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    Clinical Trial Results:
    A Phase I/IIa trial of AZD4547 in combination with Cisplatin and Capecitabine (CX)

    Summary
    EudraCT number
    		 2011-000642-37
    Trial protocol
    		 GB  
    Global end of trial date
    12 Jan 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Dec 2019
    First version publication date
    18 Dec 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    AZD4547-2011
    Additional study identifiers
    ISRCTN number
    		 ISRCTN66171897
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Glasgow
    Sponsor organisation address
    University Avenue, GLASGOW, United Kingdom, G128QQ
    Public contact
    Dr Debra Stuart, University of Glasgow, 0141 3304539, debra.stuart@glasgow.ac.uk
    Scientific contact
    Dr Debra Stuart, University of Glasgow, 0141 3304539, debra.stuart@glasgow.ac.uk
    Sponsor organisation name
    NHS Greater Glasgow and Clyde
    Sponsor organisation address
    Clinical Research and Development Central Office, Ward 11, Dykebar Hospital, PAISLEY, United Kingdom, PA2 7DE
    Public contact
    Dr Margaret Fegen, NHS Greater Glasgow and Clyde, 0141 314 4011, margaret.fegen@ggc.scot.nhs.uk
    Scientific contact
    Dr Margaret Fegen, NHS Greater Glasgow and Clyde, 0141 314 4011, margaret.fegen@ggc.scot.nhs.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
    15 May 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Jan 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Jan 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    (Stage 1) To identify a recommended dose of AZD4547 when administered in combination with Cisplatin and Capecitabine (CX). (Stage 2) To determine the effect of AZD4547 in combination with Cisplatin and Capecitabine (AZD4547-CX) compared with Cisplatin and Capecitabine (CX) and placebo on progression-free survival (PFS) when administered to patients with locally advanced or metastatic gastro-oesophageal adenocarcinoma and with FGFR2 polysomy or amplification (FISH > 4)
    Protection of trial subjects
    As part of the study patients required to attend for additional clinic visits and investigations which would be above those considered to be standard care. The visit schedule and number and tupe of investigations were fully explained to patients verbally and in writing via the patient information sheet to ensure patients were fully aware what was entailed in participating in the trial prior to them consenting to the study. There were 2 parts to this study - Phase I (for all comers in solid tumours) and Phase IIa (for patients with advanced gastro-oesophageal adenocarcinoma whose tumours have FGFR2 polysomy or amplification). There were 3 separate patient information sheet and consent forms - 1 for Phase I patients only 1 for Phase IIa patients for testing of FSH status and 1 for Phase IIa patients consenting to randomisation into the main trial. The patient information sheets fully explained the design of the study and that for Phase IIa patients - half the patient would receive AZD4547 and half would receive placebo in combination with cisplatin and capecitabine (for Phase I patients this was open label with no randomisation). The side effects of all 3 study drugs were explained in the patient information sheet. All patients were closely monitored throughout the course of the study for adverse events and advised to report any side effects to their study nurse/doctor as they arose.
    Background therapy
    		 Not Applicable
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 May 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: 32
    Worldwide total number of subjects
    32
    EEA total number of subjects
    32
    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)
    19
    From 65 to 84 years
    13
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The Stage 1 part of the study opened to recruitment 01 March 2012. 19 patients were recruited into 3 cohorts. 16 were evaluable. The Stage 2 part of the study opened to recruitment in September 2013 and was closed to recruitment on 12 January 2015. 41 patients were registered and 13 of these were randomised.

    Pre-assignment
    Screening details
    		 Patients underwent screening to ensure that that they met the eligibilty criteria. For Stage 1 they were then allocated a dose in the dose escalation phase. Only patients with FISH 4/5 or FISH 6 tumours were considered for randomisation for the Stage 2 part of the study.

    Period 1
    Period 1 title
    Stage 1 (Phase I) + Stage 2 (Phase II)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Dose level 1: 40mg BD AZD4547 with cisplatin and capecitabine
    Arm description
    		 40mg BD AZD4547 with cisplatin and capecitabine
    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
    40 mg AZD4547 given twice daily in a days 1-14, 3-weekly oral administration schedule in combination with a fixed dose of Cisplatin (80 mg/m2 intravenously) and Capecitabine (1000 mg/m2 orally twice daily on days 1 – 14) three weekly

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    80 mg/m2 intravenously

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1000 mg/m2 orally twice daily on days 1 – 14

