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    Clinical Trial Results:
    A Cancer Research UK Phase I/II Open Label Study to Evaluate the Safety, Endocrine Effects and Anti-tumour Activity of Abiraterone Acetate (CB7630) in Patients with Oestrogen (ER) or Androgen Receptor (AR) Positive Advanced or Metastatic Breast Carcinoma.

    Summary
    EudraCT number
    		 2007-003240-30
    Trial protocol
    		 GB  
    Global end of trial date
    04 Jun 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Feb 2017
    First version publication date
    17 Feb 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CR9304-21
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00755885
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Cancer Research UK
    Sponsor organisation address
    407 St John Street, London, United Kingdom, EC1V 4AD
    Public contact
    Centre for Drug Development, Cancer Research UK, +44 02072420200, regquery@cancer.org.uk
    Scientific contact
    Centre for Drug Development, Cancer Research UK, +44 02072420200, regquery@cancer.org.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
    30 Sep 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Jun 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Jun 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of this trial in post-menopausal women with ER+ or AR+ advanced or metastatic breast cancer were: Phase I 1. To determine and establish the safety profile and tolerability of abiraterone acetate administered orally continuously in a once-daily regimen. 2. To recommend a trial dose for the Phase II evaluation. Phase II 1. To evaluate the clinical benefit of abiraterone acetate at 24 weeks (i.e. after six cycles of treatment). 2. To further determine the safety profile and tolerability of abiraterone acetate administered orally continuously in a once-daily regimen.
    Protection of trial subjects
    None
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Nov 2008
    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 Kingdom: 77
    Worldwide total number of subjects
    77
    EEA total number of subjects
    77
    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)
    52
    From 65 to 84 years
    22
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 For the overall trial participants were enrolled from 05 November 2008 to 30 May 2014 in seven clinical study centres in the UK. Study participants for the Phase I part of the trial were only enrolled at two of the seven clinical study centres whereas participants for the Phase II part were enrolled across all seven clinical study centres.

    Pre-assignment
    Screening details
    		 Post-menopausal females with histologically/cytologically proven advanced/metastatic breast cancer with either ER+ (any AR status) or ER- (AR+) disease confirmed by immunohistochemistry. Patients had to have received previous treatment in the adjuvant or metastatic setting, have a WHO performance status of 0-2 and life expectancy of ≥3 months.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Phase I
    Arm description
    		 Phase I dose escalation part of the trial to evaluate the safety profile of abiraterone and identify a recommended dose for Phase II investigation. Incremental dose steps of 100% from the starting dose of 250 mg, 500 mg, 1000 mg and 2000 mg were studied.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Abiraterone acetate
    Investigational medicinal product code
    CB7630
    Other name
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Abiraterone acetate was taken orally 1 hour before breakfast once daily in a continuous 28-day cycle for all patients participating in the trial. At the start of the trial, abiraterone acetate was supplied as a simple formulation of capsules containing 250 mg of abiraterone acetate encapsulated in a gelatin capsule. Following a change in manufacturing in 2010 (Protocol Amendment 05), abiraterone acetate was supplied as tablets composed of 250 mg of abiraterone acetate and non-active ingredients (excipients). All the Phase I patients commenced treatment with the capsule formulation, with only five patients receiving both formulations. All Phase II patients received the tablet formulation.

    Arm title
    		 Phase II
    Arm description
    		 Phase II part of the trial was a Gehan two-stage study design to evaluate the clinical benefit of abiraterone acetate in the two cohorts of patients ER+ (any AR status) and ER- (AR+) disease. The starting dose for Phase II evaluation was to be established from the Phase I part of the trial, or if the maximum tolerated dose (MTD) of abiraterone acetate was not reached during the Phase I part of the trial, a daily dose of 1000 mg abiraterone acetate was to be used for further evaluation.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Abiraterone acetate
    Investigational medicinal product code
    CB7630
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Abiraterone acetate was taken orally 1 hour before breakfast once daily in a continuous 28-day cycle for all patients participating in the trial. At the start of the trial, abiraterone acetate was supplied as a simple formulation of capsules containing 250 mg of abiraterone acetate encapsulated in a gelatin capsule. Following a change in manufacturing in 2010 (Protocol Amendment 05), abiraterone acetate was supplied as tablets composed of 250 mg of abiraterone acetate and non-active ingredients (excipients). All the Phase I patients commenced treatment with the capsule formulation, with only five patients receiving both formulations. All Phase II patients received the tablet formulation.

