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    Clinical Trial Results:
    A randomised Phase II study of Enzalutamide (MDV3100) in combination with AZD5363 in Patients with Metastatic Castration - Resistant Prostate Cancer

    Summary
    EudraCT number
    2013-004091-34
    Trial protocol
    GB  
    Global end of trial date
    07 Nov 2022

    Results information
    Results version number
    v1(current)
    This version publication date
    24 Nov 2023
    First version publication date
    24 Nov 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CCR3972
    Additional study identifiers
    ISRCTN number
    ISRCTN17168679
    US NCT number
    NCT02525068
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    ICR-CTSU number: lCR-CTSU/2012/10037, Cancer Research UK Reference Number: CRUKE/12/050, REC reference number: 14/LO/0259
    Sponsors
    Sponsor organisation name
    The Institute of Cancer Research
    Sponsor organisation address
    15 Cotswold Road, Sutton, London, United Kingdom, SM2 5NG
    Public contact
    Alexa Gillman, The Institute of Cancer Research, 44 02087224188, RE-AKT-icrctsu@icr.ac.uk
    Scientific contact
    Alexa Gillman, The Institute of Cancer Research, 44 02087224188, RE-AKT-icrctsu@icr.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    07 Apr 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Apr 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Nov 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Phase I safety run in To find out how safe and how well tolerated the combination treatment of enzalutamide and AZD5363 is. To estimate the maximum dose of AZD5363 that is tolerated in combination with enzalutamide. To identify the dose of AZD5363 to use in the combination treatment in the randomised phase II trial. Randomised phase II To measure the response to AZD5363 + enzalutamide and placebo + enzalutamide. To compare the responses to AZD5363 + enzalutamide and placebo + enzalutamide. Single stage phase II expansion cohort To measure the response to AZD5363 + enzalutamide in patients who have previously progressed on enzalutamide alone
    Protection of trial subjects
    For trial entry and optional tissue donation, patients were given a verbal explanation, discussion and written information. The Principal Investigator at each site was responsible for ensuring written informed consent was obtained for each patient. Eligible patients were given as much time as they needed to consider, ask questions and come to a decision about entering the trial, prior to giving consent for entering the trial. The patient information sheet described which parties would have access to their identifiable personal information and patients were asked to give consent to this. The trial was overseen by an Independent Data Monitoring Committee, who reviewed the accumulating trial data and could recommend stopping the trial if there was any cause for concern about patient safety and if this were the case the patient's oncologist would be notified.
    Background therapy
    Prostate adenocarcinoma is the most common malignancy affecting men in the Western world, with over 570,000 new cases annually and an estimated 94, 000 deaths in Europe in 2008 and 32,050 deaths in the United States. Up to 40% of men initially diagnosed with localized prostate cancer will eventually develop metastases. In patients with advanced disease, androgen deprivation with either orchiectomy or medical castration with GnRH agonists is highly effective in shrinking tumour burden, decreasing prostate-specific antigen (PSA) levels, and enhancing quality of life. However, nearly all patients experience disease progression following hormonal manipulations, and develop castration-resistant prostate cancer (CRPC). Mitoxantrone was the first chemotherapy to show a palliative benefit for patients with CRPC, and was subsequently approved by the US Food and Drug Administration (FDA). In 2003, the TAX327 trial showed, for CRPC patients treated with 3 weekly docetaxel had a survival advantage over mitoxantrone (OS: 19.2 mo. vs. 16.3 mo., p = 0.009). Until recently, cytotoxic chemotherapy had been the only therapy shown to improve survival for patients with CRPC. In the last five years, five novel treatments have shown survival gains in phase III trials, including sipuleucel-T abiraterone acetate, alpharadin, cabazitaxel and enzalutamide.
    Evidence for comparator
    Recent preclinical data suggest that reciprocal crosstalk between the AR and PI3K/AKT signalling pathways occur in PTEN-deficient CRPC. Specifically, activation of the PI3K / AKT pathway can be associated with decreased androgen receptor signalling, and inhibition of the PI3K / AKT pathway increases AR signalling in PTEN-deficient prostate cancer cells. Proposed mechanisms to account for these observations include PI3K / AKT pathway inhibition resulting in feedback activation of AR via the up regulation of HER kinases, while inhibition of AR relieves feedback inhibition of AKT by the phosphatase PHLPP. Such reciprocal cooperativity between PI3K / AKT and AR pathways suggests that the inhibition of either one pathway, without the other, would lead to the achievement of sub-optimal clinical efficacy. Carver and co-workers actually showed that the simultaneous pharmacological inhibition of the PI3K/mTOR pathway and AR caused near complete prostate cancer regression in PTEN-deficient prostate cancer preclinical mouse models. Therefore, the combined inhibition of the AR and PIK3/AKT pathways may result in more complete inhibition of tumour cell viability and potentially more durable clinical benefit in patients with CRPC .
    Actual start date of recruitment
    17 Dec 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 138
    Worldwide total number of subjects
    138
    EEA total number of subjects
    0
    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)
    31
    From 65 to 84 years
    106
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    Phase I: between 12/2014 and 4/2016 16 patients were enrolled from 1 UK site Phase II randomised: between 6/2016 and 11/2019 100 patients were enrolled from 15 UK sites Phase II expansion: between 6/2016 and 5/2018 22 patients were enrolled from 3 UK sites