    Arm title
    		 Dose level 2: 80mg BD AZD4547 with cisplatin and capecitabine
    Arm description
    		 80mg BD AZD4547 with cisplatin and capecitabine
    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
    80 mg AZD4547 given twice daily in a days 1-14, 3-weekly oral administration schedule in combination with a fixed dose of Cisplatin (80 mg/m2 intravenously) and Capecitabine (1000 mg/m2 orally twice daily on days 1 – 14) three weekly

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    80 mg/m2 intravenously

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1000 mg/m2 orally twice daily on days 1 – 14

    Arm title
    		 Dose level -2: 60mg BD AZD4547 with cisplatin and capecitabine
    Arm description
    		 Dose level -2: 60mg BD AZD4547 with cisplatin and capecitabine
    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
    60 mg AZD4547 given twice daily in a days 1-14, 3-weekly oral administration schedule in combination with a fixed dose of Cisplatin (80 mg/m2 intravenously) and Capecitabine (1000 mg/m2 orally twice daily on days 1 – 14) three weekly

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    80 mg/m2 intravenously

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1000 mg/m2 orally twice daily on days 1 – 14

    Arm title
    		 60mg BD AZD4547 with cisplatin and capecitabine
    Arm description
    		 60mg BD AZD4547 with cisplatin and capecitabine
    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
    60 mg AZD4547 given twice daily on days 1-14, 3-weekly oral administration schedule in combination with a fixed dose of Cisplatin (80 mg/m2 intravenously) and Capecitabine (1000 mg/m2 orally twice daily on days 1 – 14) three weekly

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    80 mg/m2 intravenously

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1000 mg/m2 orally twice daily on days 1 – 14

    Arm title
    		 Placebo
    Arm description
    		 Placebo BD with cisplatin and capecitabine
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo given twice daily on days 1-14, 3-weekly oral administration schedule in combination with a fixed dose of Cisplatin (80 mg/m2 intravenously) and Capecitabine (1000 mg/m2 orally twice daily on days 1 – 14) three weekly (Stage II only)

    Number of subjects in period 1
    		Dose level 1: 40mg BD AZD4547 with cisplatin and capecitabine Dose level 2: 80mg BD AZD4547 with cisplatin and capecitabine Dose level -2: 60mg BD AZD4547 with cisplatin and capecitabine 60mg BD AZD4547 with cisplatin and capecitabine Placebo
    Started
    4
    7
    8
    7
    6
    Completed
    4
    6
    6
    7
    6
    Not completed
    0
    1
    2
    0
    0
         Non-evaluable
    -
    1
    2
    -
    -
    Period 2
    Period 2 title
    Stage 1 (Phase I)
    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: 40mg BD AZD4547 with cisplatin and capecitabine
    Arm description
    		 Dose level 1: 40mg BD AZD4547 with cisplatin and capecitabine
    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
    40 mg AZD4547 given twice daily on days 1-14, 3-weekly oral administration schedule in combination with a fixed dose of Cisplatin (80 mg/m2 intravenously) and Capecitabine (1000 mg/m2 orally twice daily on days 1 – 14) three weekly

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    80 mg/m2 intravenously

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1000 mg/m2 orally twice daily on days 1 – 14

    Arm title
    		 Dose level 2: 80mg BD AZD4547 with cisplatin and capecitabine
    Arm description
    		 Dose level 2: 80mg BD AZD4547 with cisplatin and capecitabine
    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
    80 mg AZD4547 given twice daily on days 1-14, 3-weekly oral administration schedule in combination with a fixed dose of Cisplatin (80 mg/m2 intravenously) and Capecitabine (1000 mg/m2 orally twice daily on days 1 – 14) three weekly

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    80 mg/m2 intravenously

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1000 mg/m2 orally twice daily on days 1 – 14

    Arm title
    		 Dose level -2: 60mg BD AZD4547 with cisplatin and capecitabine
    Arm description
    		 Dose level -2: 60mg BD AZD4547 with cisplatin and capecitabine
    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
    60 mg AZD4547 given twice daily on days 1-14, 3-weekly oral administration schedule in combination with a fixed dose of Cisplatin (80 mg/m2 intravenously) and Capecitabine (1000 mg/m2 orally twice daily on days 1 – 14) three weekly

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    80 mg/m2 intravenously

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1000 mg/m2 orally twice daily on days 1 – 14