    Number of subjects in period 1 [1]
    		Phase I Phase II
    Started
    25
    50
    Completed
    25
    50
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Only the safety population (i.e. enrolled patients who received abiraterone acetate) have been included (n=75). Two enrolled patients were withdrawn prior to the start of administration of abiraterone acetate (one patient in the Phase I part due to an AE of hydronephrosis and one patient in the Phase II part due to evidence of disease progression).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase I
    Reporting group description
    		 Phase I dose escalation part of the trial to evaluate the safety profile of abiraterone and identify a recommended dose for Phase II investigation. Incremental dose steps of 100% from the starting dose of 250 mg, 500 mg, 1000 mg and 2000 mg were studied.

    Reporting group title
    Phase II
    Reporting group description
    		 Phase II part of the trial was a Gehan two-stage study design to evaluate the clinical benefit of abiraterone acetate in the two cohorts of patients ER+ (any AR status) and ER- (AR+) disease. The starting dose for Phase II evaluation was to be established from the Phase I part of the trial, or if the maximum tolerated dose (MTD) of abiraterone acetate was not reached during the Phase I part of the trial, a daily dose of 1000 mg abiraterone acetate was to be used for further evaluation.

    Reporting group values
    		 Phase I Phase II Total
    Number of subjects
    		 25 50 75
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 19 32 51
        From 65-84 years
    		 6 15 21
        85 years and over
    		 0 3 3
    Gender categorical
    Units: Subjects
        Female
    		 25 50 75
        Male
    		 0 0 0
    ER/AR disease type
    Patient's intra-tumoural ER and AR expression (ER+ [any AR status] and ER-[AR+]) disease type.
    Units: Subjects
        ER+ (any AR status)
    		 23 26 49
        ER-(AR+)
    		 2 24 26
    Subject analysis sets

    Subject analysis set title
    Overall Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All enrolled patients for the overall trial who received at least one dose of abiraterone acetate.

    Subject analysis set title
    Phase II Response Population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All patients in the Phase II part of the study who were evaluable for tumour response (i.e. patients who had received at least two cycles of abiraterone acetate and had not missed more than 14 days of abiraterone treatment in one cycle).

    Subject analysis set title
    Phase I Pharmacokinetic Population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All enrolled and eligible patients who received at least one cycle of abiraterone acetate at doses ranging from 250 mg to 2000 mg and provided pre- and post-dose pharmacokinetic plasma samples.

    Subject analysis set title
    Endocrine Profile Population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All enrolled eligible patients in the Phase I and II parts of the trial who received abiraterone acetate and provided pre- and post-treatment blood samples.

    Subject analysis sets values
    		 Overall Safety Population Phase II Response Population Phase I Pharmacokinetic Population Endocrine Profile Population
    Number of subjects
    75
    40
    23
    69
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    51
    27
    17
    48
        From 65-84 years
    21
    11
    6
    18
        85 years and over
    3
    2
    0
    3
    Age continuous
    Units:
        
    ( )
    ( )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    75
    40
    23
    69
        Male
    0
    0
    0
    0
    ER/AR disease type
    Patient's intra-tumoural ER and AR expression (ER+ [any AR status] and ER-[AR+]) disease type.
    Units: Subjects
        ER+ (any AR status)
    49
    22
    21
    48
        ER-(AR+)
    26
    18
    2
    21

    End points

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    End points reporting groups
    Reporting group title
    Phase I
    Reporting group description
    		 Phase I dose escalation part of the trial to evaluate the safety profile of abiraterone and identify a recommended dose for Phase II investigation. Incremental dose steps of 100% from the starting dose of 250 mg, 500 mg, 1000 mg and 2000 mg were studied.