    Pre-assignment
    Screening details
    Patients that met the eligibility criteria were recruited into the study. Eligible patients had previous diagnosed, histologically confirmed adenocarcinoma of metastatic castration-resistant prostate cancer (mCRPC) with tumour tissue accessible for research analyses for the trial.

    Period 1
    Period 1 title
    RE-AKT trial overall (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Phase I Safety run-in
    Arm description
    This phase is to identify the safety and tolerability of enzalutamide and AZD5363 when given in a combination of once daily enzalutamide (MDV3100) with twice daily AZD5363 administered in a four days on and three days off regimen. And, to identify dose-limiting toxicities (DLTs), estimate the maximum tolerated dose (MTD) and identify a recommended Phase II dose (RP2D) of AZD5363 administered in combination with enzalutamide 160mg daily
    Arm type
    Experimental

    Investigational medicinal product name
    Enzalutimide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    160mg once a day

    Investigational medicinal product name
    AZD5363
    Investigational medicinal product code
    Other name
    Capivasertib
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Dose escalation: Level 1 - 320mg BID 4 days on, three days off Level 2 - 400mg BID 4 days on, three days off Level 3 - 480mg BID 4 days on, three days off

    Arm title
    Phase II Expansion
    Arm description
    Enzalutamide and AZD5363 in patients with previous progression on enzalutamide to explore whether the addition of AZD5363 to enzalutamide can reverse resistance
    Arm type
    Experimental

    Investigational medicinal product name
    Enzalutimide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    160mg once a day

    Investigational medicinal product name
    AZD5363
    Investigational medicinal product code
    Other name
    Capivasertib
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    400mg BID 4 days on, three days off

    Arm title
    Phase II Randomised (AZD5363)
    Arm description
    A randomised, double blind phase II trial of enzalutamide in combination with AZD5363 versus enzalutamide alone will determine if the antitumour activity of the combination therapy is superior to the antitumour activity to enzalutamide alone (enzalutamide + AZD5363 vs. enzalutamide + placebo).
    Arm type
    Experimental

    Investigational medicinal product name
    Enzalutimide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    160mg once a day

    Investigational medicinal product name
    AZD5363
    Investigational medicinal product code
    Other name
    Capivasertib
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    400mg BID 4 days on, three days off

    Arm title
    Phase II Randomised (Placebo)
    Arm description
    A randomised, double blind phase II trial of enzalutamide in combination with AZD5363 versus enzalutamide alone will determine if the antitumour activity of the combination therapy is superior to the antitumour activity to enzalutamide alone (enzalutamide + AZD5363 vs. enzalutamide + placebo).
    Arm type
    Placebo

    Investigational medicinal product name
    Enzalutimide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    160mg once a day

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo BID 4 days on, 3 days off

    Number of subjects in period 1
    Phase I Safety run-in Phase II Expansion Phase II Randomised (AZD5363) Phase II Randomised (Placebo)
    Started
    16
    22
    50
    50
    Completed
    16
    13
    50
    50
    Not completed
    0
    9
    0
    0
         Patients progressed on pre-combination enzalutamid
    -
    9
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase I Safety run-in
    Reporting group description
    This phase is to identify the safety and tolerability of enzalutamide and AZD5363 when given in a combination of once daily enzalutamide (MDV3100) with twice daily AZD5363 administered in a four days on and three days off regimen. And, to identify dose-limiting toxicities (DLTs), estimate the maximum tolerated dose (MTD) and identify a recommended Phase II dose (RP2D) of AZD5363 administered in combination with enzalutamide 160mg daily

    Reporting group title
    Phase II Expansion
    Reporting group description
    Enzalutamide and AZD5363 in patients with previous progression on enzalutamide to explore whether the addition of AZD5363 to enzalutamide can reverse resistance

    Reporting group title
    Phase II Randomised (AZD5363)
    Reporting group description
    A randomised, double blind phase II trial of enzalutamide in combination with AZD5363 versus enzalutamide alone will determine if the antitumour activity of the combination therapy is superior to the antitumour activity to enzalutamide alone (enzalutamide + AZD5363 vs. enzalutamide + placebo).

