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    Clinical Trial Results:
    A Phase III, Randomised, Double Blind, Placebo Controlled, Multicentre Study of Maintenance Olaparib Monotherapy in Patients With gBRCA Mutated Metastatic Pancreatic Cancer Whose Disease Has Not Progressed on First Line Platinum Based Chemotherapy

    Summary
    EudraCT number
    		 2014-001589-85
    Trial protocol
    		 GB   DE   BE   NL   ES   IT   FR  
    Global end of trial date
    27 Jan 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Sep 2023
    First version publication date
    30 Sep 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D081FC00001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02184195
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca AB
    Sponsor organisation address
    Södartälje, Södartälje, Sweden, 151 85
    Public contact
    Global Clinical Leader, AstraZeneca AB, +1 8772409479, information.center@astrazeneca.com
    Scientific contact
    Global Clinical Leader, AstraZeneca AB, +1 8772409479, information.center@astrazeneca.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    01 Sep 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Jan 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the efficacy of Olaparib maintenance monotherapy compared to placebo by progression free survival (PFS)
    Protection of trial subjects
    The study was performed in accordance with ethical principles that have their origin in the Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, applicable regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological Samples.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 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
    Belgium: 5
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    France: 24
    Country: Number of subjects enrolled
    Germany: 20
    Country: Number of subjects enrolled
    Israel: 23
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    Italy: 16
    Country: Number of subjects enrolled
    Korea, Republic of: 6
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    United States: 32
    Worldwide total number of subjects
    154
    EEA total number of subjects
    79
    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)
    113
    From 65 to 84 years
    41
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study randomised patients at a total of 59 study centres in 12 countries: United States of America (13), Germany (8), France (7), Israel (7), Spain (7), United Kingdom (6), Italy (4), Belgium (2), Republic of Korea (2), Australia (1), Canada (1) and Netherlands (1).

    Pre-assignment
    Screening details
    		 Screening Part 1 was only required if a patient’s gBRCAm status was unknown and Screening Part 2 was for patients with known local germline BRCA (gBRCA) test. All other screening parameters were done as per the Study Schedule.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Olaparib 300 mg twice daily (bd)
    Arm description
    		 Randomised participants received orally 300 mg bd which were made up of 2 x 150 mg tablets bd with 100 mg tablets used to manage dose reductions.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Olaparib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 300mg twice daily (2 x 150mg) tablets.

    Arm title
    		 Placebo
    Arm description
    		 Randomised participants received placebo tablets orally 300 mg bd which were made up of 2 x 150 mg tablets bd with 100 mg tablets used to manage dose reductions.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 300mg twice daily (2 x 150mg) tablets.

    Number of subjects in period 1
    		Olaparib 300 mg twice daily (bd) Placebo
    Started
    92
    62
    Completed
    19
    7
    Not completed
    73
    55
         Patient decision
    5
    2
         Eligibility criteria not fulfilled
    -
    1
         Death
    67
    44
         Other
    -
    3
         Lost to follow-up
    1
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Olaparib 300 mg twice daily (bd)
    Reporting group description
    		 Randomised participants received orally 300 mg bd which were made up of 2 x 150 mg tablets bd with 100 mg tablets used to manage dose reductions.

    Reporting group title
    Placebo
    Reporting group description
    		 Randomised participants received placebo tablets orally 300 mg bd which were made up of 2 x 150 mg tablets bd with 100 mg tablets used to manage dose reductions.

    Reporting group values
    		 Olaparib 300 mg twice daily (bd) Placebo Total
    Number of subjects
    		 92 62 154
    Age categorical
    Units: Participants
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 64 49 113
        From 65-84 years
    		 28 13 41
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 58.2 ± 10.27 56.4 ± 9.07 -
    Sex: Female, Male
    Units: Participants
        Female
    		 39 31 70
        Male
    		 53 31 84
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 1 0 1
        Asian
    		 4 2 6
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 5 0 5
        White
    		 82 59 141
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 0 1 1
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 4 2 6
        Not Hispanic or Latino
    		 88 60 148
        Unknown or Not Reported
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Olaparib 300 mg twice daily (bd)
    Reporting group description
    		 Randomised participants received orally 300 mg bd which were made up of 2 x 150 mg tablets bd with 100 mg tablets used to manage dose reductions.

