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    Clinical Trial Results:
    FGFR Inhibition for Epithelial Solid Tumours: a Phase Ib trial of AZD4547 in combination with gemcitabine and cisplatin

    Summary
    EudraCT number
    		 2011-004072-10
    Trial protocol
    		 GB  
    Global end of trial date
    24 Oct 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Aug 2019
    First version publication date
    31 Aug 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MO11/9803
    Additional study identifiers
    ISRCTN number
    		 ISRCTN44149443
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Leeds
    Sponsor organisation address
    University of Leeds, Leeds, United Kingdom, LS2 9JT
    Public contact
    Clinical Trials Research Unit, University of Leeds, +44 01133439141, medctfst@leeds.ac.uk
    Scientific contact
    Clinical Trials Research Unit, University of Leeds, +44 01133439141, medctfst@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
    24 Mar 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Nov 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Oct 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Dose Escalation Cohort To investigate the safety, tolerability and feasibility of the novel AGC (AZD4547 with gemcitabine and cisplatin) combination in advanced non-haematological malignancies. Randomised Expansion Cohort To obtain a preliminary indication of the relative toxicities of AGC compared to GC in locally-advanced/metastatic TCC of the urinary bladder (and other urothelial) cancers.
    Protection of trial subjects
    Patients were monitored regularly throughout trial treatment and may have required extra hospital visits. Every effort was made to schedule appointments for tests to coincide with scheduled visits to the hospital. Extra blood samples may have been required for the trial at some appointments, some of these required additional needle punctures but were carried out at the same testing point where possible. Potential side effects of treatment were explained to patients in the Patient Information Sheet. Treatment modifications and supportive care could be given to minimise these. An ophthalmology exam was performed that may include inserting paper in the eye for 5 minutes. This was carried out by a qualified ophthalmologist as a standard test.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jul 2012
    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: 28
    Worldwide total number of subjects
    28
    EEA total number of subjects
    28
    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)
    17
    From 65 to 84 years
    11
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were identified in routine clinic visits at NHS hospitals running the trial. Patients were consented and registered. Screening tests performed and treatment began.

    Pre-assignment
    Screening details
    		 Participants underwent screening to ensure they met the eligibility criteria including ophthalmology examination and isotopic GFR. They were then allocated a dose in the dose escalation phase or randomised in the expanded phase.

    Period 1
    Period 1 title
    Dose Escalation Cohort
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Dose level 1: GC & AZD4547 40mg BD
    Arm description
    		 Gemcitabine, Cisplatin, AZD4547 at 40mg BD
    Arm type
    		 Experimental

    Investigational medicinal product name
    AZD4547
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    40mg twice daily, oral doses of AZD4547 for 14 days at the beginning of each 21-day cycle, for up to 6 cycles.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1000mg/m2 (IV days 1 & 8 of each 21-day cycle, for up to 6 cycles) To be given by IV infusion over 30-60 minutes, before Cisplatin

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    70mg/m2 (IV day 1 of each 21-day cycle, for up to 6 cycles) To be given by IV infusion over 2-4 hours

    Arm title
    		 Dose level 2: GC & AZD4547 80mg BD
    Arm description
    		 Gemcitabine, Cisplatin and AZD4547 at 80mg BD
    Arm type
    		 Experimental

    Investigational medicinal product name
    AZD4547
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    80mg twice daily, oral doses of AZD4547 for 14 days at the beginning of each 21-day cycle, for up to 6 cycles.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1000mg/m2 (IV days 1 & 8 of each 21-day cycle, for up to 6 cycles) To be given by IV infusion over 30-60 minutes, before Cisplatin

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    70mg/m2 (IV day 1 of each 21-day cycle, for up to 6 cycles) To be given by IV infusion over 2-4 hours

    Arm title
    		 Dose level 3: GC & AZD4547 100mg BD
    Arm description
    		 Gemcitabine, Cisplatin and AZD4547 at 100mg BD
    Arm type
    		 Experimental

    Investigational medicinal product name
    AZD4547
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100mg twice daily, oral doses of AZD4547 for 14 days at the beginning of each 21-day cycle, for up to 6 cycles.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1000mg/m2 (IV days 1 & 8 of each 21-day cycle, for up to 6 cycles) To be given by IV infusion over 30-60 minutes, before Cisplatin