    Reporting group title
    Phase II Randomised (Placebo)
    Reporting group description
    A randomised, double blind phase II trial of enzalutamide in combination with AZD5363 versus enzalutamide alone will determine if the antitumour activity of the combination therapy is superior to the antitumour activity to enzalutamide alone (enzalutamide + AZD5363 vs. enzalutamide + placebo).

    Reporting group values
    Phase I Safety run-in Phase II Expansion Phase II Randomised (AZD5363) Phase II Randomised (Placebo) Total
    Number of subjects
    16 22 50 50 138
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    70.4 (68 to 72.6) 65.4 (61.9 to 73.2) 72.3 (67.5 to 77.9) 71.5 (67.7 to 76.2) -
    Gender categorical
    Units: Subjects
        Female
    0 0 0 0 0
        Male
    16 22 50 50 138
    Disease status at trial entry
    Disease status presented at trial entry
    Units: Subjects
        Measurable soft-tissue disease (+/- bone lesions)
    10 15 31 25 81
        Non-measurable soft-tissue (+/- bone lesions)
    3 4 10 8 25
        Bone lesions only
    3 3 9 17 32
        Not recorded
    0 0 0 0 0
    Time since histological confirmation of prostate cancer
    Time since confirmation of castrate resistant disease (years) presented as median (IQR)
    Units: Years
        median (inter-quartile range (Q1-Q3))
    6.0 (2.6 to 9.2) 6.3 (3.0 to 13.9) 6.7 (4.2 to 11.1) 5.9 (2.9 to 8.7) -
    Time since confirmation of castrate resistant disease
    Time since confirmation of castrate resistant disease (years), presented as median (IQR)
    Units: Years
        median (inter-quartile range (Q1-Q3))
    4.9 (3.6 to 6.3) 2.7 (1.7 to 4.4) 3.7 (2.4 to 5.4) 3.7 (2.6 to 5.4) -
    PSA at trial entry
    PSA at trial entry (ng/ml) – median (Q1-Q3)
    Units: ng/ml
        median (inter-quartile range (Q1-Q3))
    162 (27.3 to 766) 35.1 (11.0 to 91.0) 144.2 (60 to 240.3) 245 (79.3 to 591) -
    Subject analysis sets

    Subject analysis set title
    Evaluable - randomised phase 2 - AZD5363
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Evaluable population for randomised phase 2 - experimental arm - evaluable for primary endpoint overall response

    Subject analysis set title
    Evaluable - randomised phase 2 - placebo
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Evaluable population for randomised phase 2 - placebo arm - evaluable for primary endpoint overall response

    Subject analysis set title
    Phase I - Dose level 1 - 320mg
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Patients allocated to dose elevel 1 of dose-fiding phase I

    Subject analysis set title
    Phase I - Dose level 2 - 480mg
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Patients allocated to dose elevel 2 of dose-fiding phase I

    Subject analysis set title
    Phase I - Dose level 1A - 400mg
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Patients allocated to dose elevel 1A of dose-fiding phase I

    Subject analysis sets values
    Evaluable - randomised phase 2 - AZD5363 Evaluable - randomised phase 2 - placebo Phase I - Dose level 1 - 320mg Phase I - Dose level 2 - 480mg Phase I - Dose level 1A - 400mg
    Number of subjects
    47
    48
    3
    6
    7
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    72.3 (67.4 to 77.9)
    71.5 (68.0 to 75.7)
    67.7 (66.3 to 74.1)
    68.5 (68.2 to 70.7)
    73.0 (70.8 to 75.2)
    Gender categorical
    Units: Subjects
        Female
    0
    0
    0
    0
    0
        Male
    47
    48
    3
    6
    7
    Disease status at trial entry
    Disease status presented at trial entry
    Units: Subjects
        Measurable soft-tissue disease (+/- bone lesions)
        Non-measurable soft-tissue (+/- bone lesions)
        Bone lesions only
        Not recorded
    Time since histological confirmation of prostate cancer
    Time since confirmation of castrate resistant disease (years) presented as median (IQR)
    Units: Years
        median (inter-quartile range (Q1-Q3))
    Time since confirmation of castrate resistant disease
    Time since confirmation of castrate resistant disease (years), presented as median (IQR)
    Units: Years
        median (inter-quartile range (Q1-Q3))
    PSA at trial entry
    PSA at trial entry (ng/ml) – median (Q1-Q3)
    Units: ng/ml
        median (inter-quartile range (Q1-Q3))