    Number of subjects in period 2 [1]
    		Dose level 1: 40mg BD AZD4547 with cisplatin and capecitabine Dose level 2: 80mg BD AZD4547 with cisplatin and capecitabine Dose level -2: 60mg BD AZD4547 with cisplatin and capecitabine
    Started
    4
    7
    8
    Completed
    4
    6
    6
    Not completed
    0
    1
    2
         Non-evaluable
    -
    1
    2
    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 is in 2 parts: Stage 1 (dose escalation) and Stage 2 (phase II/ dose expansion). Period 1 reports Stages 1 & 2 combined and therefore the periods do not follow on from each other.
    Period 3
    Period 3 title
    Stage 2 (Phase II / dose expansion)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 60mg BD AZD4547 with cisplatin and capecitabine
    Arm description
    		 60mg BD AZD4547 with cisplatin and capecitabine
    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
    60 mg AZD4547 given twice daily in a days 1-14, 3-weekly oral administration schedule in combination with a fixed dose of Cisplatin (80 mg/m2 intravenously) and Capecitabine (1000 mg/m2 orally twice daily on days 1 – 14) three weekly

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    80 mg/m2 intravenously

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1000 mg/m2 orally twice daily on days 1 – 14

    Arm title
    		 Placebo
    Arm description
    		 Placebo BD with cisplatin and capecitabine
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo given twice daily on days 1-14, 3-weekly oral administration schedule in combination with a fixed dose of Cisplatin (80 mg/m2 intravenously) and Capecitabine (1000 mg/m2 orally twice daily on days 1 – 14) three weekly

    Number of subjects in period 3 [2]
    		60mg BD AZD4547 with cisplatin and capecitabine Placebo
    Started
    7
    6
    Completed
    7
    6
    Notes
    [2] - 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 is in 2 parts: Stage 1 (dose escalation) and Stage 2 (phase II/ dose expansion). Period 1 reports Stages 1 & 2 combined and therefore the periods do not follow on from each other.

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Dose level 1: 40mg BD AZD4547 with cisplatin and capecitabine
    Reporting group description
    		 40mg BD AZD4547 with cisplatin and capecitabine

    Reporting group title
    Dose level 2: 80mg BD AZD4547 with cisplatin and capecitabine
    Reporting group description
    		 80mg BD AZD4547 with cisplatin and capecitabine

    Reporting group title
    Dose level -2: 60mg BD AZD4547 with cisplatin and capecitabine
    Reporting group description
    		 Dose level -2: 60mg BD AZD4547 with cisplatin and capecitabine

    Reporting group title
    60mg BD AZD4547 with cisplatin and capecitabine
    Reporting group description
    		 60mg BD AZD4547 with cisplatin and capecitabine

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo BD with cisplatin and capecitabine

    Reporting group values
    		 Dose level 1: 40mg BD AZD4547 with cisplatin and capecitabine Dose level 2: 80mg BD AZD4547 with cisplatin and capecitabine Dose level -2: 60mg BD AZD4547 with cisplatin and capecitabine 60mg BD AZD4547 with cisplatin and capecitabine Placebo Total
    Number of subjects
    		 4 7 8 7 6 32
    Age categorical
    Age at study registration
    Units: Subjects
        In utero
    		 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0
        Adults (18-64 years)
    		 3 5 5 4 2 19
        From 65-84 years
    		 1 2 3 3 4 13
        85 years and over
    		 0 0 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 2 2 4 2 0 10
        Male
    		 2 5 4 5 6 22
    Subject analysis sets

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All evaluable patients (n=16) from Stage 1 and patients randomised (n=13) in Stage 2.

    Subject analysis set title
    60mg AZD4547 (phase I + II)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients receiving 60mg AZD4547 in phase I or phase II

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Placebo arm from phase II

    Subject analysis sets values
    		 ITT 60mg AZD4547 (phase I + II) Placebo
    Number of subjects
    29
    12
    6
    Age categorical
    Age at study registration
    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)
    17
    8
    2
        From 65-84 years
    12
    5
    4
        85 years and over
    0
    0
    0
    Age continuous
    Units:
        
    ±
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
    9
    5
    0
        Male
    20
    8
    6

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Dose level 1: 40mg BD AZD4547 with cisplatin and capecitabine
    Reporting group description
    		 40mg BD AZD4547 with cisplatin and capecitabine

    Reporting group title
    Dose level 2: 80mg BD AZD4547 with cisplatin and capecitabine
    Reporting group description
    		 80mg BD AZD4547 with cisplatin and capecitabine

    Reporting group title
    Dose level -2: 60mg BD AZD4547 with cisplatin and capecitabine
    Reporting group description
    		 Dose level -2: 60mg BD AZD4547 with cisplatin and capecitabine