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    70mg/m2 (IV day 1 of each 21-day cycle, for up to 6 cycles) To be given by IV infusion over 2-4 hours

    Number of subjects in period 1
    		Dose level 1: GC & AZD4547 40mg BD Dose level 2: GC & AZD4547 80mg BD Dose level 3: GC & AZD4547 100mg BD
    Started
    4
    6
    9
    Completed
    4
    6
    9
    Period 2
    Period 2 title
    Randomised Expansion Cohort
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 AZD4547, Gemcitabine + Cisplatin
    Arm description
    		 AZD4547, Gemcitabine, Cisplatin
    Arm type
    		 Experimental

    Investigational medicinal product name
    AZD4547
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    80mg twice daily, oral doses of AZD4547 for 14 days at the beginning of each 21-day cycle, for up to 6 cycles.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1000mg/m2 (IV days 1 & 8 of each 21-day cycle, for up to 6 cycles) To be given by IV infusion over 30-60 minutes, before Cisplatin

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    70mg/m2 (IV day 1 of each 21-day cycle, for up to 6 cycles) To be given by IV infusion over 2-4 hours

    Arm title
    		 Gemcitabine + Cisplatin
    Arm description
    		 Gemcitabine, Cisplatin
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1000mg/m2 (IV days 1 & 8 of each 21-day cycle, for up to 6 cycles) To be given by IV infusion over 30-60 minutes, before Cisplatin

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    70mg/m2 (IV day 1 of each 21-day cycle, for up to 6 cycles) To be given by IV infusion over 2-4 hours

    Number of subjects in period 2 [1] [2]
    		AZD4547, Gemcitabine + Cisplatin Gemcitabine + Cisplatin
    Started
    4
    5
    Completed
    5
    5
    Joined
    1
    0
         Transferred in from other group/arm
    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: The trial analysis is undertaken in two components: dose escalation and randomised expansion. Therefore the periods are not "periods" in the usual sense (i.e. they do not follow on from each other).
    [2] - The number of subjects transferring in and out of the arms in the period are not the same. It is expected the net number of transfers in and out of the arms in a period, will be zero.
    Justification: One patient received AZD4547 at the RDST in the dose escalation phase and was eligible for the randomised expansion phase, therefore was included in the randomised expansion analysis population as per the trial definition.
    Period 3
    Period 3 title
    Baseline
    Is this the baseline period?
    		 Yes [3]
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Dose escalation
    Arm description
    		 Gemcitabine, Cisplatin, AZD4547 at 40mg BD - 100mg BD Includes one patient receiving AZD4547 at 80mg BD who is also included in the randomised expansion group due to being eligible for analysis in this group.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AZD4547
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    40mg - 100mg (escalating cohorts) twice daily, oral doses of AZD4547 for 14 days at the beginning of each 21-day cycle, for up to 6 cycles.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1000mg/m2 (IV days 1 & 8 of each 21-day cycle, for up to 6 cycles) To be given by IV infusion over 30-60 minutes, before Cisplatin

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    70mg/m2 (IV day 1 of each 21-day cycle, for up to 6 cycles) To be given by IV infusion over 2-4 hours

    Arm title
    		 Randomised expansion
    Arm description
    		 Randomised expansion analysis population: 9 patients randomised plus one patient who received AGC at the RDST in the escalation phase who fulfilled the eligibility criteria for expansion.
    Arm type
    		 Combined for baseline

    Investigational medicinal product name
    AZD4547
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    80mg twice daily, oral doses of AZD4547 for 14 days at the beginning of each 21-day cycle, for up to 6 cycles. [ACG arm only]

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1000mg/m2 (IV days 1 & 8 of each 21-day cycle, for up to 6 cycles) To be given by IV infusion over 30-60 minutes, before Cisplatin

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    70mg/m2 (IV day 1 of each 21-day cycle, for up to 6 cycles) To be given by IV infusion over 2-4 hours

    Notes
    [3] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: The trial analysis is undertaken in two components: dose escalation and randomised expansion. Therefore neither period 1 or 2 are baseline, rather both are. As such, both had to be entered into a separate "period", period 3.
    Number of subjects in period 3
    		Dose escalation Randomised expansion
    Started
    19
    10
    Completed
    19
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dose escalation
    Reporting group description
    		 Gemcitabine, Cisplatin, AZD4547 at 40mg BD - 100mg BD Includes one patient receiving AZD4547 at 80mg BD who is also included in the randomised expansion group due to being eligible for analysis in this group.

