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    Clinical Trial Results:
    A Phase II Trial to Evaluate the Efficacy of AZD6094 (HMPL-504) in Patients with Papillary Renal Cell Carcinoma (PRCC)

    Summary
    EudraCT number
    		 2014-001858-41
    Trial protocol
    		 GB   ES  
    Global end of trial date
    29 Jan 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Apr 2021
    First version publication date
    08 Apr 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D5082C00002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02127710
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Sarah Cannon Development Innovations: GU 111
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    N/A, Södertälje, Sweden, S-151 85
    Public contact
    Senior Medical Director, Savolitinib, AstraZeneca, ClinicalTrialTransparency@astrazeneca.com
    Scientific contact
    Senior Medical Director, Savolitinib, AstraZeneca, ClinicalTrialTransparency@astrazeneca.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    22 Jul 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Jan 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jan 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the trial was to assess the anti-tumor activity of AZD6094 in patients with Papillary Renal Cell Carcinoma (PRCC), and in the subgroup of MET-positive patients as measured by Investigator assessment of overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. MET-driven PRCC was defined as any of the following: chromosome 7 copy gain, focal MET or HGF gene amplification, or MET kinase domain mutations.
    Protection of trial subjects
    The primary mechanism for protection of the subjects in the trial was the Steering Committee comprised of multidisciplinary members selected by AstraZeneca and Sarah Cannon Development Innovations. The committee had nine members who were experts able to provide clinical and methodological expertise as it related to the development of AZD6094 in renal cancer. Any outcome of review by the Steering Committee that affected patient safety or study design was communicated in a timely manner to all participating sites by Sarah Cannon Development Innovations.
    Background therapy
    		 None
    Evidence for comparator
    		 This was a single arm study - there was no comparator.
    Actual start date of recruitment
    30 Apr 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 68
    Country: Number of subjects enrolled
    United Kingdom: 20
    Country: Number of subjects enrolled
    Canada: 16
    Country: Number of subjects enrolled
    Spain: 5
    Worldwide total number of subjects
    109
    EEA total number of subjects
    5
    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)
    59
    From 65 to 84 years
    49
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 One hundred thirty-one (131) subjects gave informed consent to be screened; 111 patients were enrolled; 20 patients were screen failures; 109 patients received at least one dose of AZD6094. Two patients were withdrawn prior to receiving any study drug. The study was conducted at 23 international sites in the US, Canada, UK, and Spain.

    Pre-assignment
    Screening details
    		 All patients were required to provide an archived or fresh tumour sample at enrolment to confirm eligibility, and for performance of the c-MET biomarker analysis. C-MET biomarker results determined the subgroup placement for data analyses as follows: c-MET positive (n=44), c-MET negative (n=46) and c-MET unknown (n=19).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 c-MET positive
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    AZD6094
    Investigational medicinal product code
    Other name
    savolitinib
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    600 mg/day

    Arm title
    		 c-MET negative
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    AZD6094
    Investigational medicinal product code
    Other name
    savolitinib
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    600 mg/day

    Arm title
    		 c-MET Status Unknown
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    AZD6094
    Investigational medicinal product code
    Other name
    savolitinib
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    600 mg/day

    Number of subjects in period 1
    		c-MET positive c-MET negative c-MET Status Unknown
    Started
    46
    47
    16
    Completed
    46
    47
    16
    Period 2
    Period 2 title
    Full Study
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Safety Analysis Set
    Arm description
    		 All participants who received at least one dose of AZD6094 are included in the Safety Analysis Set
    Arm type
    		 Experimental

    Investigational medicinal product name
    AZD6094
    Investigational medicinal product code
    Other name
    savolitinib
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    600 mg/day

    Arm title
    		 Efficacy Analysis Set
    Arm description
    		 The efficacy analysis set consisted of 84 patients with central laboratory PRCC pathology confirmed and with measurable disease.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AZD6094
    Investigational medicinal product code
    Other name
    savolitinib
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    600 mg/day

    Number of subjects in period 2
    		Safety Analysis Set Efficacy Analysis Set
    Started
    109
    85
    Completed
    109
    85
    Period 3
    Period 3 title
    Pharmacokinetic Study Period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Pharmacokinetic (PK) Analysis Set
    Arm description
    		 The PK analysis set included all patients who received at least one dose of AZD6094 and had at least one AZD6094 plasma concentration measurement.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AZD6094
    Investigational medicinal product code
    Other name
    savolitinib
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    600 mg/day