    Reporting group title
    60mg BD AZD4547 with cisplatin and capecitabine
    Reporting group description
    		 60mg BD AZD4547 with cisplatin and capecitabine

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo BD with cisplatin and capecitabine
    Reporting group title
    Dose level 1: 40mg BD AZD4547 with cisplatin and capecitabine
    Reporting group description
    		 Dose level 1: 40mg BD AZD4547 with cisplatin and capecitabine

    Reporting group title
    Dose level 2: 80mg BD AZD4547 with cisplatin and capecitabine
    Reporting group description
    		 Dose level 2: 80mg BD AZD4547 with cisplatin and capecitabine

    Reporting group title
    Dose level -2: 60mg BD AZD4547 with cisplatin and capecitabine
    Reporting group description
    		 Dose level -2: 60mg BD AZD4547 with cisplatin and capecitabine
    Reporting group title
    60mg BD AZD4547 with cisplatin and capecitabine
    Reporting group description
    		 60mg BD AZD4547 with cisplatin and capecitabine

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo BD with cisplatin and capecitabine

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All evaluable patients (n=16) from Stage 1 and patients randomised (n=13) in Stage 2.

    Subject analysis set title
    60mg AZD4547 (phase I + II)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients receiving 60mg AZD4547 in phase I or phase II

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Placebo arm from phase II

    Primary: Stage 1 (Phase I) Primary analysis - MTD

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    End point title
    		 Stage 1 (Phase I) Primary analysis - MTD [1]
    End point description
    The maximum tolerated dose of AZD4547 in combination with Cisplatin and Capecitabine is defined as the highest dose at which < 2 of 6 patients experience dose limiting toxicity (DLT) with the first 3-week cycle of study treatment. Dose limiting toxicity was based on the clinical and laboratory toxicity assessments (NCI-CTC version 4.02; Appendix 5): • Grade IV neutropenia lasting for >7 days • Grade III/IV neutropenia with sepsis or with fever > 38.5 0C • Grade IV thrombocytopenia • Grade IV diarrhoea • Grade > III other non-haematological toxicities except for alopecia, and except for nausea or vomiting unless patients are taking optimal prophylaxis or supportive measures • QTc prolongation > 500 msec or QTc increase > 60 msec above screening value • Delay of > 2 weeks in administration of cycle 2 of treatment due to haematological or non-haematological toxicities • Failure to de
    End point type
    Primary
    End point timeframe
    DLTs in first 3-week cycle of study treatment to establish the MTD
    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 the Phase I part of the trial, the primary endpoint relates to descriptive data summaries.
    End point values
    		 Dose level 1: 40mg BD AZD4547 with cisplatin and capecitabine Dose level 2: 80mg BD AZD4547 with cisplatin and capecitabine Dose level -2: 60mg BD AZD4547 with cisplatin and capecitabine
    Number of subjects analysed
    4
    6
    6
    Units: DLTs
    0
    2
    1
    Attachments
    		 DLTs by cohort
    No statistical analyses for this end point

    Primary: Progression-free survival

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    End point title
    		 Progression-free survival [2]
    End point description
    Patients were evaluated for disease response every 9 weeks during chemotherapy with the same imaging methods (usually CT scanning) as used at the baseline (pre-chemotherapy) assessment of disease status. Patients in Stage 2 of the study continued to undergo disease response assessments at 9-week intervals after completion of up to 6 cycles of AZD4547-CX or placebo-CX until disease progression.
    End point type
    Primary
    End point timeframe
    From registration/randomisation to confirmed progression or death.
    Notes
    [2] - 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 the Phase I part of the trial, the primary endpoint relates to descriptive data summaries.
    End point values
    		 60mg AZD4547 (phase I + II) Placebo
    Number of subjects analysed
    12
    6
    Units: Months
        median (confidence interval 80%)
    6.844 (4.807 to 7.162)
    6.121 (5.044 to 9.406)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From consent until resolution, or for at least 30 days after discontinuation of study medication, whichever comes first or until toxicity has resolved to baseline or < Grade 1, or until the toxicity is considered to be irreversible.
    Adverse event reporting additional description
    Non-serious AEs reported according to worst grade so number of events equals the number of patients experiencing an event.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Dose level 1: 40mg BD AZD4547 (safety population)
    Reporting group description
    		 40mg BD AZD4547 with cisplatin and capecitabine from phase I evaluable for safety population