    Reporting group title
    Randomised expansion
    Reporting group description
    		 Randomised expansion analysis population: 9 patients randomised plus one patient who received AGC at the RDST in the escalation phase who fulfilled the eligibility criteria for expansion.

    Reporting group values
    		 Dose escalation Randomised expansion Total
    Number of subjects
    		 19 10 28
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 11 7 17
        From 65-84 years
    		 8 3 11
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 58 (39 to 75) 61 (50 to 81) -
    Gender categorical
    Units: Subjects
        Female
    		 8 2 9
        Male
    		 11 8 19
    Type of Cancer
    Units: Subjects
        TCC Bladder
    		 3 8 10
        TCC Urinary Tract
    		 0 1 1
        Other
    		 16 1 17
    Number of target lesions
    Units: number of lesions
        median (full range (min-max))
    		 2 (0 to 5) 1.5 (0 to 2) -
    Time from most recent relapse/progression to registration
    Units: Months
        median (full range (min-max))
    		 2.5 (0.5 to 30.8) 1.4 (1 to 2.7) -

    End points

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    End points reporting groups
    Reporting group title
    Dose level 1: GC & AZD4547 40mg BD
    Reporting group description
    		 Gemcitabine, Cisplatin, AZD4547 at 40mg BD

    Reporting group title
    Dose level 2: GC & AZD4547 80mg BD
    Reporting group description
    		 Gemcitabine, Cisplatin and AZD4547 at 80mg BD

    Reporting group title
    Dose level 3: GC & AZD4547 100mg BD
    Reporting group description
    		 Gemcitabine, Cisplatin and AZD4547 at 100mg BD
    Reporting group title
    AZD4547, Gemcitabine + Cisplatin
    Reporting group description
    		 AZD4547, Gemcitabine, Cisplatin

    Reporting group title
    Gemcitabine + Cisplatin
    Reporting group description
    		 Gemcitabine, Cisplatin
    Reporting group title
    Dose escalation
    Reporting group description
    		 Gemcitabine, Cisplatin, AZD4547 at 40mg BD - 100mg BD Includes one patient receiving AZD4547 at 80mg BD who is also included in the randomised expansion group due to being eligible for analysis in this group.

    Reporting group title
    Randomised expansion
    Reporting group description
    		 Randomised expansion analysis population: 9 patients randomised plus one patient who received AGC at the RDST in the escalation phase who fulfilled the eligibility criteria for expansion.

    Primary: DLTs, within the first cycle (until cycle 2, day 1), in order to establish the MTD of AZD4547 in combination with GC

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    End point title
    		 DLTs, within the first cycle (until cycle 2, day 1), in order to establish the MTD of AZD4547 in combination with GC [1]
    End point description
    Maximum Tolerated Dose: the highest dose level at which no more than 1 participant experiences a DLT, during the first cycle of treatment i.e. the dose level below that at which 2 or more participants experiences a DLT. Dose-Limiting Toxicities: • Complicated grade 4 neutropenia with fever >38oC and/or haemodynamic compromise • Absolute Neutrophil Count (ANC) <0.5 x 109/L lasting for 7 days or more • Grade 4 thrombocytopenia (platelets <25 x 109/L) lasting for 7 days or more • Grade 3 or 4 thrombocytopenia (platelets <50 x 109/L) with significant active bleeding • Any unexpected grade 3 or 4 non-haematological toxicity that is considered related to treatment. • Hyperphosphataemia (serum phosphate level above 4.5 mmol/l or > 56 mg/dl) • Delay of commencement of 2nd cycle by more than 14 days, due to significant toxicity or tolerability issue • Any other event which, in the opinion of the SRC, is considered to be clinically significant and related to treatment
    End point type
    Primary
    End point timeframe
    Within the first cycle, up to cycle 2 day 1
    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 relates to data summaries only.
    End point values
    		 Dose level 1: GC & AZD4547 40mg BD Dose level 2: GC & AZD4547 80mg BD Dose level 3: GC & AZD4547 100mg BD
    Number of subjects analysed
    4 [2]
    6
    6 [3]
    Units: Number of DLTs
        Unexpected grade 3 or 4 non-haematological tox
    0
    0
    1
        No DLT
    4
    5
    4
        Grade 4 thrombocytopenia
    0
    1
    0
        Grade 3/4 thrombocytopenia with bleeding
    0
    0
    1
    Notes
    [2] - 1 patient received <80% of one treatment cycle so unevaluable for DLTs
    [3] - 3 patients received <80% of one treatment cycle so unevaluable for DLTs
    No statistical analyses for this end point