    End points

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    End points reporting groups
    Reporting group title
    Phase I Safety run-in
    Reporting group description
    This phase is to identify the safety and tolerability of enzalutamide and AZD5363 when given in a combination of once daily enzalutamide (MDV3100) with twice daily AZD5363 administered in a four days on and three days off regimen. And, to identify dose-limiting toxicities (DLTs), estimate the maximum tolerated dose (MTD) and identify a recommended Phase II dose (RP2D) of AZD5363 administered in combination with enzalutamide 160mg daily

    Reporting group title
    Phase II Expansion
    Reporting group description
    Enzalutamide and AZD5363 in patients with previous progression on enzalutamide to explore whether the addition of AZD5363 to enzalutamide can reverse resistance

    Reporting group title
    Phase II Randomised (AZD5363)
    Reporting group description
    A randomised, double blind phase II trial of enzalutamide in combination with AZD5363 versus enzalutamide alone will determine if the antitumour activity of the combination therapy is superior to the antitumour activity to enzalutamide alone (enzalutamide + AZD5363 vs. enzalutamide + placebo).

    Reporting group title
    Phase II Randomised (Placebo)
    Reporting group description
    A randomised, double blind phase II trial of enzalutamide in combination with AZD5363 versus enzalutamide alone will determine if the antitumour activity of the combination therapy is superior to the antitumour activity to enzalutamide alone (enzalutamide + AZD5363 vs. enzalutamide + placebo).

    Subject analysis set title
    Evaluable - randomised phase 2 - AZD5363
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Evaluable population for randomised phase 2 - experimental arm - evaluable for primary endpoint overall response

    Subject analysis set title
    Evaluable - randomised phase 2 - placebo
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Evaluable population for randomised phase 2 - placebo arm - evaluable for primary endpoint overall response

    Subject analysis set title
    Phase I - Dose level 1 - 320mg
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Patients allocated to dose elevel 1 of dose-fiding phase I

    Subject analysis set title
    Phase I - Dose level 2 - 480mg
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Patients allocated to dose elevel 2 of dose-fiding phase I

    Subject analysis set title
    Phase I - Dose level 1A - 400mg
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Patients allocated to dose elevel 1A of dose-fiding phase I

    Primary: Overall composite response

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    End point title
    Overall composite response [1]
    End point description
    The primary endpoint of response is defined on the basis of the following outcomes; if any of these occur without evidence of RECIST progression patients are considered to have responded: • PSA decline of ≥50% confirmed by a second reading after 4 weeks • Objective response (complete and/or partial response) by RECIST v1.1 • ONLY for patients with detectable circulating tumour cell counts ≥5/7.5ml blood at baseline, conversion of CTC to <5/7.5ml blood nadir confirmed by a second reading after 4 weeks. Only PSA and CTC assessments from week 12 onwards (to coincide with the first RECIST assessment) are considered to evaluate response, unless a PSA or CTC response are reached before cycle 4, and the response is maintained after 12 weeks of treatment and no evidence of radiological progression is seen at 12 weeks. This will also compute as a response in the primary endpoint.
    End point type
    Primary
    End point timeframe
    While on combination treatment
    Notes
    [1] - 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: Two cohorts forming part of the RE-AKT platform trial are single arm, non comparative. Therefore, we have not reported statistical analysis.
    End point values
    Phase I Safety run-in Phase II Expansion Evaluable - randomised phase 2 - AZD5363 Evaluable - randomised phase 2 - placebo
    Number of subjects analysed
    10
    13
    47
    48
    Units: responses
    3
    1
    9
    9
    Statistical analysis title
    Randomised phase 2 - primary endpoint
    Comparison groups
    Evaluable - randomised phase 2 - placebo v Evaluable - randomised phase 2 - AZD5363
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.58
    Method
    Fisher exact
    Parameter type
    Risk difference (RD)
    Point estimate
    0.4
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -12.8
         upper limit
    13.6

    Primary: Dose-Limiting Toxicity - Phase I

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    End point title
    Dose-Limiting Toxicity - Phase I [2]
    End point description
    End point type
    Primary
    End point timeframe
    35-day DLT window
    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: The RE-AKT phase I was a dose-finding study, with only descriptive statistics and rules to decide MDT were used; no statistical analysis was done.
    End point values
    Phase I - Dose level 1 - 320mg Phase I - Dose level 2 - 480mg Phase I - Dose level 1A - 400mg
    Number of subjects analysed
    3
    4 [3]
    6 [4]
    Units: Toxicities
    0
    2
    1
    Notes
    [3] - 4 evaluable for DLT decisions
    [4] - 6 evaluable for dose-escalating decisions
    No statistical analyses for this end point