    Reporting group title
    Dose level 2: 80mg BD AZD4547 (safety population)
    Reporting group description
    		 80mg BD AZD4547 with cisplatin and capecitabine from phase I evaluable for safety population

    Reporting group title
    60mg BD AZD4547 (safety population)
    Reporting group description
    		 60mg BD AZD4547 with cisplatin and capecitabine from phase I and II evaluable for safety population

    Reporting group title
    Placebo (safety population)
    Reporting group description
    		 Placebo patients evaluable for safety population

    Serious adverse events
    		 Dose level 1: 40mg BD AZD4547 (safety population) Dose level 2: 80mg BD AZD4547 (safety population) 60mg BD AZD4547 (safety population) Placebo (safety population)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 4 (50.00%)
    3 / 7 (42.86%)
    10 / 13 (76.92%)
    2 / 5 (40.00%)
         number of deaths (all causes)
    4
    7
    11
    2
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignancy and unspecified - other
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 7 (28.57%)
    2 / 13 (15.38%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 13 (7.69%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thromboembolic event
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 7 (28.57%)
    0 / 13 (0.00%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 13 (7.69%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fever
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 7 (28.57%)
    1 / 13 (7.69%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 13 (7.69%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnea
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 7 (14.29%)
    0 / 13 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
    0 / 13 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    0 / 13 (0.00%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Cardiac troponin T increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 13 (7.69%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Creatinine increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
    0 / 13 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
    1 / 13 (7.69%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 13 (7.69%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 13 (7.69%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
    0 / 13 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
    0 / 13 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Depresed level of consciousness
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
    0 / 13 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 13 (7.69%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 13 (7.69%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    3 / 13 (23.08%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 13 (7.69%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 13 (7.69%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    2 / 13 (15.38%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
    1 / 13 (7.69%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 13 (7.69%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    0 / 13 (0.00%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Esophageal pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    0 / 13 (0.00%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders - other
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    0 / 13 (0.00%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
    3 / 13 (23.08%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stomach pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 13 (7.69%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 13 (7.69%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
    3 / 13 (23.08%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal and urinary disorders - other
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 13 (7.69%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 13 (7.69%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscle weakness lower limb
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 13 (7.69%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Lung infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    2 / 13 (15.38%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 13 (7.69%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 13 (7.69%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 13 (7.69%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 13 (7.69%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 13 (7.69%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 13 (7.69%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 13 (7.69%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Dose level 1: 40mg BD AZD4547 (safety population) Dose level 2: 80mg BD AZD4547 (safety population) 60mg BD AZD4547 (safety population) Placebo (safety population)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 4 (100.00%)
    7 / 7 (100.00%)
    13 / 13 (100.00%)
    5 / 5 (100.00%)
    Vascular disorders
    Thromboembolic event
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 7 (28.57%)
    5 / 13 (38.46%)
    2 / 5 (40.00%)
         occurrences all number
    0
    2
    5
    2
    Hypotension
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 13 (7.69%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 4 (75.00%)
    6 / 7 (85.71%)
    12 / 13 (92.31%)
    5 / 5 (100.00%)
         occurrences all number
    3
    6
    12
    5
    Fever
         subjects affected / exposed
    0 / 4 (0.00%)
    4 / 7 (57.14%)
    2 / 13 (15.38%)
    1 / 5 (20.00%)
         occurrences all number
    0
    4
    2
    1
    Pain