    Reporting group title
    Phase II
    Reporting group description
    		 Phase II part of the trial was a Gehan two-stage study design to evaluate the clinical benefit of abiraterone acetate in the two cohorts of patients ER+ (any AR status) and ER- (AR+) disease. The starting dose for Phase II evaluation was to be established from the Phase I part of the trial, or if the maximum tolerated dose (MTD) of abiraterone acetate was not reached during the Phase I part of the trial, a daily dose of 1000 mg abiraterone acetate was to be used for further evaluation.

    Subject analysis set title
    Overall Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All enrolled patients for the overall trial who received at least one dose of abiraterone acetate.

    Subject analysis set title
    Phase II Response Population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All patients in the Phase II part of the study who were evaluable for tumour response (i.e. patients who had received at least two cycles of abiraterone acetate and had not missed more than 14 days of abiraterone treatment in one cycle).

    Subject analysis set title
    Phase I Pharmacokinetic Population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All enrolled and eligible patients who received at least one cycle of abiraterone acetate at doses ranging from 250 mg to 2000 mg and provided pre- and post-dose pharmacokinetic plasma samples.

    Subject analysis set title
    Endocrine Profile Population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All enrolled eligible patients in the Phase I and II parts of the trial who received abiraterone acetate and provided pre- and post-treatment blood samples.

    Primary: Safety

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    End point title
    		 Safety [1]
    End point description
    The causality and severity grading of each adverse event (AE) to abiraterone acetate, according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. AEs with a causality of possibly, probably or almost certainly related were considered to indicate relatedness. Dose limiting toxicity (DLT) was defined as almost certainly or probably related to abiraterone acetate and occurring during Cycle 1: a) Absolute neutrophil count <0.5 x 10^9/L for more than 7 days or <0.5 x 10^9/L with neutropenic fever/sepsis. b) Platelet count <25 x 10^9/L. c) Non-haematological ≥Grade 3 toxicity excluding Grade 3 fatigue, nausea, vomiting, diarrhoea, myalgia, arthralgia (in patients who had not received prophylactic/therapeutic measures). d) Toxicities due to elevated mineralocorticoids if concurrent therapeutic measures failed to suppress the ACTH feedback loop. e) Grade 4 hypertension. f) Any toxicity deemed by the Sponsor/Investigators as a DLT.
    End point type
    Primary
    End point timeframe
    From patient consent to 28 days post last dose of abiraterone acetate.
    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: All safety data were presented in a descriptive fashion, with AEs presented by CTCAE adverse event term by worst grade observed.
    End point values
    		 Phase I Phase II Overall Safety Population
    Number of subjects analysed
    25
    50
    75
    Units: Number of AEs
        All AEs
    251
    551
    802
        Related AEs
    56
    185
    241
        DLTs
    0
    0
    0
    No statistical analyses for this end point

    Primary: Clinical benefit rate at 24 weeks

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    End point title
    		 Clinical benefit rate at 24 weeks [2]
    End point description
    For the Phase II part of the trial only, the determination of the number of patients with an objective response (partial response, complete response or stable disease) after six cycles of abiraterone acetate (i.e. at least 24 weeks) according to RECIST (Version 1.0).
    End point type
    Primary
    End point timeframe
    From the start of abiraterone acetate daily dosing until at least 24 weeks (i.e. six cycles of treatment).
    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: Proportion of Phase II patients with an objective response after six cycles presented as per the study protocol.
    End point values
    		 Phase II Response Population
    Number of subjects analysed
    40
    Units: Number of patients
        Objective response (ER+ [any AR])
    4
        No objective response (ER+ [any AR])
    18
        Objective response (ER- [AR+])
    2
        No objective response (ER- [AR+])
    16
    No statistical analyses for this end point