    Number of subjects in period 3
    		Pharmacokinetic (PK) Analysis Set
    Started
    109
    Completed
    100
    Not completed
    9
         Samples for PK analysis were not collected.
    9

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    c-MET positive
    Reporting group description
    		 -

    Reporting group title
    c-MET negative
    Reporting group description
    		 -

    Reporting group title
    c-MET Status Unknown
    Reporting group description
    		 -

    Reporting group values
    		 c-MET positive c-MET negative c-MET Status Unknown Total
    Number of subjects
    		 46 47 16 109
    Age Categorical
    Units: Subjects
        <=18 years
    		 0 0 0 0
        Between 18 and 65 years
    		 24 26 9 59
        >=65 years
    		 22 21 7 50
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.9 ( 12.88 ) 60.7 ( 10.88 ) 58.5 ( 13.69 ) -
    Gender, Male/Female
    Units: Subjects
        Female
    		 13 11 7 31
        Male
    		 33 36 9 78
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 40 41 15 96
        Black or African American
    		 5 2 1 8
        Asian
    		 0 1 0 1
        Other
    		 1 3 0 4
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 6 6 2 14
        Not Hispanic or Latino
    		 40 41 14 95
    ECOG Performance Status
    ECOG Performance Status: (0) = Fully active; (1) = Restricted in physically strenuous activity; (2) = Ambulatory and capable of self-care; (3) = Capable of limited self-care; (4) = Completely disabled
    Units: Subjects
        PS = 0
    		 19 25 7 51
        PS = 1
    		 27 22 9 58
    PRCC Confirmation from Central Laboratory
    Units: Subjects
        PRCC Confirmed
    		 37 40 8 85
        PRCC Not Confirmed
    		 9 7 8 24
    Stage Classification
    Units: Subjects
        Low
    		 1 4 0 5
        Intermediate
    		 8 12 4 24
        High
    		 13 15 3 31
        Missing
    		 24 16 9 49
    Renal Cell Classification
    Units: Subjects
        Type I papillary RCC
    		 12 2 2 16
        Type II papillary RCC
    		 25 38 6 69
        Missing or Unknown
    		 9 7 8 24
    MSKCC risk group
    Risk categories for patients were obtained from the Memorial Sloan Kettering Cancer Center (MSKCC) risk category prognostic model in advanced renal cell cancer, as follows: Favourable risk = 0 risk factors; Intermediate risk = 1 or 2 risk factors; Poor risk = 3 or more risk factors. Risk factors include: Karnofsky performance status < 80%; time from diagnosis to salvage treatment < 1 year; haemoglobin < LLN; corrected serum calcium > ULN; and serum LDH > 1.5 x ULN.
    Units: Subjects
        Favourable risk
    		 3 10 2 15
        Intermediate risk
    		 28 14 7 49
        Poor risk
    		 3 5 2 10
        Missing
    		 12 18 5 35
    Age Continuous |
    Units: years
        median (full range (min-max))
    		 64 (23 to 87) 64 (29 to 75) 61 (37 to 80) -
    Weight
    Units: kilograms
        arithmetic mean (standard deviation)
    		 78.42 ( 20.74 ) 85.38 ( 23.84 ) 84.90 ( 12.55 ) -
    Weight
    Units: kilograms
        median (full range (min-max))
    		 76.5 (42 to 134) 83.5 (47 to 160.6) 87.65 (59.3 to 101.6) -

    End points

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    End points reporting groups
    Reporting group title
    c-MET positive
    Reporting group description
    		 -

    Reporting group title
    c-MET negative
    Reporting group description
    		 -

    Reporting group title
    c-MET Status Unknown
    Reporting group description
    		 -
    Reporting group title
    Safety Analysis Set
    Reporting group description
    		 All participants who received at least one dose of AZD6094 are included in the Safety Analysis Set

    Reporting group title
    Efficacy Analysis Set
    Reporting group description
    		 The efficacy analysis set consisted of 84 patients with central laboratory PRCC pathology confirmed and with measurable disease.
    Reporting group title
    Pharmacokinetic (PK) Analysis Set
    Reporting group description
    		 The PK analysis set included all patients who received at least one dose of AZD6094 and had at least one AZD6094 plasma concentration measurement.