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
    2 / 13 (15.38%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 4 (25.00%)
    3 / 7 (42.86%)
    2 / 13 (15.38%)
    2 / 5 (40.00%)
         occurrences all number
    1
    3
    2
    2
    Cough
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 7 (0.00%)
    2 / 13 (15.38%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    2
    0
    Dyspnea
         subjects affected / exposed
    1 / 4 (25.00%)
    3 / 7 (42.86%)
    0 / 13 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    3
    0
    0
    Productive cough
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
    1 / 13 (7.69%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Sore throat
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 7 (28.57%)
    0 / 13 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Investigations
    White blood cell count decreased
    Additional description: Cannot differentiate between grade 0 and 1 as lower limit of normal not available so reporting considers grade 2 and above as an occurence.
         subjects affected / exposed
    1 / 4 (25.00%)
    4 / 7 (57.14%)
    8 / 13 (61.54%)
    2 / 5 (40.00%)
         occurrences all number
    1
    4
    8
    2
    Platelet count decreased
    Additional description: Cannot differentiate between grade 0 and 1 as lower limit of normal not available so reporting considers grade 2 and above as an occurrence.
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
    4 / 13 (30.77%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    4
    0
    Neutrophil count decreased
    Additional description: Cannot differentiate between grade 0 and 1 as lower limit of normal not available so reporting considers grade 2 and above as an occurrence.
         subjects affected / exposed
    1 / 4 (25.00%)
    5 / 7 (71.43%)
    7 / 13 (53.85%)
    3 / 5 (60.00%)
         occurrences all number
    1
    5
    7
    3
    Alkaline phosphatase increased
         subjects affected / exposed
    3 / 4 (75.00%)
    5 / 7 (71.43%)
    5 / 13 (38.46%)
    1 / 5 (20.00%)
         occurrences all number
    3
    5
    5
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 4 (50.00%)
    2 / 7 (28.57%)
    3 / 13 (23.08%)
    1 / 5 (20.00%)
         occurrences all number
    2
    2
    3
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 4 (50.00%)
    2 / 7 (28.57%)
    5 / 13 (38.46%)
    2 / 5 (40.00%)
         occurrences all number
    2
    2
    5
    2
    Creatinine increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
    2 / 13 (15.38%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Weight loss
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    4 / 13 (30.77%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
    1 / 13 (7.69%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Cardiac troponin T increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
    1 / 13 (7.69%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Nervous system disorders
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
    2 / 13 (15.38%)
    2 / 5 (40.00%)
         occurrences all number
    1
    0
    2
    2
    Peripheral motor neuropathy
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 7 (14.29%)
    2 / 13 (15.38%)
    0 / 5 (0.00%)
         occurrences all number
    1
    1
    2
    0
    Lethargy
         subjects affected / exposed
    0 / 4 (0.00%)
    3 / 7 (42.86%)
    2 / 13 (15.38%)
    1 / 5 (20.00%)
         occurrences all number
    0
    3
    2
    1
    Dizziness
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
    3 / 13 (23.08%)
    1 / 5 (20.00%)
         occurrences all number
    1
    0
    3
    1
    Dysgeusia
         subjects affected / exposed
    0 / 4 (0.00%)
    3 / 7 (42.86%)
    2 / 13 (15.38%)
    0 / 5 (0.00%)
         occurrences all number
    0
    3
    2
    0
    Dysphasia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 13 (7.69%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    1
    Headache
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 13 (7.69%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    1
    Syncope
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    2 / 13 (15.38%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Blood and lymphatic system disorders
    Anaemia
    Additional description: Cannot differentiate between grade 0 and 1 as lower limit of normal not available so reporting considers grade 2 and above as an occurence.
         subjects affected / exposed
    2 / 4 (50.00%)
    3 / 7 (42.86%)
    10 / 13 (76.92%)
    3 / 5 (60.00%)
         occurrences all number
    2
    3
    10
    3
    Febrile neutropenia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
    1 / 13 (7.69%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Ear and labyrinth disorders
    Hearing loss
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 7 (28.57%)
    5 / 13 (38.46%)
    0 / 5 (0.00%)
         occurrences all number
    0
    2
    5
    0
    Ear and labyrinth disorders - other
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    2 / 13 (15.38%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    2
    1
    Tinnitus
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
    1 / 13 (7.69%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 7 (14.29%)
    3 / 13 (23.08%)
    0 / 5 (0.00%)
         occurrences all number
    1
    1
    3
    0
    Dry eye
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
    1 / 13 (7.69%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Punctuate keratopathy
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
    1 / 13 (7.69%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Eye disorders - other