    Secondary: Tumour response

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    End point title
    		 Tumour response
    End point description
    All patients who met eligibility criteria, received at least two cycles of abiraterone acetate (56 days continuous daily dosing), had a baseline assessment of disease and at least one repeat disease assessment were evaluable for response. A patient in Phase I must have received at least 21 of the 28 days of dosing in the first cycle and patients in the Phase II part of the trial were considered to be evaluable for response as long as they had not missed >14 days of treatment in one cycle. Any response, complete response (CR) or partial response (PR), or stable disease (SD), in any of the patients was defined by Response Evaluation Criteria in Solid Tumours (RECIST). For a status of CR or PR, changes in tumour measurements had to be confirmed by repeat measurements performed no less than 4 weeks after the response criteria were met. For a status of SD, follow-up measurements had to meet SD criteria at least once and at least 8 weeks after study treatment had started.
    End point type
    Secondary
    End point timeframe
    From baseline assessment and then after every two cycles.
    End point values
    		 Phase I Phase II
    Number of subjects analysed
    25
    50
    Units: Number of patients
        Complete Response
    0
    0
        Partial Response
    1
    0
        Stable Disease
    5
    25
        Progressive Disease
    12
    15
        Early Progression
    1
    2
        Not Evaluable
    6
    8
    No statistical analyses for this end point

    Secondary: Abiraterone acetate pharmacokinetic profile

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    End point title
    		 Abiraterone acetate pharmacokinetic profile
    End point description
    Performed in patients enrolled in the Phase I dose escalation part of the trial, who received at least one cycle of abiraterone acetate and provided pre- and post-dose pharmacokinetic plasma samples. Pharmacokinetic parameters estimated included: time of maximum observed concentration (Tmax), maximum concentration (Cmax), terminal half-life of the drug (HL Lamda z), area under the concentration v time curve from time of dosing to the last measureable concentration (AUClast), area under the concentration v time curve from time of dosing extrapolated to infinity (AUCINF obs), total body clearance (Cl F obs) and volume of distribution (Vz F obs).
    End point type
    Secondary
    End point timeframe
    Pre-treatment (within one week prior to dosing), Cycle 1 Day 1 through to Cycle 2 Day 1 and off-study.
    End point values
    		 Phase I Pharmacokinetic Population
    Number of subjects analysed
    23
    Units: Number of patients
        Dose level 250 mg
    6
        Dose Level 500 mg
    6
        Dose Level 1000 mg
    5
        Dose Level 2000 mg
    6
    Attachments
    		 Untitled (Filename: CR9304-21 Mean Pharmacokinetc Parameters for Abiraterone Acetate.pdf)
    No statistical analyses for this end point

    Secondary: Two-year survival

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    End point title
    		 Two-year survival [3]
    End point description
    Two-year survival was measured for all eligible patients in the Phase II part of the trial who received abiraterone acetate (measured from the date of their first dose of abiraterone acetate).
    End point type
    Secondary
    End point timeframe
    For the Phase II patients only, two-year survival measured from Cycle 1 Day 1 of abiraterone acetate administration.
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The evaluation of two-year survival was only evaluated for patients in the Phase II part of the trial as defined in the study protocol.
    End point values
    		 Phase II
    Number of subjects analysed
    50
    Units: months
    median (full range (min-max))
        ER+ (any AR) patients
    7.8 (1.3 to 19.8)
        ER- (AR+) patients
    8.2 (0.8 to 21.6)
        All Phase II patients
    7.9 (0.8 to 21.6)
    No statistical analyses for this end point