    Primary: Objective Response Rate (RECIST Version 1.1) Stratified by c-MET Status in Efficacy Analysis Set (n=85)

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    End point title
    		 Objective Response Rate (RECIST Version 1.1) Stratified by c-MET Status in Efficacy Analysis Set (n=85) [1]
    End point description
    Assess the anti-tumour activity of AZD6094 in patients with PRCC, and in the subgroup of MET-positive patients, as measured by Investigator-assessment of overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumours (RECIST) Version 1.1.
    End point type
    Primary
    End point timeframe
    Up to 12 months
    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 per SAP (Appendix 12.1.9), ORR is defined as the percentage of patients with a confirmed programmatically calculated response of CR or PR. This is presented in this table.No statistical testing undertaken
    End point values
    		 c-MET positive c-MET negative Efficacy Analysis Set c-MET Status Unknown
    Number of subjects analysed
    37
    40
    85
    8
    Units: Percentage
    number (not applicable)
        Complete Response
    0
    0
    0
    0
        Partial Response
    8.1
    0
    3.5
    0
    No statistical analyses for this end point

    Primary: Objective Response Rate (RECIST Version 1.1) Stratified by c-MET Status in Safety Analysis (n=109)

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    End point title
    		 Objective Response Rate (RECIST Version 1.1) Stratified by c-MET Status in Safety Analysis (n=109) [2]
    End point description
    AAssess the anti-tumour activity of AZD6094 in patients with PRCC, and in the subgroup of MET-positive patients, as measured by Investigator-assessment of overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumours (RECIST) Version 1.1.
    End point type
    Primary
    End point timeframe
    Up to 12 months
    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 per CSP dated 4th August 2017, this objective is to characterise the PK of AZD6094 regardless c-MET status
    End point values
    		 c-MET positive Safety Analysis Set c-MET negative c-MET Status Unknown
    Number of subjects analysed
    46
    109
    47
    16
    Units: Percentage
    number (not applicable)
        Complete Response
    0
    0
    0
    0
        Partial Response
    17.4
    7.3
    0
    0
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS) Stratified by c-MET Status in the Efficacy Analysis Set (n = 85)

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    End point title
    		 Progression Free Survival (PFS) Stratified by c-MET Status in the Efficacy Analysis Set (n = 85)
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 12 months
    End point values
    		 c-MET positive c-MET negative Efficacy Analysis Set c-MET Status Unknown
    Number of subjects analysed
    37
    40
    85
    8
    Units: weeks
        median (confidence interval 95%)
    18.3 (12.3 to 35.4)
    9.7 (6.1 to 12.4)
    12.3 (6.7 to 17.6)
    6.1 (5.1 to 999999.9)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) Stratified by c-MET Status in the Efficacy Analysis Set (n = 85)

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    End point title
    		 Overall Survival (OS) Stratified by c-MET Status in the Efficacy Analysis Set (n = 85)
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 12 months
    End point values
    		 c-MET positive c-MET negative c-MET Status Unknown
    Number of subjects analysed
    37
    40
    8
    Units: weeks
        median (confidence interval 95%)
    999999.9 (34.6 to 999999.9)
    61.1 (29.4 to 999999.9)
    51.5 (8.1 to 999999.9)
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS) Stratified by c-MET Status in the Safety Analysis Set (n = 109)

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    End point title
    		 Progression Free Survival (PFS) Stratified by c-MET Status in the Safety Analysis Set (n = 109)
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 12 months
    End point values
    		 c-MET positive c-MET negative c-MET Status Unknown
    Number of subjects analysed
    46
    47
    16
    Units: weeks
        median (confidence interval 95%)
    24.7 (17.7 to 35.4)
    6.6 (6.1 to 11.9)
    12.1 (6.1 to 41.9)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) Stratified by c-MET Status in the Safety Analysis Set (n = 109)