    Secondary: Radiographic Progression-Free Survival (rPFS)

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    End point title
    Radiographic Progression-Free Survival (rPFS) [5]
    End point description
    Radiographic progression-free survival (rPFS) is defined by either RECIST progression and /or progression on bone scan. It is measured from the date of randomisation to the first occurrence of radiographic progression or death from any cause.
    End point type
    Secondary
    End point timeframe
    rPFS is measured from the date of randomisation to the first occurrence of radiographic progression or death from any cause.
    Notes
    [5] - 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: Two cohorts forming part of the RE-AKT platform trial are single arm, non comparative. Therefore, we have not reported statistical analysis.
    End point values
    Phase II Randomised (AZD5363) Phase II Randomised (Placebo) Evaluable - randomised phase 2 - AZD5363 Evaluable - randomised phase 2 - placebo
    Number of subjects analysed
    50
    50
    47
    48
    Units: Years
        median (inter-quartile range (Q1-Q3))
    5.6 (2.8 to 11.0)
    3.5 (2.7 to 8.4)
    5.6 (2.8 to 11.0)
    3.3 (2.7 to 8.4)
    Statistical analysis title
    Comparing treatment group - all patients
    Comparison groups
    Phase II Randomised (AZD5363) v Phase II Randomised (Placebo)
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.33
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.78
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.47
         upper limit
    1.3
    Statistical analysis title
    Comparing treatment group - evaluable patients
    Comparison groups
    Evaluable - randomised phase 2 - placebo v Evaluable - randomised phase 2 - AZD5363
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.24
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.74
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.44
         upper limit
    1.24

    Secondary: Progression-Free Survival (PFS)

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    End point title
    Progression-Free Survival (PFS) [6]
    End point description
    Progression-free survival (PFS) was measured from the date of trial entry until radiographic progression, unequivocal clinical progression or death. If no such event occurred while on observation, then PFS was censored at the last scheduled disease assessment on study.
    End point type
    Secondary
    End point timeframe
    Progression-free survival (PFS) was measured from the date of trial entry until radiographic progression, unequivocal clinical progression or death.
    Notes
    [6] - 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: Two cohorts forming part of the RE-AKT platform trial are single arm, non comparative. Therefore, we have not reported statistical analysis.
    End point values
    Phase II Randomised (AZD5363) Phase II Randomised (Placebo) Evaluable - randomised phase 2 - AZD5363 Evaluable - randomised phase 2 - placebo
    Number of subjects analysed
    50
    50
    47
    48
    Units: Years
        median (inter-quartile range (Q1-Q3))
    5.3 (2.8 to 8.3)
    2.9 (2.6 to 8.3)
    5.3 (2.8 to 8.3)
    2.9 (2.6 to 8.3)
    Statistical analysis title
    Comparing treatment group - all patients
    Comparison groups
    Phase II Randomised (AZD5363) v Phase II Randomised (Placebo)
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.24
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.77
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.49
         upper limit
    1.2
    Statistical analysis title
    Comparing treatment group - evaluable patients
    Comparison groups
    Evaluable - randomised phase 2 - AZD5363 v Evaluable - randomised phase 2 - placebo
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.22
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.76
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.48
         upper limit
    1.19

    Secondary: Overall survival (OS)

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    End point title
    Overall survival (OS) [7]
    End point description
    End point type
    Secondary
    End point timeframe
    Overall survival is measured from the date of randomisation to the date of death (whatever the cause).
    Notes
    [7] - 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: Two cohorts forming part of the RE-AKT platform trial are single arm, non comparative. Therefore, we have not reported statistical analysis.
    End point values
    Phase II Randomised (AZD5363) Phase II Randomised (Placebo) Evaluable - randomised phase 2 - AZD5363 Evaluable - randomised phase 2 - placebo
    Number of subjects analysed
    50
    50
    47
    48
    Units: Years
        median (inter-quartile range (Q1-Q3))
    13.9 (6.3 to 20.5)
    11.0 (5.6 to 19.7)
    12.7 (6.4 to 20.0)
    11.0 (5.6 to 19.7)
    Statistical analysis title
    Comparing treatment group - all patients
    Comparison groups
    Phase II Randomised (AZD5363) v Phase II Randomised (Placebo)
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.19
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.76
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.51
         upper limit
    1.15
    Statistical analysis title
    Comparing treatment group - evaluable patients
    Comparison groups
    Evaluable - randomised phase 2 - AZD5363 v Evaluable - randomised phase 2 - placebo
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.69
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.92
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.6
         upper limit
    1.4