    Primary: CTCAE grade 3 or 4 toxicity within the first 3 cycles of treatment to determine the RDST

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    End point title
    		 CTCAE grade 3 or 4 toxicity within the first 3 cycles of treatment to determine the RDST [4]
    End point description
    Maximum CTCAE grade of each AE reported. Definition of Recommended Dose for Sustained Tolerability Once the MTD has been established, a minimum of 6 participants will be treated at this dose level in order to establish the RDST. The RDST will be defined as: The highest dose level at which 3 or more of 6 evaluable participants complete 3 or more consecutive cycles without toxicity which, in the opinion of the Safety Review Committee, is clinically significant, unacceptable and attributable to the addition of AZD4547 to gemcitabine and cisplatin. The RDST will be determined by the Safety Review Committee upon review of toxicities observed throughout cycles 1-3, along with any other safety data which are deemed clinically relevant.
    End point type
    Primary
    End point timeframe
    Within first 3 cycles of treatment.
    Notes
    [4] - 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 relates to data summaries only.
    End point values
    		 Dose level 1: GC & AZD4547 40mg BD Dose level 2: GC & AZD4547 80mg BD Dose level 3: GC & AZD4547 100mg BD
    Number of subjects analysed
    4
    6
    9
    Units: Number of participants
        Grade 2
    2
    0
    3
        Grade 3
    2
    2
    2
        Grade 4
    0
    4
    4
    No statistical analyses for this end point

    Primary: Proportion of participants treated who experience any grade 3 or 4 CTCAE toxicity throughout all treatment cycles

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    End point title
    		 Proportion of participants treated who experience any grade 3 or 4 CTCAE toxicity throughout all treatment cycles [5]
    End point description
    The proportion of participants treated who experience any grade 3 or 4 CTCAE toxicity will be calculated as number of participants who experience any grade 3 or 4 CTCAE toxicity throughout their treatment cycle in each arm, as a proportion of those participants who receive at least one dose of study treatment within each arm. Maximum CTCAE grade of AE reported across all treatment cycles.
    End point type
    Primary
    End point timeframe
    All treatment cycles
    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: As this is a phase I study, the primary endpoint relates to data summaries only.
    End point values
    		 AZD4547, Gemcitabine + Cisplatin Gemcitabine + Cisplatin
    Number of subjects analysed
    5
    5
    Units: Number of patients
        Grade 2
    0
    1
        Grade 3
    2
    2
        Grade 4
    3
    2
    No statistical analyses for this end point

    Secondary: Objective response rate and disease control rate

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    End point title
    		 Objective response rate and disease control rate
    End point description
    Objective response = complete response or partial response Disease control = complete response, partial response or stable disease
    End point type
    Secondary
    End point timeframe
    Within the treatment period
    End point values
    		 AZD4547, Gemcitabine + Cisplatin Gemcitabine + Cisplatin
    Number of subjects analysed
    5 [6]
    5
    Units: Number of patients
        Complete response
    1
    1
        Partial response
    0
    2
        Stable disease
    2
    1
        Non CR / non PD (no target lesions)
    0
    1
        Clinical progression
    1
    0
        No scan performed, not clinically progressed
    1
    0
    Notes
    [6] - Includes patient receiving AGC at RDST in escalation and eligible for expansion
    No statistical analyses for this end point