    Reporting group title
    Placebo
    Reporting group description
    		 Randomised participants received placebo tablets orally 300 mg bd which were made up of 2 x 150 mg tablets bd with 100 mg tablets used to manage dose reductions.

    Primary: Progression-free survival (PFS) by blinded independent central review (BICR) using modified Response Evaluation Criteria in Solid Tumours. This study used modified RECIST version (v) 1.1 (RECIST v1.1)

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    End point title
    		 Progression-free survival (PFS) by blinded independent central review (BICR) using modified Response Evaluation Criteria in Solid Tumours. This study used modified RECIST version (v) 1.1 (RECIST v1.1)
    End point description
    To determine the efficacy of olaparib maintenance monotherapy compared to placebo by PFS. The PFS was defined as the time from randomisation until the date of objective radiological disease progression according to modified RECIST v1.1 or death (by any cause in the absence of disease progression) regardless of whether the patient withdrew from randomized therapy or received another anticancer therapy prior to disease progression. Intention to treat (ITT): All randomised patients, Myriad confirmed Breast cancer susceptibility gene mutation (gBRCAm) subgroup.
    End point type
    Primary
    End point timeframe
    Up to 4 years
    End point values
    		 Olaparib 300 mg twice daily (bd) Placebo
    Number of subjects analysed
    92
    62
    Units: Months
        median (confidence interval 95%)
    7.4 (4.14 to 11.01)
    3.8 (3.52 to 4.86)
    Statistical analysis title
    		 Olaparib vs Placebo
    Comparison groups
    Olaparib 300 mg twice daily (bd) v Placebo
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0038
    Method
    		 Log-rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.531
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.346
         upper limit
    		 0.815

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    To determine the efficacy by assessment of OS of olaparib maintenance monotherapy compared to placebo. The OS was defined as the time from the date of randomization until death due to any cause. Intention to treat (ITT): All randomised patients, Myriad confirmed Breast cancer susceptibility gene mutation (gBRCAm) subgroup.
    End point type
    Secondary
    End point timeframe
    Upto 4 years
    End point values
    		 Olaparib 300 mg twice daily (bd) Placebo
    Number of subjects analysed
    92
    62
    Units: Months
        median (confidence interval 95%)
    19.0 (15.28 to 26.32)
    19.2 (14.32 to 26.12)
    Statistical analysis title
    		 Olaparib vs Placebo
    Comparison groups
    Olaparib 300 mg twice daily (bd) v Placebo
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3487
    Method
    		 Log-rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.831
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.564
         upper limit
    		 1.224

    Secondary: Time from randomisation to second subsequent therapy or death (TSST)

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    End point title
    		 Time from randomisation to second subsequent therapy or death (TSST)
    End point description
    To determine the efficacy by assessment of TSST of olaparib maintenance monotherapy compared to placebo. The TSST was defined as time to second subsequent therapy or death. Intention to treat (ITT): All randomised patients, Myriad confirmed Breast cancer susceptibility gene mutation (gBRCAm) subgroup.
    End point type
    Secondary
    End point timeframe
    Up to 4 years
    End point values
    		 Olaparib 300 mg twice daily (bd) Placebo
    Number of subjects analysed
    92
    62
    Units: Months
        median (confidence interval 95%)
    14.9 (9.13 to 19.78)
    9.6 (8.34 to 12.98)
    Statistical analysis title
    		 Olaparib vs Placebo
    Comparison groups
    Olaparib 300 mg twice daily (bd) v Placebo
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0111
    Method
    		 Log-rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.611
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.418
         upper limit
    		 0.894

    Secondary: Time from randomisation to first subsequent therapy or death (TFST)

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    End point title
    		 Time from randomisation to first subsequent therapy or death (TFST)
    End point description
    To determine the efficacy by assessment of TFST of olaparib maintenance monotherapy compared to placebo. The TFST was defined as time to first subsequent therapy or death. Intention to treat (ITT): All randomised patients, Myriad confirmed Breast cancer susceptibility gene mutation (gBRCAm) subgroup.
    End point type
    Secondary
    End point timeframe
    Up to 4 years
    End point values
    		 Olaparib 300 mg twice daily (bd) Placebo
    Number of subjects analysed
    92
    62
    Units: Months
        median (confidence interval 95%)
    9.0 (6.21 to 12.85)
    5.4 (3.94 to 6.21)
    Statistical analysis title
    		 Olaparib vs Placebo
    Comparison groups
    Olaparib 300 mg twice daily (bd) v Placebo
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Log-rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.442
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.297
         upper limit
    		 0.658