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    End point title
    		 Overall Survival (OS) Stratified by c-MET Status in the Safety Analysis Set (n = 109)
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 12 months
    End point values
    		 c-MET positive c-MET negative c-MET Status Unknown
    Number of subjects analysed
    46
    47
    16
    Units: weeks
        median (confidence interval 95%)
    999999.9 (42.9 to 999999.9)
    61.1 (40.6 to 106.7)
    54.9 (18.4 to 999999.9)
    No statistical analyses for this end point

    Secondary: Change from Baseline in Target Lesion Tumour Size at 12 Weeks in Efficacy Analysis Set (n=85)

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    End point title
    		 Change from Baseline in Target Lesion Tumour Size at 12 Weeks in Efficacy Analysis Set (n=85)
    End point description
    End point type
    Secondary
    End point timeframe
    12 Weeks (at 12 weeks timepoint)
    End point values
    		 c-MET positive c-MET negative c-MET Status Unknown
    Number of subjects analysed
    22
    14
    1
    Units: percentage
        arithmetic mean (standard deviation)
    -6.3 ( 21.56 )
    3.4 ( 20.05 )
    7.1 ( 0 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Target Lesion Tumour Size at 12 Weeks in Safety Analysis Set (n=109)

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    End point title
    		 Change from Baseline in Target Lesion Tumour Size at 12 Weeks in Safety Analysis Set (n=109)
    End point description
    End point type
    Secondary
    End point timeframe
    12 Weeks (at 12 weeks timepoint)
    End point values
    		 c-MET positive c-MET negative c-MET Status Unknown
    Number of subjects analysed
    30
    16
    6
    Units: percentage
        arithmetic mean (standard deviation)
    -10.9 ( 21.39 )
    4.3 ( 18.96 )
    5.1 ( 17.41 )
    No statistical analyses for this end point

    Secondary: Peak Plasma Concentration (Cmax) of AZD6094 Following Single Dose

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    End point title
    		 Peak Plasma Concentration (Cmax) of AZD6094 Following Single Dose
    End point description
    End point type
    Secondary
    End point timeframe
    24 Hours
    End point values
    		 Pharmacokinetic (PK) Analysis Set
    Number of subjects analysed
    53
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        AZD6094 peak plasma concentration
    3038.8984 ( 44.4184 )
    No statistical analyses for this end point

    Secondary: Time to Peak Plasma Concentration (tmax) of AZD6094 After Single Dose

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    End point title
    		 Time to Peak Plasma Concentration (tmax) of AZD6094 After Single Dose
    End point description
    End point type
    Secondary
    End point timeframe
    24 Hours
    End point values
    		 Pharmacokinetic (PK) Analysis Set
    Number of subjects analysed
    53
    Units: Hours
        median (full range (min-max))
    2.0 (0.5 to 8.0)
    No statistical analyses for this end point

    Secondary: Apparent Volume of Distribution of AZD6094 Following Single Dose

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    End point title
    		 Apparent Volume of Distribution of AZD6094 Following Single Dose
    End point description
    End point type
    Secondary
    End point timeframe
    24 Hours
    End point values
    		 Pharmacokinetic (PK) Analysis Set
    Number of subjects analysed
    19
    Units: Liters
        arithmetic mean (standard deviation)
    137.4237 ( 36.5971 )
    No statistical analyses for this end point

    Secondary: Area Under Plasma Concentration Time Curve for AZD6094 After Single Dose

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    End point title
    		 Area Under Plasma Concentration Time Curve for AZD6094 After Single Dose
    End point description
    End point type
    Secondary
    End point timeframe
    24 Hours
    End point values
    		 Pharmacokinetic (PK) Analysis Set
    Number of subjects analysed
    19
    Units: h*ng/mL
        geometric mean (geometric coefficient of variation)
    13144.7381 ( 36.4328 )
    No statistical analyses for this end point

    Secondary: Area Under Plasma Concentration Time Curve for AZD6094 After Single Dose (time zero to last measurement)

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    End point title
    		 Area Under Plasma Concentration Time Curve for AZD6094 After Single Dose (time zero to last measurement)
    End point description
    End point type
    Secondary
    End point timeframe
    24 Hours
    End point values
    		 Pharmacokinetic (PK) Analysis Set
    Number of subjects analysed
    53
    Units: h*ng/mL
        geometric mean (geometric coefficient of variation)
    13214.2441 ( 46.4616 )
    No statistical analyses for this end point