    Secondary: Change in tumour size

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    End point title
    		 Change in tumour size
    End point description
    Change in tumour size is defined as change from baseline assessment. Presented as change from baseline to best response (i.e. largest decrease, or smallest increase from baseline).
    End point type
    Secondary
    End point timeframe
    Within the treatment period
    End point values
    		 AZD4547, Gemcitabine + Cisplatin Gemcitabine + Cisplatin
    Number of subjects analysed
    5 [7]
    5
    Units: Difference in tumour size, mm
        -1mm
    1
    0
        -14mm
    1
    0
        -4mm
    1
    0
        +4mm
    0
    1
        -37mm
    0
    1
        -22mm
    0
    1
        -53.9mm
    0
    1
        No scan performed
    2
    0
        No target lesions
    0
    1
    Notes
    [7] - Includes patient receiving AGC at the RDST in the escalation phase and eligible for expansion
    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 dose allocation/randomisation 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.
    End point type
    Secondary
    End point timeframe
    From dose allocation or randomisation until disease progression or death.
    End point values
    		 AZD4547, Gemcitabine + Cisplatin Gemcitabine + Cisplatin
    Number of subjects analysed
    5 [8]
    5
    Units: Months
        median (confidence interval 95%)
    6.47 (0.39 to 12.6)
    11.4 (4.83 to 11.4)
    Notes
    [8] - Includes patient receiving AGC at the RDST in the escalation phase and eligible for expansion
    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 randomisation to date of death from any cause. Participants who are still alive at the time of analysis will be censored at the last date they were known to be alive. N.B -9999999999=-Inf and 9999999999=Inf
    End point type
    Secondary
    End point timeframe
    From randomisation (or dose allocation) to death.
    End point values
    		 AZD4547, Gemcitabine + Cisplatin Gemcitabine + Cisplatin
    Number of subjects analysed
    5 [9]
    5
    Units: Months
        median (confidence interval 95%)
    8.57 (0.39 to 9999999999)
    12.7 (-9999999999 to 9999999999)
    Notes
    [9] - Includes patient receiving AGC at the RDST in the escalation phase and eligible for expansion
    No statistical analyses for this end point

    Secondary: Withdrawals from treatment

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    End point title
    		 Withdrawals from treatment
    End point description
    End point type
    Secondary
    End point timeframe
    Throughout treatment
    End point values
    		 Dose level 1: GC & AZD4547 40mg BD Dose level 2: GC & AZD4547 80mg BD Dose level 3: GC & AZD4547 100mg BD AZD4547, Gemcitabine + Cisplatin Gemcitabine + Cisplatin
    Number of subjects analysed
    4
    6
    9
    5 [10]
    5
    Units: Number of patients
        Withdrawn from treatment
    1
    0
    0
    0
    0
    Notes
    [10] - Includes patient receiving AGC at the RDST in the escalation phase and eligible for expansion
    No statistical analyses for this end point

    Secondary: FGFR3 expression

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    End point title
    		 FGFR3 expression
    End point description
    End point type
    Secondary
    End point timeframe
    At entry to trial
    End point values
    		 Dose level 1: GC & AZD4547 40mg BD Dose level 2: GC & AZD4547 80mg BD Dose level 3: GC & AZD4547 100mg BD AZD4547, Gemcitabine + Cisplatin Gemcitabine + Cisplatin
    Number of subjects analysed
    1 [11]
    1 [12]
    4 [13]
    2 [14]
    1 [15]
    Units: Number of patients
        0: all negative
    0
    1
    1
    0
    0
        1: faint but detectable
    1
    0
    2
    0
    0
        2: weak but extensive postivity
    0
    0
    0
    2
    0
        3: strong positivity
    0
    0
    0
    0
    1
        Some 3, mostly 1
    0
    0
    1
    0
    0
    Notes
    [11] - Expression only gained for 1 patient
    [12] - Expression only gained for 1 patient
    [13] - Expression only gained for 4 patients
    [14] - Expression only gained for 2 patients
    [15] - Expression only gained for 1 patient
    No statistical analyses for this end point

    Secondary: FGFR3 mutation status

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    End point title
    		 FGFR3 mutation status
    End point description
    End point type
    Secondary
    End point timeframe
    At entry to trial
    End point values
    		 Dose level 1: GC & AZD4547 40mg BD Dose level 2: GC & AZD4547 80mg BD Dose level 3: GC & AZD4547 100mg BD AZD4547, Gemcitabine + Cisplatin Gemcitabine + Cisplatin
    Number of subjects analysed
    1 [16]
    1 [17]
    3 [18]
    2 [19]
    1 [20]
    Units: Number of patients
        wild-type
    1
    1
    3
    2
    0
        mutant (S249C)
    0
    0
    0
    0
    1
    Notes
    [16] - Mutation status only gained for 1 patient
    [17] - Mutation status only gained for 1 patient
    [18] - Mutation status only gained for 3 patients
    [19] - Mutation status only gained for 2 patients
    [20] - Mutation status only gained for 1 patient
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs and SAEs: from the time of written informed consent until 28 days following dosing with an IMP. SARs and SUSARs: from the time of written informed consent until the end of the trial.
    Adverse event reporting additional description
    Reporting of AEs prompted on CRFs at day 8 and 15 of each treatment cycle, and at the end of treatment. Due to the way events collected on the trial: 1. SAEs are also reported as AEs 2. For AEs, the number of occurrences is equal to the number of patients apart from "other" events where each event under other is listed once per patient
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Dose level 1: GC + AZD4547 40mg BD
    Reporting group description
    		 -