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
    3 / 13 (23.08%)
    2 / 5 (40.00%)
         occurrences all number
    1
    0
    3
    2
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 4 (50.00%)
    6 / 7 (85.71%)
    11 / 13 (84.62%)
    4 / 5 (80.00%)
         occurrences all number
    2
    6
    11
    4
    Mucositis oral
         subjects affected / exposed
    2 / 4 (50.00%)
    6 / 7 (85.71%)
    10 / 13 (76.92%)
    2 / 5 (40.00%)
         occurrences all number
    2
    6
    10
    2
    Diarrhoea
         subjects affected / exposed
    3 / 4 (75.00%)
    6 / 7 (85.71%)
    5 / 13 (38.46%)
    1 / 5 (20.00%)
         occurrences all number
    3
    6
    5
    1
    Vomiting
         subjects affected / exposed
    2 / 4 (50.00%)
    3 / 7 (42.86%)
    7 / 13 (53.85%)
    2 / 5 (40.00%)
         occurrences all number
    2
    3
    7
    2
    Constipation
         subjects affected / exposed
    0 / 4 (0.00%)
    5 / 7 (71.43%)
    9 / 13 (69.23%)
    0 / 5 (0.00%)
         occurrences all number
    0
    5
    9
    0
    Abdominal pain
         subjects affected / exposed
    1 / 4 (25.00%)
    3 / 7 (42.86%)
    2 / 13 (15.38%)
    0 / 5 (0.00%)
         occurrences all number
    1
    3
    2
    0
    Dry mouth
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    3 / 13 (23.08%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Gastrointestinal disorders - other
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    2 / 13 (15.38%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    2
    1
    Dyspepsia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
    1 / 13 (7.69%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Dysphagia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
    0 / 13 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    0
    1
    Gastroesophageal reflux disease
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
    0 / 13 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    0
    1
    Skin and subcutaneous tissue disorders
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 7 (28.57%)
    3 / 13 (23.08%)
    1 / 5 (20.00%)
         occurrences all number
    1
    2
    3
    1
    Alopecia
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 7 (14.29%)
    1 / 13 (7.69%)
    0 / 5 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Abnormal growth
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    1 / 13 (7.69%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    1
    Skin and subcutaneous tissue disorders - other
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 7 (28.57%)
    1 / 13 (7.69%)
    1 / 5 (20.00%)
         occurrences all number
    1
    2
    1
    1
    Dry skin
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
    0 / 13 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    0
    1
    Rash maculo-papular
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    2 / 13 (15.38%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Renal and urinary disorders
    Renal and urinary disorders - other
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    2 / 13 (15.38%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal and connective tissue disorders - other
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    2 / 13 (15.38%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Infections and infestations
    Lung infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    2 / 13 (15.38%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    2
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
    1 / 13 (7.69%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    1
    1
    Penile infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
    0 / 13 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    0
    1
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    3 / 4 (75.00%)
    3 / 7 (42.86%)
    8 / 13 (61.54%)
    3 / 5 (60.00%)
         occurrences all number
    3
    3
    8
    3
    Hyperkalaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 7 (14.29%)
    2 / 13 (15.38%)
    2 / 5 (40.00%)
         occurrences all number
    0
    1
    2
    2
    Hypokalaemia
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 7 (28.57%)
    5 / 13 (38.46%)
    1 / 5 (20.00%)
         occurrences all number
    1
    2
    5
    1
    Hypercalcaemia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
    1 / 13 (7.69%)
    1 / 5 (20.00%)
         occurrences all number
    1
    0
    1
    1
    Hypocalcaemia
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 7 (14.29%)
    3 / 13 (23.08%)
    2 / 5 (40.00%)
         occurrences all number
    1
    1
    3
    2
    Hypoalbuminaemia
         subjects affected / exposed
    2 / 4 (50.00%)
    2 / 7 (28.57%)
    7 / 13 (53.85%)
    3 / 5 (60.00%)
         occurrences all number
    2
    2
    7
    3
    Blood bilirubin increased
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 7 (28.57%)
    1 / 13 (7.69%)
    1 / 5 (20.00%)
         occurrences all number
    0
    2
    1
    1
    Hypermagnesaemia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 7 (0.00%)
    2 / 13 (15.38%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Hypomagnesaemia
         subjects affected / exposed
    2 / 4 (50.00%)
    6 / 7 (85.71%)
    10 / 13 (76.92%)
    5 / 5 (100.00%)
         occurrences all number
    2
    6
    10
    5
    Anorexia
         subjects affected / exposed
    2 / 4 (50.00%)
    4 / 7 (57.14%)
    6 / 13 (46.15%)
    3 / 5 (60.00%)
         occurrences all number
    2
    4
    6
    3
    Dehydration
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 7 (0.00%)
    2 / 13 (15.38%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    2