    Secondary: Endocrine impact of abiraterone acetate

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    End point title
    		 Endocrine impact of abiraterone acetate
    End point description
    All eligible patients in the Phase I and II parts of the trial who received abiraterone acetate and provided pre- and post-treatment blood samples were examined to assess the endocrine impact of abiraterone acetate on the pituitary-adrenal-gonad endocrine axis to determine the relationship with dose (Phase I) and tumour response rates (Phase II). Blood samples were taken to measure the endocrine levels of the following: oestrone, oestradiol [oestradiol-17 beta, E2], 17-OH-progesterone, testosterone, cortisol, corticosterone, androstenedione, dehydroepiandrosterone (DHEA), DHEA-sulphate, lutenising hormone, follicle stimulating hormone, and sex hormone binding globulin.
    End point type
    Secondary
    End point timeframe
    Blood samples were taken at baseline, Cycle 1 and throughout the trial until the time of disease progression.
    End point values
    		 Endocrine Profile Population
    Number of subjects analysed
    69
    Units: Number of Patients
        Phase I pateints
    25
        Phase II patients
    44
    Attachments
    		 Untitled (Filename: Abiraterone Endocrine Profile CSR extract _prepared_31Jan2017.pdf)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From patient consent to 28 days post last dose of abiraterone acetate.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    3.0
    Reporting groups
    Reporting group title
    Phase I
    Reporting group description
    		 Phase I dose escalation part of the trial to evaluate the safety profile of abiraterone and identify a recommended dose for Phase II investigation. Incremental dose steps of 100% from the starting dose of 250 mg, 500 mg, 1000 mg and 2000 mg were studied.

    Reporting group title
    Phase II
    Reporting group description
    		 Phase II part of the trial was a Gehan two-stage study design to evaluate the clinical benefit of abiraterone acetate in the two cohorts of patients ER+ (any AR status) and ER- (AR+) disease. The starting dose for Phase II evaluation was to be established from the Phase I part of the trial, or if the maximum tolerated dose (MTD) of abiraterone acetate was not reached during the Phase I part of the trial, a daily dose of 1000 mg abiraterone acetate was to be used for further evaluation.

    Reporting group title
    Overall Trial
    Reporting group description
    		 All patients treated with abiraterone acetate in both parts of the trial (Phase I and II).