    Reporting group title
    Dose level 2: GC + AZD4547 80mg BD
    Reporting group description
    		 -

    Reporting group title
    Dose level 3: GC + AZD4547 100mg BD
    Reporting group description
    		 -

    Reporting group title
    AZD4547, Gemcitabine + Cisplatin
    Reporting group description
    		 AGC analysis population, including 1 patient receiving AGC at the RDST in the dose escalation phase.

    Reporting group title
    Gemcitabine + Cisplatin
    Reporting group description
    		 -

    Serious adverse events
    		 Dose level 1: GC + AZD4547 40mg BD Dose level 2: GC + AZD4547 80mg BD Dose level 3: GC + AZD4547 100mg BD AZD4547, Gemcitabine + Cisplatin Gemcitabine + Cisplatin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 4 (75.00%)
    3 / 6 (50.00%)
    4 / 9 (44.44%)
    4 / 5 (80.00%)
    1 / 5 (20.00%)
         number of deaths (all causes)
    2
    2
    3
    4
    2
         number of deaths resulting from adverse events
    0
    0
    0
    1
    0
    Investigations
    Platelet count decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    2 / 9 (22.22%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Thromboembolic event
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    0 / 9 (0.00%)
    1 / 5 (20.00%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Stroke
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ileus
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 6 (33.33%)
    0 / 9 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    1 / 9 (11.11%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Other
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    2 / 5 (40.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Metabolism and nutrition disorders
    Hypomagnesaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Dose level 1: GC + AZD4547 40mg BD Dose level 2: GC + AZD4547 80mg BD Dose level 3: GC + AZD4547 100mg BD AZD4547, Gemcitabine + Cisplatin Gemcitabine + Cisplatin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 4 (100.00%)
    6 / 6 (100.00%)
    9 / 9 (100.00%)
    5 / 5 (100.00%)
    5 / 5 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    2 / 9 (22.22%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    2
    0
    1
    Hypotension
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 6 (33.33%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Phlebitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Thromboembolic event
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 6 (33.33%)
    1 / 9 (11.11%)
    1 / 5 (20.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    2
    1
    1
    1
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Oedema limbs
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    2 / 9 (22.22%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    1
    2
    0
    1
    Fatigue
         subjects affected / exposed
    3 / 4 (75.00%)
    5 / 6 (83.33%)
    7 / 9 (77.78%)
    3 / 5 (60.00%)
    5 / 5 (100.00%)
         occurrences all number
    3
    5
    7
    3
    5
    Fever
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Malaise
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    1 / 9 (11.11%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    1
    1
    0
    1
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 5 (20.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Pain
         subjects affected / exposed
    2 / 4 (50.00%)
    2 / 6 (33.33%)
    1 / 9 (11.11%)
    0 / 5 (0.00%)
    2 / 5 (40.00%)
         occurrences all number
    2
    2
    1
    0
    2
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Testicular pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    1 / 9 (11.11%)
    1 / 5 (20.00%)
    2 / 5 (40.00%)
         occurrences all number
    1
    1
    1
    1
    2
    Dyspnoea
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    1
    0
    0
    1
    Epistaxis
         subjects affected / exposed
    2 / 4 (50.00%)
    1 / 6 (16.67%)
    3 / 9 (33.33%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    1
    3
    1
    0
    Hiccups
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Hoarseness
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Confusion
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    0
    0
    0
    1
    Depression
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Insomnia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    2 / 9 (22.22%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    2
    0
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 4 (25.00%)
    5 / 6 (83.33%)
    4 / 9 (44.44%)
    4 / 5 (80.00%)
    4 / 5 (80.00%)
         occurrences all number
    1
    5
    4
    4
    4
    Alkaline phosphatase increased
         subjects affected / exposed
    1 / 4 (25.00%)
    3 / 6 (50.00%)
    4 / 9 (44.44%)
    2 / 5 (40.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    3
    4
    2
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 9 (0.00%)
    1 / 5 (20.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    0