    Secondary: Time from randomisation to second progression (PFS2)

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    End point title
    		 Time from randomisation to second progression (PFS2)
    End point description
    To determine efficacy by assessment of PFS2 of olaparib maintenance monotherapy compared to placebo. The PFS2 was defined as the time from the date of randomisation to the earliest of the progression event subsequent to that used for the primary variable PFS or death. Intention to treat (ITT): All randomised patients, Myriad confirmed Breast cancer susceptibility gene mutation (gBRCAm) subgroup.
    End point type
    Secondary
    End point timeframe
    Up to 4 years
    End point values
    		 Olaparib 300 mg twice daily (bd) Placebo
    Number of subjects analysed
    92
    62
    Units: Months
        median (confidence interval 95%)
    16.9 (8.21 to 23.85)
    9.3 (8.15 to 13.54)
    Statistical analysis title
    		 Olaparib vs Placebo
    Comparison groups
    Olaparib 300 mg twice daily (bd) v Placebo
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0613
    Method
    		 Log-rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.659
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.426
         upper limit
    		 1.02

    Secondary: Time from randomisation to study treatment discontinuation or death (TDT)

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    End point title
    		 Time from randomisation to study treatment discontinuation or death (TDT)
    End point description
    To determine the efficacy by assessment of TDT compared to placebo. compared to placebo. The TDT was defined as time to study treatment discontinuation or death. Intention to treat (ITT): All randomised patients, Myriad confirmed Breast cancer susceptibility gene mutation (gBRCAm) subgroup.
    End point type
    Secondary
    End point timeframe
    Up to 4 years
    End point values
    		 Olaparib 300 mg twice daily (bd) Placebo
    Number of subjects analysed
    92
    62
    Units: Months
        median (confidence interval 95%)
    7.5 (5.52 to 10.97)
    3.8 (3.61 to 4.80)
    Statistical analysis title
    		 Olaparib vs Placebo
    Comparison groups
    Olaparib 300 mg twice daily (bd) v Placebo
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Log-rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.425
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.289
         upper limit
    		 0.627

    Secondary: Disease control rate (DCR) by BICR using modified RECIST 1.1

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    End point title
    		 Disease control rate (DCR) by BICR using modified RECIST 1.1
    End point description
    Efficacy by assessment of disease control rate according to modified RECIST 1.1 of olaparib maintenance monotherapy compared to placebo. Intention to treat (ITT): All randomised patients
    End point type
    Secondary
    End point timeframe
    At 16 weeks
    End point values
    		 Olaparib 300 mg twice daily (bd) Placebo
    Number of subjects analysed
    92
    62
    Units: Participants
        Yes
    51
    24
        No
    34
    34
        Not evaluable/missing
    7
    4
    No statistical analyses for this end point

    Secondary: Number of participants with objective response rate (ORR) by BICR using modified RECIST 1.1

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    End point title
    		 Number of participants with objective response rate (ORR) by BICR using modified RECIST 1.1
    End point description
    To determine efficacy by assessment of objective response rate according to modified RECIST 1.1 of olaparib maintenance monotherapy compared to placebo. The ORR is defined as the number of with a BoR of CR and PR according to the BICR data divided by the number of patients in the treatment group with measurable disease at baseline. All randomised patients with measurable disease at baseline.
    End point type
    Secondary
    End point timeframe
    Up to 4 years
    End point values
    		 Olaparib 300 mg twice daily (bd) Placebo
    Number of subjects analysed
    72
    49
    Units: Participants
        Participants with response
    22
    11
    Statistical analysis title
    		 Olaparib vs Placebo
    Comparison groups
    Olaparib 300 mg twice daily (bd) v Placebo
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3273
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.668
         upper limit
    		 3.61

    Secondary: Adjusted mean change from baseline up to 6 months in global quality of life (QoL) score from the EORTC-QLQ-C30 questionnaire