    Secondary: Apparent Total Clearance of AZD6094 from Plasma After Single Dose

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    End point title
    		 Apparent Total Clearance of AZD6094 from Plasma After Single Dose
    End point description
    End point type
    Secondary
    End point timeframe
    24 Hours
    End point values
    		 Pharmacokinetic (PK) Analysis Set
    Number of subjects analysed
    19
    Units: L/hour
        arithmetic mean (standard deviation)
    48.4938 ( 17.3386 )
    No statistical analyses for this end point

    Secondary: Mean Residence Time of AZD6094 After Single Dose

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    End point title
    		 Mean Residence Time of AZD6094 After Single Dose
    End point description
    End point type
    Secondary
    End point timeframe
    24 Hours
    End point values
    		 Pharmacokinetic (PK) Analysis Set
    Number of subjects analysed
    19
    Units: Hours
        arithmetic mean (standard deviation)
    3.9837 ( 0.4813 )
    No statistical analyses for this end point

    Secondary: Elimination Half-Life of AZD6094 After Single Dose

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    End point title
    		 Elimination Half-Life of AZD6094 After Single Dose
    End point description
    End point type
    Secondary
    End point timeframe
    24 Hours
    End point values
    		 Pharmacokinetic (PK) Analysis Set
    Number of subjects analysed
    19
    Units: Hours
        arithmetic mean (standard deviation)
    2.0499 ( 0.3820 )
    No statistical analyses for this end point

    Secondary: Duration of Response

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    End point title
    		 Duration of Response
    End point description
    Duration of Response is the time from the first documentation of CR/PR until the date of progression, or death in the absence of progression. There were 8 responders: one of whom subsequently progressed or died and seven of whom were still classified as responders at the time of data cut-off and were therefore censored. It was not possible to determine a median or 75th percentile.
    End point type
    Secondary
    End point timeframe
    Up to 12 months
    End point values
    		 Safety Analysis Set
    Number of subjects analysed
    8 [3]
    Units: weeks
        median (inter-quartile range (Q1-Q3))
    999999.9 (18.1 to 999999.9)
    Notes
    [3] - The median was not calculable because at data cut-off some participants were still responding.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 12 months
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    AZD6094 600 mg per day orally
    Reporting group description
    		 -