    1
    1
    GGT increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    3 / 5 (60.00%)
         occurrences all number
    0
    0
    0
    0
    3
    Other
         subjects affected / exposed
    1 / 4 (25.00%)
    5 / 6 (83.33%)
    6 / 9 (66.67%)
    3 / 5 (60.00%)
    4 / 5 (80.00%)
         occurrences all number
    2
    8
    11
    3
    15
    Platelet count decreased
         subjects affected / exposed
    1 / 4 (25.00%)
    6 / 6 (100.00%)
    7 / 9 (77.78%)
    2 / 5 (40.00%)
    5 / 5 (100.00%)
         occurrences all number
    1
    6
    7
    2
    5
    Weight loss
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 6 (33.33%)
    1 / 9 (11.11%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    2
    1
    1
    0
    White blood cell count decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    6 / 6 (100.00%)
    7 / 9 (77.78%)
    3 / 5 (60.00%)
    5 / 5 (100.00%)
         occurrences all number
    0
    6
    7
    3
    5
    Injury, poisoning and procedural complications
    Bruising
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    0 / 9 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    1
    0
    1
    0
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    0 / 9 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    1
    0
    1
    0
    Nervous system disorders
    Aphonia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Dizziness
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    1 / 9 (11.11%)
    0 / 5 (0.00%)
    2 / 5 (40.00%)
         occurrences all number
    1
    1
    1
    0
    2
    Dysgeusia
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 6 (33.33%)
    1 / 9 (11.11%)
    1 / 5 (20.00%)
    2 / 5 (40.00%)
         occurrences all number
    1
    2
    1
    1
    2
    Headache
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    1 / 9 (11.11%)
    1 / 5 (20.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    1
    1
    1
    1
    Other
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    0
    0
    0
    1
    Olfactory nerve disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    3 / 9 (33.33%)
    0 / 5 (0.00%)
    2 / 5 (40.00%)
         occurrences all number
    1
    1
    3
    0
    2
    Presyncope
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Stroke
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 4 (25.00%)
    6 / 6 (100.00%)
    8 / 9 (88.89%)
    4 / 5 (80.00%)
    5 / 5 (100.00%)
         occurrences all number
    1
    6
    8
    4
    5
    Leukocytosis
         subjects affected / exposed
    1 / 4 (25.00%)
    3 / 6 (50.00%)
    5 / 9 (55.56%)
    2 / 5 (40.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    3
    5
    2
    0
    Ear and labyrinth disorders
    Other
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Ear pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Hearing impaired
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 6 (33.33%)
    2 / 9 (22.22%)
    1 / 5 (20.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    2
    2
    1
    1
    Eye disorders
    Blurred vision
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    1 / 9 (11.11%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    1
    1
    0
    0
    Dry eye
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Other
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    2 / 9 (22.22%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    2
    0
    0
    Glaucoma
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Retinal detachment
         subjects affected / exposed
    0 / 4 (0.00%)
    4 / 6 (66.67%)
    5 / 9 (55.56%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    4
    5
    1
    0
    Watering eyes
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 4 (25.00%)
    3 / 6 (50.00%)
    3 / 9 (33.33%)
    1 / 5 (20.00%)
    2 / 5 (40.00%)
         occurrences all number
    1
    3
    3
    1
    2
    Cheilitis
         subjects affected / exposed
    3 / 4 (75.00%)
    4 / 6 (66.67%)
    5 / 9 (55.56%)
    3 / 5 (60.00%)
    1 / 5 (20.00%)
         occurrences all number
    3
    4
    5
    3
    1
    Constipation
         subjects affected / exposed
    2 / 4 (50.00%)
    4 / 6 (66.67%)
    5 / 9 (55.56%)
    3 / 5 (60.00%)
    2 / 5 (40.00%)
         occurrences all number
    2
    4
    5
    3
    2
    Diarrhoea
         subjects affected / exposed
    1 / 4 (25.00%)
    4 / 6 (66.67%)
    4 / 9 (44.44%)
    3 / 5 (60.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    4
    4
    3
    1
    Dyspepsia
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    1
    0
    0
    Oesophagitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Gastroesophageal reflux disease
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    3 / 5 (60.00%)
         occurrences all number
    0
    1
    0
    0
    3
    Other
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Ileus
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Nausea
         subjects affected / exposed