    Serious adverse events
    		 Phase I Phase II Overall Trial
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 25 (44.00%)
    21 / 50 (42.00%)
    32 / 75 (42.67%)
         number of deaths (all causes)
    1
    4
    5
         number of deaths resulting from adverse events
    0
    0
    0
    Vascular disorders
    Thrombosis/thrombus/embolism
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 50 (2.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    General disorders and administration site conditions
    Oedema limb
         subjects affected / exposed
    0 / 25 (0.00%)
    3 / 50 (6.00%)
    3 / 75 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 50 (4.00%)
    2 / 75 (2.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fever
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 50 (4.00%)
    2 / 75 (2.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death - disease progression
         subjects affected / exposed
    1 / 25 (4.00%)
    2 / 50 (4.00%)
    3 / 75 (4.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
    Immune system disorders
    Allergy - other specify
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 50 (2.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    3 / 25 (12.00%)
    4 / 50 (8.00%)
    7 / 75 (9.33%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 4
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 50 (2.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Hypotension
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 50 (0.00%)
    2 / 75 (2.67%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Left ventricular systolic dysfunction
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 50 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 50 (2.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mood anxiety
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 50 (2.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neurology - other specify
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 50 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 50 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain - neuralgia/peripheral
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 50 (2.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 25 (4.00%)
    4 / 50 (8.00%)
    5 / 75 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 50 (2.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Distension
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 50 (4.00%)
    2 / 75 (2.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 50 (2.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 50 (2.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain - abdomen not otherwise specified
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 50 (2.00%)
    2 / 75 (2.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain - peritoneum
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 50 (2.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 50 (2.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Obstruction gentiourinary - ureter
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 50 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 50 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Endocrine - other specify
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 50 (2.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal - extremity lower
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 50 (2.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain - back
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 50 (2.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain - bone
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 50 (2.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain - chest wall
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 50 (2.00%)
    2 / 75 (2.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Infection - other specify
         subjects affected / exposed
    2 / 25 (8.00%)
    4 / 50 (8.00%)
    6 / 75 (8.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection normal ANC - catheter-related
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 50 (2.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    2 / 25 (8.00%)
    5 / 50 (10.00%)
    7 / 75 (9.33%)
         occurrences causally related to treatment / all
    2 / 2
    4 / 5
    6 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bilirubin
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 50 (2.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Phase I Phase II Overall Trial
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 25 (100.00%)
    49 / 50 (98.00%)
    74 / 75 (98.67%)
    Investigations
    Weight gain
         subjects affected / exposed
    0 / 25 (0.00%)
    5 / 50 (10.00%)
    5 / 75 (6.67%)
         occurrences all number
    0
    6
    6
    Weight loss
         subjects affected / exposed
    4 / 25 (16.00%)
    0 / 50 (0.00%)
    4 / 75 (5.33%)
         occurrences all number
    4
    0
    4
    Cardiac disorders
    Hypertension
         subjects affected / exposed
    1 / 25 (4.00%)
    4 / 50 (8.00%)
    5 / 75 (6.67%)
         occurrences all number
    1
    5
    6
    Hypotension
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 50 (2.00%)
    3 / 75 (4.00%)
         occurrences all number
    2
    1
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    6 / 25 (24.00%)
    7 / 50 (14.00%)
    13 / 75 (17.33%)
         occurrences all number
    6
    7
    13
    Neurology - other specify
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 50 (0.00%)
    2 / 75 (2.67%)
         occurrences all number
    2
    0
    2
    Neuropathy sensory
         subjects affected / exposed
    5 / 25 (20.00%)
    6 / 50 (12.00%)
    11 / 75 (14.67%)
         occurrences all number
    5
    11
    16
    Pain headache
         subjects affected / exposed
    3 / 25 (12.00%)
    3 / 50 (6.00%)
    6 / 75 (8.00%)
         occurrences all number
    5
    3
    8
    Pain neuralgia/peripheral nerve
         subjects affected / exposed
    0 / 25 (0.00%)
    3 / 50 (6.00%)
    3 / 75 (4.00%)
         occurrences all number
    0
    3
    3
    Blood and lymphatic system disorders
    Haemoglobin
         subjects affected / exposed
    3 / 25 (12.00%)
    5 / 50 (10.00%)
    8 / 75 (10.67%)
         occurrences all number
    3
    12
    15
    Neutrophils
         subjects affected / exposed
