysis set
    Number of subjects analysed
    10
    12
    Units: Deaths
        Died
    5
    2
        Not died
    5
    12
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All AEs occurring for all participants from the time of written informed consent until 30 days post cessation of trial therapy.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    Safety population
    Reporting group description
    		 The safety population includes all participants who have received at least one dose of any trial treatment. Only patients for whom written informed consent was not received are excluded.

    Serious adverse events
    		 Safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 22 (72.73%)
         number of deaths (all causes)
    7
         number of deaths resulting from adverse events
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    1 / 7
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 7
    Epistaxis
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 7
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 7
    Gastrointestinal disorders
    Diarrhoea, vomiting and C-difficile
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 7
    Dehydration, vomiting and nausea
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 7
    Nausea and diarrhoea
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 7
    Diarrhoea
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 7
    Respiratory, thoracic and mediastinal disorders
    Chest infection
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 7
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 7
    Raised creatinine
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 7
    Acute kidney injury / creatinine increased
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 7
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 7
    Soft tissue infection
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 7
    Urinary tract infection
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 7
    Lung infection
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 7
    Infection
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 7
    Fever
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 7
    Flu like symptoms
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 7
    Fever and upper respiratory tract infection
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 7
    Frequency threshold for reporting non-serious adverse events: 0.05%
    Non-serious adverse events
    		 Safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    22 / 22 (100.00%)
    Vascular disorders
    Thromboembolic event
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Hypertension
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    17 / 22 (77.27%)
         occurrences all number
    17
    Fever
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    3
    Edema limbs
         subjects affected / exposed
    5 / 22 (22.73%)
         occurrences all number
    5
    Pain in extremity
         subjects affected / exposed
    5 / 22 (22.73%)
         occurrences all number
    5
    Pain
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Lethargy
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Localized edema
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Other
         subjects affected / exposed
    12 / 22 (54.55%)
         occurrences all number
    12
    Reproductive system and breast disorders
    Vaginal discharge
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    3
    Dyspnea
         subjects affected / exposed
    6 / 22 (27.27%)
         occurrences all number
    6
    Cough
         subjects affected / exposed
    5 / 22 (22.73%)
         occurrences all number
    5
    Hiccups
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Pharyngitis
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Sore throat
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Insomnia
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Anxiety
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Confusion
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Irritability
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Investigations
    Platelet count decreased
         subjects affected / exposed
    15 / 22 (68.18%)
         occurrences all number
    15
    White blood cell count decreased
         subjects affected / exposed
    12 / 22 (54.55%)
         occurrences all number
    12
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    3
    Lymphocyte count decreased
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    3
    Creatinine increased
         subjects affected / exposed
    6 / 22 (27.27%)
         occurrences all number
    6
    CPK increased
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Investigations - other, specify
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    3
    Neutrophil count decreased
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Weight loss
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    INR increased
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Alkaline phosphatase increased
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Spinal fracture
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Cardiac disorders - other, specify
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Ventricular arrhythmia
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Nervous system disorders
    Peripheral sensory neuropathy
         subjects affected / exposed
    8 / 22 (36.36%)
         occurrences all number
    8
    Dysgeusia
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    3
    Dizziness
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Headache
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Nervous system disorders - other, specify
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Peripheral motor neuropathy
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    radiculitis
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    16 / 22 (72.73%)
         occurrences all number
    16
    Hematoma
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Hypokalemia
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    3
    Oral haemorrhage
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Eye disorders
    Blurred vision
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Cataracts
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Watering eyes
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    13 / 22 (59.09%)
         occurrences all number
    13
    Nausea
         subjects affected / exposed
    15 / 22 (68.18%)
         occurrences all number
    15
    Vomiting
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    3
    Dry mouth
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    3
    Abdominal pain
         subjects affected / exposed
    5 / 22 (22.73%)
         occurrences all number
    5
    Enterocolitis infectious
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Dyspepsia
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Constipation
         subjects affected / exposed
    7 / 22 (31.82%)
         occurrences all number
    7
    Mucositis
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Gastroesophageal reflux disease
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Gastrointestinal disorders - other, specify
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Flushing
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Pruritus
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Rash maculo-papular
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Dry skin
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Skin ulceration
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    allergic rhinitis
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Hyperuricemia
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    3
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    5 / 22 (22.73%)
         occurrences all number
    5
    Back pain
         subjects affected / exposed
    4 / 22 (18.18%)
         occurrences all number
    4
    Myalgia
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Arthralgia
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    neck pain
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Infections and infestations
    Upper respiratory infection
         subjects affected / exposed
    8 / 22 (36.36%)
         occurrences all number
    8
    Lung infection
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    3
    Urinary tract infection
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    3
    Infections and infestations - other, specify
         subjects affected / exposed
    4 / 22 (18.18%)
         occurrences all number
    4
    Soft tissue infection
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Flu like symptoms
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    3
    Tooth infection
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    6 / 22 (27.27%)
         occurrences all number
    6
    Hypercalcemia
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Hypoalbuminaemia
         subjects affected / exposed
    4 / 22 (18.18%)
         occurrences all number
    4
    Anorexia
         subjects affected / exposed
    14 / 22 (63.64%)
         occurrences all number
    14
    Dehydration
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Hypomagnesaemia
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Hypermagnesemia
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Hypernatremia
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Hypocalcemia
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    hyperglycemia
         subjects affected / exposed
    5 / 22 (22.73%)
         occurrences all number
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Dec 2011
    Protocol v3.0
    14 Mar 2012
    Protocol v4.0
    16 Aug 2013
    Protocol v5
    04 Jul 2014
    Protocol v6
    11 Sep 2014
    Protocol v7

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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