    Secondary: Proportion of patients with at least 1 skeletal event

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    End point title
    Proportion of patients with at least 1 skeletal event [8]
    End point description
    End point type
    Secondary
    End point timeframe
    Skeletal-related events are defined as either the use of external beam radiotherapy to relieve skeletal symptoms or the occurrence of new symptomatic bone fractures (vertebral or non-vertebral) or the occurrence of spinal cord compression or a tumour rela
    Notes
    [8] - 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: Two cohorts forming part of the RE-AKT platform trial are single arm, non comparative. Therefore, we have not reported statistical analysis.
    End point values
    Phase II Randomised (AZD5363) Phase II Randomised (Placebo)
    Number of subjects analysed
    50
    50
    Units: Patients
    6
    14
    Statistical analysis title
    Comparing treatment group - all patients
    Comparison groups
    Phase II Randomised (AZD5363) v Phase II Randomised (Placebo)
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.04
    Method
    Fisher exact
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    After commencement of study treatment and within 30 days of last administration of study treatment.
    Adverse event reporting additional description
    Non-serious adverse events reported are treatment emergent events. Treatment-emergent AEs are defined as any events that occur or worsen on or after first dose of study drug up through 30 days post last administration of study treatment.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15
    Reporting groups
    Reporting group title
    Phase I Safety run-in
    Reporting group description
    This population includes all enrolled patients who received at least 1 treatment dose of either of the treatment drugs.

    Reporting group title
    Phase II Expansion
    Reporting group description
    This population includes all enrolled patients due to start combination treatment who received at least 1 dose of either of the treatment drugs in the combination.

    Reporting group title
    Phase II Randomised (AZD5363)
    Reporting group description
    This population includes all enrolled patients who received at least 1 treatment of either of the treatment drugs.

    Reporting group title
    Phase II Randomised (Placebo)
    Reporting group description
    This population includes all enrolled patients who received at least 1 treatment of either of the treatment drugs.