    2 / 25 (8.00%)
    2 / 50 (4.00%)
    4 / 75 (5.33%)
         occurrences all number
    2
    2
    4
    General disorders and administration site conditions
    Constitutional symptoms - other
         subjects affected / exposed
    0 / 25 (0.00%)
    3 / 50 (6.00%)
    3 / 75 (4.00%)
         occurrences all number
    0
    3
    3
    Fatigue
         subjects affected / exposed
    8 / 25 (32.00%)
    28 / 50 (56.00%)
    36 / 75 (48.00%)
         occurrences all number
    9
    35
    44
    Fever
         subjects affected / exposed
    1 / 25 (4.00%)
    5 / 50 (10.00%)
    6 / 75 (8.00%)
         occurrences all number
    2
    6
    8
    Oedema limb
         subjects affected / exposed
    6 / 25 (24.00%)
    11 / 50 (22.00%)
    17 / 75 (22.67%)
         occurrences all number
    6
    16
    22
    Oedema head and neck
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 50 (2.00%)
    3 / 75 (4.00%)
         occurrences all number
    2
    1
    3
    Pain chest/thorax not otherwise specified
         subjects affected / exposed
    2 / 25 (8.00%)
    2 / 50 (4.00%)
    4 / 75 (5.33%)
         occurrences all number
    2
    2
    4
    Pain - other specify
         subjects affected / exposed
    2 / 25 (8.00%)
    4 / 50 (8.00%)
    6 / 75 (8.00%)
         occurrences all number
    2
    4
    6
    Flu-like syndrome
         subjects affected / exposed
    3 / 25 (12.00%)
    3 / 50 (6.00%)
    6 / 75 (8.00%)
         occurrences all number
    3
    3
    6
    Oedema trunk/genital
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 50 (0.00%)
    2 / 75 (2.67%)
         occurrences all number
    2
    0
    2
    Hypothermia
         subjects affected / exposed
    0 / 25 (0.00%)
    3 / 50 (6.00%)
    3 / 75 (4.00%)
         occurrences all number
    0
    6
    6
    Gastrointestinal disorders
    Anorexia
         subjects affected / exposed
    4 / 25 (16.00%)
    9 / 50 (18.00%)
    13 / 75 (17.33%)
         occurrences all number
    4
    11
    15
    Constipation
         subjects affected / exposed
    7 / 25 (28.00%)
    15 / 50 (30.00%)
    22 / 75 (29.33%)
         occurrences all number
    8
    18
    26
    Diarrhoea
         subjects affected / exposed
    4 / 25 (16.00%)
    8 / 50 (16.00%)
    12 / 75 (16.00%)
         occurrences all number
    5
    12
    17
    Dry mouth
         subjects affected / exposed
    3 / 25 (12.00%)
    6 / 50 (12.00%)
    9 / 75 (12.00%)
         occurrences all number
    3
    6
    9
    Heartburn
         subjects affected / exposed
    2 / 25 (8.00%)
    6 / 50 (12.00%)
    8 / 75 (10.67%)
         occurrences all number
    2
    9
    11
    Nausea
         subjects affected / exposed
    11 / 25 (44.00%)
    18 / 50 (36.00%)
    29 / 75 (38.67%)
         occurrences all number
    16
    23
    39
    Oesophagitis
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 50 (2.00%)
    3 / 75 (4.00%)
         occurrences all number
    2
    1
    3
    Vomiting
         subjects affected / exposed
    6 / 25 (24.00%)
    14 / 50 (28.00%)
    20 / 75 (26.67%)
         occurrences all number
    7
    23
    30
    Pain abdomen not otherwise specified
         subjects affected / exposed
    6 / 25 (24.00%)
    3 / 50 (6.00%)
    9 / 75 (12.00%)
         occurrences all number
    7
    3
    10
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 25 (20.00%)
    12 / 50 (24.00%)
    17 / 75 (22.67%)
         occurrences all number
    6
    14
    20
    Dyspnoea
         subjects affected / exposed
    8 / 25 (32.00%)
    11 / 50 (22.00%)
    19 / 75 (25.33%)
         occurrences all number
    8
    13
    21
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    3 / 25 (12.00%)
    7 / 50 (14.00%)
    10 / 75 (13.33%)
         occurrences all number
    3
    8
    11
    Mood anxiety
         subjects affected / exposed
    1 / 25 (4.00%)
    3 / 50 (6.00%)
    4 / 75 (5.33%)
         occurrences all number
    1
    4
    5
    Mood depression
         subjects affected / exposed
    0 / 25 (0.00%)
    3 / 50 (6.00%)
    3 / 75 (4.00%)
         occurrences all number
    0
    3
    3
    Endocrine disorders
    Hot flashes
         subjects affected / exposed
    5 / 25 (20.00%)
    9 / 50 (18.00%)
    14 / 75 (18.67%)
         occurrences all number
    5
    9
    14
    Musculoskeletal and connective tissue disorders
    Pain back
         subjects affected / exposed
    6 / 25 (24.00%)
    7 / 50 (14.00%)
    13 / 75 (17.33%)
         occurrences all number
    7
    7
    14
    Pain bone
         subjects affected / exposed
    7 / 25 (28.00%)
    3 / 50 (6.00%)
    10 / 75 (13.33%)
         occurrences all number
    9
    5
    14
    Pain chest wall
         subjects affected / exposed
    2 / 25 (8.00%)
    4 / 50 (8.00%)
    6 / 75 (8.00%)
         occurrences all number
    2
    5
    7
    Pain extremity limb
         subjects affected / exposed
    4 / 25 (16.00%)
    9 / 50 (18.00%)
    13 / 75 (17.33%)
         occurrences all number
    4
    10
    14
    Pain joint
         subjects affected / exposed
    7 / 25 (28.00%)
    9 / 50 (18.00%)
    16 / 75 (21.33%)
         occurrences all number
    7
    12
    19
    Pain muscle
         subjects affected / exposed
    0 / 25 (0.00%)
    6 / 50 (12.00%)
    6 / 75 (8.00%)
         occurrences all number
    0
    7
    7
    Infections and infestations
    Infection- other specify
         subjects affected / exposed
    6 / 25 (24.00%)
    11 / 50 (22.00%)
    17 / 75 (22.67%)
         occurrences all number
    8
    17
    25
    Metabolism and nutrition disorders
    ALT
         subjects affected / exposed
    1 / 25 (4.00%)
    4 / 50 (8.00%)
    5 / 75 (6.67%)
         occurrences all number
    1
    4
    5
    AST
         subjects affected / exposed
    2 / 25 (8.00%)
    4 / 50 (8.00%)
    6 / 75 (8.00%)
         occurrences all number
    2
    4
    6
    Hyperkalaemia
         subjects affected / exposed
    0 / 25 (0.00%)
    4 / 50 (8.00%)
    4 / 75 (5.33%)
         occurrences all number
    0
    9
    9
    Hypokalaemia
         subjects affected / exposed
    16 / 25 (64.00%)
    17 / 50 (34.00%)
    33 / 75 (44.00%)
         occurrences all number
    33
    31
    64
    Metabolic/Lab - other specify
         subjects affected / exposed
    1 / 25 (4.00%)
    4 / 50 (8.00%)
    5 / 75 (6.67%)
         occurrences all number
    1
    7
    8