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Nov 2011
    Protocol Version 2 17th October 2011 Protocol updated in view of MHRA Grounds for Non-Acceptance •Section 6.1.3 amended to include the dose escalation information. •Page 35 amended to be consistent with the schedule of events on Page 9 (this now reads that serum phosphate, calcium and magnesium should be included in the standard clinical chemistry safety bloods which should be taken week for the first two treatment cycles and then weekly thereafter. •The Schedule of Events/Investigations on Page 9 amended so that the ECGs and assessment of the QTc are consistent with page 46 of the protocol. Patient information sheets also updated with this information
    06 Dec 2011
    Change in PI Christie Hospital from Professor Malcolm Ranson to Dr Fiona Thistlethwaite
    20 Aug 2012
    Protocol Version 3, 30th August 2012 •Non-negligent harm information updated on IRAS form and patient information sheets •Extension of time from consent to patient registration from 28 to 42 days. •Exclusion criteria for toxicities from previous treatments amended from > grade 1 to > grade 1. •Reporting of SAEs from consent only for SAEs relating to NIMPs •A new section (9.7 Reference Safety Information) has been added
    07 Mar 2013
    Protocol Version 4, 7th March 2013 •In order to optimise the maintenance monotherapy dose of AZD4547/placebo after completion of chemotherapy we have written into the protocol intrapatient dose escalation to a maximum of 80mg which was the maximum tolerated dose in the Phase I monotherapy study •There will no longer be the formulation of a 100mg tablet, this will now be an 80mg tablet (along with the 20mg tablet) •Clarification has been added to advise sites that there will be no exceptions to the eligibility criteria •A section has been added regarding Incident Reporting and Serious Breaches so that sites are aware of their responsibilities for reporting these •The reference safety information section has been updated •AstraZeneca have updated their guidelines for the management of RPED (Retinal Epithelial Detachment). There is now evidence that the condition is reversible and that it can be identified, monitored and managed. The protocol has been updated to include these guidelines (Figures 4, 5 and 6) •The time for the resolution of CTC grade 2 toxicities and raised calcium:phosphate product/serum phosphate from 14 days to 21 days before treatment recommences or the patient discontinues, in line with the time patients spend off treatment in the new RPED algorithm
    13 Aug 2013
    Addition of new sites: •Taunton and Somerset NHS Trust, Musgrove Park Hospital, PI Dr Emma Cattell •Guy’s and St Thomas’ NHS Trust, PI Dr Nick Maisey •Clatterbridge Cancer Centre NHS Foundation Trust, PI Dr Adrian Moss •University Hospitals Morecambe Bay Trust, PI Dr David Fyfe Change in PI, Hammersmith Hospital from Professor Hani Gabra to Dr Dani Power
    04 Sep 2013
    Protocol Version 5, 4th September 2013 •New Manufacturing Authorisation provided by AstraZeneca for their site in Molndal, Sweden •To allow for same day/research nurse consent for the FISH tumour testing part of the Stage 2 of the study •To allow for Troponin T to be measured as an alternative to Troponin I •Further administrative changes
    14 Nov 2013
    Addition of new sites: •Dr Alan Anthoney, The Leeds Teaching Hospitals NHS Trust, St James’s University Hospital •Dr Liz Toy, Royal Devon & Exeter NHS Foundation Trust •Dr Srinivasan Madhusudan, Nottingham University Hospitals NHS Trust, City Hospital •Dr Tim Iveson, University Hospital Southampton NHS Foundation Trust, Southampton General Hospital •Dr Justin Waters, Maidstone & Tunbridge Wells NHS Trust, Maidstone Hospital Change in PI Belfast City Hospital from Dr Martin Eatock to Dr Colin Purcell
    24 Jun 2014
    Temporary Halt of Study: Shortly after commencing the randomised phase II part of the FACING, Astra Zeneca reviewed data from their own studies, and concluded that the selection biomarker for FGFR2, performed at Quintiles, Edinburgh was not robust for patient selection, and AZ no longer supported this patient selection assay. We were offered to establish our own patient selection assay in an academic environment, but given the complexity of this and the very challenging timescales given to us by AZ, this became impossible and the study was closed prematurely after only a small proportion of the planned patient sample size had been enrolled.
    19 Nov 2014
    Addition of new site: •Charing Cross Hospital, Imperial Healthcare NHS Trust, PI Dr Danielle Power Changes in PI: •Clatterbridge Centre for Oncology previous PI Dr Adrian Moss, new PI Dr Ayman Madi •Belfast City Hospital previous PI Dr Colin Purcell, new PI Dr Richard Turkingston

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    09 Jun 2014
    Shortly after commencing the randomised phase II part of the FACING, Astra Zeneca reviewed data from their own studies, and concluded that the selection biomarker for FGFR2, performed at Quintiles, Edinburgh was not robust for patient selection, and AZ no longer supported this patient selection assay. We were offered to establish our own patient selection assay in an academic environment, but given the complexity of this and the very challenging timescales given to us by AZ, this became impossible and the study was closed prematurely after only a small proportion of the planned patient sample size had been enrolled.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to the early termination of this study, only 13/140 patients were randomised to the Phase IIa part of the study.
    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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