    4 / 4 (100.00%)
    4 / 6 (66.67%)
    5 / 9 (55.56%)
    4 / 5 (80.00%)
    4 / 5 (80.00%)
         occurrences all number
    4
    4
    5
    4
    4
    Periodontal disease
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Vomiting
         subjects affected / exposed
    2 / 4 (50.00%)
    2 / 6 (33.33%)
    5 / 9 (55.56%)
    2 / 5 (40.00%)
    1 / 5 (20.00%)
         occurrences all number
    2
    2
    5
    2
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 9 (0.00%)
    1 / 5 (20.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    0
    1
    1
    Dry skin
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Nail loss
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Pruritis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Other
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    2
    0
    0
    0
    1
    Skin hyperpigmentation
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 6 (33.33%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    2
    0
    0
    1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 4 (25.00%)
    4 / 6 (66.67%)
    7 / 9 (77.78%)
    5 / 5 (100.00%)
    2 / 5 (40.00%)
         occurrences all number
    1
    4
    7
    5
    2
    Haematuria
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 9 (0.00%)
    1 / 5 (20.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    0
    1
    1
    Urinary retention
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    1 / 9 (11.11%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Back pain
         subjects affected / exposed
    2 / 4 (50.00%)
    2 / 6 (33.33%)
    2 / 9 (22.22%)
    2 / 5 (40.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    2
    2
    2
    0
    Soft tissue necrosis lower
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Infections and infestations
    Other
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Lung infection
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    0 / 5 (0.00%)
    2 / 5 (40.00%)
         occurrences all number
    1
    0
    1
    0
    2
    Mucosal infection
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    1 / 9 (11.11%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    1
    1
    0
    1
    Sepsis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Skin infection
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    1 / 9 (11.11%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    1
    1
    0
    0
    Upper respiratory infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    2 / 9 (22.22%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    2
    0
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 6 (33.33%)
    4 / 9 (44.44%)
    4 / 5 (80.00%)
    3 / 5 (60.00%)
         occurrences all number
    0
    2
    4
    4
    3
    Metabolism and nutrition disorders
    anorexia
         subjects affected / exposed
    1 / 4 (25.00%)
    3 / 6 (50.00%)
    2 / 9 (22.22%)
    1 / 5 (20.00%)
    3 / 5 (60.00%)
         occurrences all number
    1
    3
    2
    1
    3
    Dehydration
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Hypercalcaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    2 / 9 (22.22%)
    2 / 5 (40.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    2
    2
    1
    Hypernatraemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Hypoalbuminaemia
         subjects affected / exposed
    2 / 4 (50.00%)
    2 / 6 (33.33%)
    8 / 9 (88.89%)
    2 / 5 (40.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    2
    8
    2
    0
    Hypocalcaemia
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 6 (33.33%)
    4 / 9 (44.44%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    2
    4
    0
    1
    Hypokalaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    4 / 9 (44.44%)
    1 / 5 (20.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    4
    1
    1
    Hypomagnesaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 6 (33.33%)
    2 / 9 (22.22%)
    1 / 5 (20.00%)
    2 / 5 (40.00%)
         occurrences all number
    0
    2
    2
    1
    2
    Hyponatraemia
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 6 (33.33%)
    4 / 9 (44.44%)
    3 / 5 (60.00%)
    2 / 5 (40.00%)
         occurrences all number
    1
    2
    4
    3
    2
    Hypophosphataemia
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    4 / 9 (44.44%)
    0 / 5 (0.00%)
    2 / 5 (40.00%)
         occurrences all number
    1
    1
    4
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Jul 2012
    Protocol v2
    21 Nov 2012
    Protocol v3
    15 Feb 2013
    Protocol v4
    12 Feb 2014
    Protocol v5
    18 May 2015
    Protocol v6

    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.
    Recruitment to the trial was slower than expected so the sample size for the randomised expansion phase was not reached. The number of patients included in this analysis is therefore lower than desired.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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