    Serious adverse events
    Phase I Safety run-in Phase II Expansion Phase II Randomised (AZD5363) Phase II Randomised (Placebo)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 15 (60.00%)
    7 / 13 (53.85%)
    25 / 48 (52.08%)
    24 / 50 (48.00%)
         number of deaths (all causes)
    2
    12
    45
    49
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 13 (0.00%)
    0 / 48 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vasovagal collapse
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 13 (7.69%)
    0 / 48 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Blocked Catheter
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 13 (7.69%)
    0 / 48 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    1 / 48 (2.08%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    1 / 48 (2.08%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    1 / 48 (2.08%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    2 / 48 (4.17%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    3 / 48 (6.25%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    1 / 48 (2.08%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    1 / 48 (2.08%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    2 / 48 (4.17%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    0 / 48 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 13 (0.00%)
    1 / 48 (2.08%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood creatine increased
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 13 (7.69%)
    1 / 48 (2.08%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    1 / 48 (2.08%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    0 / 48 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    0 / 48 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Confusional state
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 13 (7.69%)
    1 / 48 (2.08%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    1 / 48 (2.08%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    1 / 48 (2.08%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    1 / 48 (2.08%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 13 (15.38%)
    3 / 48 (6.25%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinopathy
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 13 (0.00%)
    0 / 48 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 13 (7.69%)
    1 / 48 (2.08%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    4 / 48 (8.33%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    4 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    1 / 48 (2.08%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 13 (7.69%)
    1 / 48 (2.08%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    2 / 48 (4.17%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    0 / 48 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    1 / 48 (2.08%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 13 (15.38%)
    4 / 48 (8.33%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    3 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    2 / 48 (4.17%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 13 (15.38%)
    2 / 48 (4.17%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    4 / 48 (8.33%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    1 / 48 (2.08%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    0 / 48 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    1 / 48 (2.08%)
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    3 / 48 (6.25%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mobility decreased
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    0 / 48 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    0 / 48 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    0 / 48 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    0 / 48 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    1 / 48 (2.08%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    1 / 48 (2.08%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Impending femur fracture
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 13 (0.00%)
    0 / 48 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 13 (0.00%)
    1 / 48 (2.08%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    1 / 48 (2.08%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    1 / 48 (2.08%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    2 / 48 (4.17%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    1 / 48 (2.08%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    0 / 48 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Genitourinary tract infection
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    1 / 48 (2.08%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes simplex
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    1 / 48 (2.08%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 13 (0.00%)
    0 / 48 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    1 / 48 (2.08%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    1 / 48 (2.08%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    1 / 48 (2.08%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Phase I Safety run-in Phase II Expansion Phase II Randomised (AZD5363) Phase II Randomised (Placebo)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 15 (100.00%)
    13 / 13 (100.00%)
    48 / 48 (100.00%)
    50 / 50 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 13 (15.38%)
    4 / 48 (8.33%)
    6 / 50 (12.00%)
         occurrences all number
    0
    2
    4
    6
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 13 (7.69%)
    4 / 48 (8.33%)
    1 / 50 (2.00%)
         occurrences all number
    2
    1
    4
    1
    Fatigue
         subjects affected / exposed
    6 / 15 (40.00%)
    7 / 13 (53.85%)
    29 / 48 (60.42%)
    26 / 50 (52.00%)
         occurrences all number
    6
    7
    29
    26
    Oedema peripheral
         subjects affected / exposed
    3 / 15 (20.00%)
    1 / 13 (7.69%)
    3 / 48 (6.25%)
    3 / 50 (6.00%)
         occurrences all number
    3
    1
    3
    3
    Pyrexia
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 13 (0.00%)
    3 / 48 (6.25%)
    3 / 50 (6.00%)
         occurrences all number
    2
    0
    3
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 13 (7.69%)
    6 / 48 (12.50%)
    3 / 50 (6.00%)
         occurrences all number
    1
    1
    6
    3
    Dyspnoea
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    7 / 48 (14.58%)
    7 / 50 (14.00%)
         occurrences all number
    0
    0
    7
    7
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 13 (7.69%)
    2 / 48 (4.17%)
    2 / 50 (4.00%)
         occurrences all number
    2
    1
    2
    2
    Insomnia
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 13 (0.00%)
    4 / 48 (8.33%)
    2 / 50 (4.00%)
         occurrences all number
    2
    0
    4
    2
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    3 / 15 (20.00%)
    2 / 13 (15.38%)
    3 / 48 (6.25%)
    3 / 50 (6.00%)
         occurrences all number
    3
    2
    3
    3
    Neutrophil count decreased
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    4 / 48 (8.33%)
    3 / 50 (6.00%)
         occurrences all number
    0
    0
    4