    Serious adverse events
    		 AZD6094 600 mg per day orally
    Total subjects affected by serious adverse events
         subjects affected / exposed
    27 / 109 (24.77%)
         number of deaths (all causes)
    59
         number of deaths resulting from adverse events
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Rectal cancer
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Pain
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oedema
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Confused memory and fantasy
    Additional description: Reporting PT: Confusional State
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Transaminases increased
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Pericarditis
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Hepatic encephalopathy
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Consciousness loss
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 109 (2.75%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal incarcerated hernia
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ascites
         subjects affected / exposed
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Small intestine carcinoma
    Additional description: Reporting PT Term: Small Intestinal Obstruction
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    4 / 109 (3.67%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Flank pain
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung Infection
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyperkalemia
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 AZD6094 600 mg per day orally
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    107 / 109 (98.17%)
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    18 / 109 (16.51%)
         occurrences all number
    30
    Aspartate aminotransferase increased
         subjects affected / exposed
    15 / 109 (13.76%)
         occurrences all number
    29
    Weight decreased
         subjects affected / exposed
    14 / 109 (12.84%)
         occurrences all number
    18
    Alanine aminotransferase increased
         subjects affected / exposed
    12 / 109 (11.01%)
         occurrences all number
    29
    Weight increased
         subjects affected / exposed
    8 / 109 (7.34%)
         occurrences all number
    14
    Blood alklaine phosphatase increased
         subjects affected / exposed
    7 / 109 (6.42%)
         occurrences all number
    8
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    11 / 109 (10.09%)
         occurrences all number
    11
    Dysgeusia
         subjects affected / exposed
    9 / 109 (8.26%)
         occurrences all number
    10
    Headache
         subjects affected / exposed
    8 / 109 (7.34%)
         occurrences all number
    9
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    17 / 109 (15.60%)
         occurrences all number
    31
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    49 / 109 (44.95%)
         occurrences all number
    63
    Peripheral oedema
         subjects affected / exposed
    35 / 109 (32.11%)
         occurrences all number
    69
    Asthenia
         subjects affected / exposed
    8 / 109 (7.34%)
         occurrences all number
    17
    Oedema
         subjects affected / exposed
    8 / 109 (7.34%)
         occurrences all number
    9
    Chest pain
         subjects affected / exposed
    7 / 109 (6.42%)
         occurrences all number
    7
    Mucosal inflammation
         subjects affected / exposed
    6 / 109 (5.50%)
         occurrences all number
    6
    Pain
         subjects affected / exposed
    5 / 109 (4.59%)
         occurrences all number
    8
    Chills
         subjects affected / exposed
    5 / 109 (4.59%)
         occurrences all number
    7
    Pyrexia
         subjects affected / exposed
    5 / 109 (4.59%)
         occurrences all number
    6
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    56 / 109 (51.38%)
         occurrences all number
    81
    Vomiting
         subjects affected / exposed
    34 / 109 (31.19%)
         occurrences all number
    51
    Constipation
         subjects affected / exposed
    29 / 109 (26.61%)
         occurrences all number
    31
    Diarrhoea
         subjects affected / exposed
    18 / 109 (16.51%)
         occurrences all number
    21
    Abdominal pain
         subjects affected / exposed
    9 / 109 (8.26%)
         occurrences all number
    20
    Abdominal distension
         subjects affected / exposed
    6 / 109 (5.50%)
         occurrences all number
    11
    Stomatitis
         subjects affected / exposed
    6 / 109 (5.50%)
         occurrences all number
    7
    Ascites drainage
         subjects affected / exposed
    5 / 109 (4.59%)
         occurrences all number
    6
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    16 / 109 (14.68%)
         occurrences all number
    18
    Dyspnoea
         subjects affected / exposed
    16 / 109 (14.68%)
         occurrences all number
    27
    Dyspnoea exertional
         subjects affected / exposed
    11 / 109 (10.09%)
         occurrences all number
    12
    Pleural effusion
         subjects affected / exposed
    5 / 109 (4.59%)
         occurrences all number
    6
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    11 / 109 (10.09%)
         occurrences all number
    21
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    5 / 109 (4.59%)
         occurrences all number
    5
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    16 / 109 (14.68%)
         occurrences all number
    20
    Arthalgia
         subjects affected / exposed
    13 / 109 (11.93%)
         occurrences all number
    24
    Musculoskeletal chest pain
         subjects affected / exposed
    9 / 109 (8.26%)
         occurrences all number
    10
    Pain in extremity
         subjects affected / exposed
    11 / 109 (10.09%)
         occurrences all number
    21
    Flank pain
         subjects affected / exposed
    9 / 109 (8.26%)
         occurrences all number
    14
    Musculoskeletal pain
         subjects affected / exposed
    10 / 109 (9.17%)
         occurrences all number
    11
    Muscle spasm
         subjects affected / exposed
    7 / 109 (6.42%)
         occurrences all number
    7
    Myalgia
         subjects affected / exposed
    6 / 109 (5.50%)
         occurrences all number
    6
    Metabolism and nutrition disorders
    Hypoalbuminaemia
         subjects affected / exposed
    13 / 109 (11.93%)
         occurrences all number
    20
    Decreased appetite
         subjects affected / exposed
    25 / 109 (22.94%)
         occurrences all number
    37
    Hyperglycaemia
         subjects affected / exposed
    8 / 109 (7.34%)
         occurrences all number
    14
    Hyponatraemia
         subjects affected / exposed
    8 / 109 (7.34%)
         occurrences all number
    12
    Hyperkalemia
         subjects affected / exposed
    7 / 109 (6.42%)
         occurrences all number
    16
    Hypomagneseama
         subjects affected / exposed
    6 / 109 (5.50%)
         occurrences all number
    9
    Fluid balance positive
         subjects affected / exposed
    5 / 109 (4.59%)
         occurrences all number
    8