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Dec 2008
    Changes to the inclusion/exclusion criteria, including the amendment to allow ER- patients to be enrolled into the trial and revision of the lower diastolic pressure limit for eligibility and DLT assessment. Addition of anti-tumour activity as a secondary objective in the Phase I part of the trial and removal of immunohistochemistry as a primary assay. DLT criteria amended to include Grade 4 hypertension. Several non-substantial changes made to rectify text omissions and provide further clarifications of the trial schedule.
    30 Oct 2009
    Additional section added to the protocol to describe the management of abnormal liver function tests (LFTs), including the addition of extra blood sampling following observation of Grade 2 abnormal LFTs. Clarification of the dose reduction and delay requirements plus the addition of non-hepatic toxicity relating to the management of hypokalaemia. Time frame and details added to clarify when measures should be taken in the event potassium supplements fail to maintain serum potassium levels.
    11 Feb 2010
    Addition and clarification of the mandated use of prophylactic hydrocortisone during abiraterone acetate administration to manage potential endocrine toxicities, along with clarifications relating to the management of hypokalaemia and hypertension. Further clarification of the protocol sections relating to the observation and management of abnormal LFTs. Change to allow the use of ECHO scans as well as MUGA scans to monitor cardiac function.
    16 Aug 2010
    Addition of four new study centres. Clarification of inclusion/exclusion criteria including previous lines of treatment for malignant disease, persistent Grade 2 toxicities, requirement of an ACTH stimulation test (Phase II) and allowing chest CT to be used as part of the screening evaluations. Additional guidance provided on the long term management of hypertension.
    19 Aug 2010
    Change of formulation from capsules to tablets as continued capsule manufacture was not considered suitable for large scale manufacture.
    12 Sep 2011
    Amendment to the definition of post-menopausal to clarify the accepted scenarios for confirming patient eligibility. Updates to the pharmacodynamic parameters and sampling time points.
    01 May 2013
    Additional guidance regarding the handling of abiraterone acetate and the risk to pregnant women or women who may become pregnant.
    15 Jan 2014
    Survival objective and endpoint amended from 'overall survival' to 'two-year survival' after treatment, along with clarification of the associated change to the definition of End of Trial.
    15 Apr 2014
    Change in manufacturer responsible for packaging, labelling, storage, and dispatch to sites.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported.
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