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 13 (7.69%)
    3 / 48 (6.25%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    3
    1
    White blood cell count decreased
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 13 (0.00%)
    3 / 48 (6.25%)
    2 / 50 (4.00%)
         occurrences all number
    1
    0
    3
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    6 / 48 (12.50%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    6
    1
    Dysgeusia
         subjects affected / exposed
    1 / 15 (6.67%)
    2 / 13 (15.38%)
    3 / 48 (6.25%)
    2 / 50 (4.00%)
         occurrences all number
    1
    2
    3
    2
    Lethargy
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    2 / 48 (4.17%)
    4 / 50 (8.00%)
         occurrences all number
    0
    0
    2
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 15 (33.33%)
    8 / 13 (61.54%)
    19 / 48 (39.58%)
    13 / 50 (26.00%)
         occurrences all number
    5
    8
    19
    13
    Abdominal pain
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 13 (0.00%)
    7 / 48 (14.58%)
    2 / 50 (4.00%)
         occurrences all number
    2
    0
    7
    2
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    5 / 15 (33.33%)
    3 / 13 (23.08%)
    9 / 48 (18.75%)
    13 / 50 (26.00%)
         occurrences all number
    5
    3
    9
    13
    Diarrhoea
         subjects affected / exposed
    10 / 15 (66.67%)
    11 / 13 (84.62%)
    36 / 48 (75.00%)
    15 / 50 (30.00%)
         occurrences all number
    10
    11
    36
    15
    Nausea
         subjects affected / exposed
    7 / 15 (46.67%)
    5 / 13 (38.46%)
    20 / 48 (41.67%)
    15 / 50 (30.00%)
         occurrences all number
    7
    5
    20
    15
    Vomiting
         subjects affected / exposed
    4 / 15 (26.67%)
    2 / 13 (15.38%)
    19 / 48 (39.58%)
    8 / 50 (16.00%)
         occurrences all number
    4
    2
    19
    8
    Dyspepsia
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 13 (0.00%)
    1 / 48 (2.08%)
    3 / 50 (6.00%)
         occurrences all number
    2
    0
    1
    3
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    3 / 15 (20.00%)
    1 / 13 (7.69%)
    8 / 48 (16.67%)
    0 / 50 (0.00%)
         occurrences all number
    3
    1
    8
    0
    Rash
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    10 / 48 (20.83%)
    3 / 50 (6.00%)
         occurrences all number
    0
    0
    10
    3
    Pruritus
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 13 (15.38%)
    4 / 48 (8.33%)
    0 / 50 (0.00%)
         occurrences all number
    0
    2
    4
    0
    Dry skin
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 13 (7.69%)
    3 / 48 (6.25%)
    2 / 50 (4.00%)
         occurrences all number
    0
    1
    3
    2
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    6 / 48 (12.50%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    6
    1
    Haematuria
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 13 (7.69%)
    5 / 48 (10.42%)
    1 / 50 (2.00%)
         occurrences all number
    2
    1
    5
    1
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 13 (0.00%)
    7 / 48 (14.58%)
    9 / 50 (18.00%)
         occurrences all number
    2
    0
    7
    9
    Pain in extremity
         subjects affected / exposed
    3 / 15 (20.00%)
    3 / 13 (23.08%)
    7 / 48 (14.58%)
    10 / 50 (20.00%)
         occurrences all number
    3
    3
    7
    10
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 13 (7.69%)
    6 / 48 (12.50%)
    5 / 50 (10.00%)
         occurrences all number
    2
    1
    6
    5
    Bone pain
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 13 (15.38%)
    3 / 48 (6.25%)
    4 / 50 (8.00%)
         occurrences all number
    0
    2
    3
    4
    Muscular weakness
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 13 (0.00%)
    5 / 48 (10.42%)
    2 / 50 (4.00%)
         occurrences all number
    1
    0
    5
    2
    Arthralgia
         subjects affected / exposed
    6 / 15 (40.00%)
    3 / 13 (23.08%)
    12 / 48 (25.00%)
    11 / 50 (22.00%)
         occurrences all number
    6
    3
    12
    11
    Back pain
         subjects affected / exposed
    4 / 15 (26.67%)
    3 / 13 (23.08%)
    13 / 48 (27.08%)
    20 / 50 (40.00%)
         occurrences all number
    4
    3
    13
    20
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 13 (0.00%)
    4 / 48 (8.33%)
    3 / 50 (6.00%)
         occurrences all number
    1
    0
    4
    3
    Urinary tract infection
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    6 / 48 (12.50%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    6
    1
    Weight decreased
         subjects affected / exposed
    3 / 15 (20.00%)
    3 / 13 (23.08%)
    5 / 48 (10.42%)
    7 / 50 (14.00%)
         occurrences all number
    3
    3
    5
    7
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    8 / 15 (53.33%)
    4 / 13 (30.77%)
    18 / 48 (37.50%)
    17 / 50 (34.00%)
         occurrences all number
    8
    4
    18
    17
    Hyperglycaemia
         subjects affected / exposed
    8 / 15 (53.33%)
    1 / 13 (7.69%)
    5 / 48 (10.42%)
    2 / 50 (4.00%)
         occurrences all number
    8
    1
    5
    2
    Hypokalaemia
         subjects affected / exposed
    4 / 15 (26.67%)
    3 / 13 (23.08%)
    7 / 48 (14.58%)
    4 / 50 (8.00%)
         occurrences all number
    4
    3
    7
    4
    Hyponatraemia
         subjects affected / exposed
    3 / 15 (20.00%)
    0 / 13 (0.00%)
    2 / 48 (4.17%)
    2 / 50 (4.00%)
         occurrences all number
    3
    0
    2
    2
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    3 / 48 (6.25%)
    3 / 50 (6.00%)
         occurrences all number
    0
    0
    3
    3

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Jul 2015
    Updates of adverse events in line with AZD5363 IB Edition 6. Remove reference to PCWG2, removed definition of progression from within the definition of response, as it is not needed. Change of phase I method to 3+3 instead of rolling six and clarification of wording to better reflect dose-escalation rule. Update to Phase I inclusion criteria. Clarification that the 9 PTEN patients must be fully evaluable for evaluation for the primary outcome in expansion cohort. Clarification of laboratory tests. Update to reflect switch from capsules of AZD5363 to tablets. Clarification to provide further details of the definition of evaluable population.
    16 Nov 2016
    Update to change the study design of the Expansion cohort within the protocol. Change to the eligibility criteria within the protocol. Addition of new sites/PI, removal of 1 site/PI. Update to Expansion cohort patient information sheet, consent for and GP letter. New patient documents for a sole Enzalutamide run-in phase within the Expansion cohort. e.g. patient diary card and patient card. Submission of AZD5363 Investigator Brochure Edition 7 for information.
    12 Feb 2018
    Updating the RSI and the protocol in line with AZD5363 IB Ed. 8 14/12/2016 and Enzalutamide SmPC dated 12/10/2017 undesirable effects.
    24 May 2019
    Updated to reflect change in formulation of AZD5363

    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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