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Mar 2014
    Amendment 1 revised the protocol as follows: 1) Exclude any patient receiving strong CYP1A2 inhibitor within 2 weeks prior to entry and instructions for investigators to advise patients to avoid concomitant use of strong CYP1A2 because CYP1A2 is active in the formation of metabolite M2; 2) Amended dose modification criteria to discontinue AZD6094 for patients who develop ≥ Grade 3 toxicity that does not resolve to ≤ Grade 1 within 2 weeks; 3) An echocardiogram or MUGA scan to assess LVEF will be conducted at Screening – Baseline and 12 weeks after study start; 4) Thyroid Stimulating Hormone (TSH), Free Thyroxine (Free T4) and Lactate Dehydrogenase (LDH) were added to the standard laboratory safety assessment panel; 5) An assessment of risk criteria in accordance with the Memorial Sloan Kettering Cancer Centre (MSKCC) risk category prognostic model in advanced renal cell cancer was added.
    18 Dec 2014
    Amendment 2 revised the protocol as follows: 1) The section regarding risk minimization activities was revised to add hepatic encephalopathy and to include information regarding a fatal event of hepatic encephalopathy; 2) Inclusion criteria regarding patients with known tumour thrombus or deep vein thrombosis (DVT) are eligible if stable on low molecular weight heparin (LMWH) for ≥ 2 weeks; 3) Revised exclusion criteria to allow patients with limited prior or current treatment with a c-MET inhibitor to enter the study if discussed with the Medical Monitor; 4) The section regarding restrictions during the study was revised to specify that acetaminophen (paracetamol) daily dose was limited to 3 grams/day or the maximum dose approved locally (if less than 3 grams/day) during the study; 5) The section regarding restrictions during the study was revised to specify that patients should abstain from eating large amounts of grapefruit or Seville oranges (and other products containing these fruits [e.g., juice or marmalade] during the study; 6) Advise Investigators to review the patient's concomitant medications, and evaluate the need for the patient to continue on hepatic metabolism modifying agents, such as statins; 7) The study plan was revised to include additional liver function monitoring; 8) To specify that patients should be in a fasted state at Cycle 1 Day 8 at 2-3 hours post-dose for the collection of a biopsy sample and blood for a PK sample.
    05 Jun 2015
    Amendment 3 revised the protocol as follows: 1) Information regarding safety, efficacy, and potential benefit in humans was updated to align with the Investigator's Brochure; 2) Include information on the potential for drug-drug interactions; 3) The primary and secondary objectives of the study were revised to include tumour assessment in the subgroup of MET-positive patients.; 4) The futility threshold for continuation of the study to Stage 2 was revised slightly; 5) The protocol was clarified to provide further detail on the non-binding futility analysis to be conducted after 20 evaluable patients were enrolled, marking the completion of Stage 1; 6) Formal hypothesis testing was added - if the study passes the futility analysis at the end of Stage 1, than the end-of-study analysis will be performed on the total data from the patients in both stages 1 and 2 combined; 7) At the end of the study the primary end-point (ORR) will be tested against the null hypothesis Ho; ORR ≤ 25% at the one-sided significance level of α = 0.025 in two populations as co-primary objectives; the total population of confirmed PRCC patients and the subgroup of MET positive PRCC patients; 8) The sample size was expanded to a total of 75 evaluable patients provided the futility analysis of Stage 1 was satisfied.
    18 Apr 2016
    Amendment 4 revised the protocol as follows: 1) Extended follow-up and response assessments for patients without disease progression at the time of discontinuing study treatment was added; 2) The collection of urine for PK analysis was clarified.
    27 May 2016
    Amendment 5 revised the protocol as follows: New information on drug-drug interactions was included (metformin, digoxin, quinidine, loperamide, saquinavir and ritonavir). AZD6094 is a weak inhibitor of OATP1B1, OATP1B3 and BCRP in vitro, and the use of statins should be avoided as far as possible; AZD6094 is also an inhibitor of MATE1 and MATE2K, thus metformin should be used with caution in case of increased metformin exposure.
    05 Dec 2016
    Amendment 6 revised the protocol as follows: 1) New information and guidance regarding Stevens-Johnson syndrome was added; 2) Guidance for hepatotoxicity and dose modifications was updated and revised; 3) Investigator guidance for end of study access to the investigational drug was added and post database lock procedures for patients continuing to receive study drug.

    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.
    The secondary endpoint overall survival in both the Safety Analysis Set and the Efficacy Analysis could not be calculated as a finite number. Due to limitations of the EudraCT it was entered 999999.9 as system doesn’t recognise values like N/A.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/28644771
    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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