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    End point title
    		 Adjusted mean change from baseline up to 6 months in global quality of life (QoL) score from the EORTC-QLQ-C30 questionnaire
    End point description
    To assess the effect of olaparib on health-related quality of life (QoL) as measured by the EORTC-QLQ-C30 global QoL scale. The EORTC-QLQ-C30 is defined as EORTC QLQ-C30: a questionnaire (30 questions) used to evaluate disease symptoms, functional impacts (eg, physical functioning), and HRQoL and to characterize clinical benefit from the patient perspective. The HRQoL score ranges from 0 to 100. A higher score indicates better QoL. A score change of 10 points was pre-defined as clinically meaningful. bd twice daily. Patient reported outcome (PRO) analysis set was defined as the analysis population for PRO data were a subset of the FAS (ITT) population who had evaluable baseline EORTC QLQ-C30 or QLQ-PAN26 forms where evaluable meant that at least 1 sub-scale baseline score could be determined from at least 1 of the 2 forms.
    End point type
    Secondary
    End point timeframe
    From baseline up to 6 months
    End point values
    		 Olaparib 300 mg twice daily (bd) Placebo
    Number of subjects analysed
    84
    55
    Units: Unit on scale
        arithmetic mean (confidence interval 95%)
    -1.03 (-3.826 to 1.759)
    1.18 (-2.585 to 4.939)
    Statistical analysis title
    		 Olaparib vs Placebo
    Comparison groups
    Olaparib 300 mg twice daily (bd) v Placebo
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.355
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.917
         upper limit
    		 2.496

    Secondary: Number of participants with adverse events (AEs)

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    End point title
    		 Number of participants with adverse events (AEs)
    End point description
    To assess the safety and tolerability of olaparib maintenance monotherapy. SAE: serious adverse events CTCAE: Common Terminology Criteria for Adverse Events Safety Analysis Set consisted of all patients who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to 4 years
    End point values
    		 Olaparib 300 mg twice daily (bd) Placebo
    Number of subjects analysed
    90
    61
    Units: Participants
        Any AE
    89
    56
        Any AE of CTCAE Grade 3 or higher
    44
    15
        Any AE with outcome = death
    1
    0
        Any SAE (including events with outcome = death)
    28
    10
        AnyAE leading to withdrawal of olaparib/placebo
    8
    1
        Any AE leading to dose interruption
    38
    4
        Any AE leading to dose reduction
    16
    3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From informed consent until 30 days after last dose + subsequent treatment-related events reported (maximum up to 4 years).
    Adverse event reporting additional description
    Only 90 patients in Olaparib and 61 patients in Placebo group were reported for safety because 3 patients did not receive study treatment and were not reported in the safety table.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Randomised participants received placebo tablets orally 300 mg bd which were made up of 2 x 150 mg tablets bd with 100 mg tablets used to manage dose reductions.

    Reporting group title
    Olaparib 300 mg twice daily (bd)
    Reporting group description
    		 Randomised participants received orally 300 mg bd which were made up of 2 x 150 mg tablets bd with 100 mg tablets used to manage dose reductions.

    Serious adverse events
    		 Placebo Olaparib 300 mg twice daily (bd)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 61 (16.39%)
    28 / 90 (31.11%)
         number of deaths (all causes)
    52
    67
         number of deaths resulting from adverse events
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder papilloma
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Vascular stenosis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device occlusion
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stent malfunction
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Platelet count decreased
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anastomotic haemorrhage
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Transient ischaemic attack
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolic stroke
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile Neutropenia
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 61 (0.00%)
    7 / 90 (7.78%)
         occurrences causally related to treatment / all
    0 / 0
    6 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Large intestinal obstruction
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incarcerated inguinal hernia
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric varices haemorrhage
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal perforation
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Constipation
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 61 (1.64%)
    4 / 90 (4.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 61 (4.92%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstruction gastric
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    1 / 61 (1.64%)
    2 / 90 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct obstruction
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bartholinitis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal infection
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Olaparib 300 mg twice daily (bd)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    56 / 61 (91.80%)
    89 / 90 (98.89%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 61 (1.64%)
    10 / 90 (11.11%)
         occurrences all number
    1
    16
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 61 (1.64%)
    8 / 90 (8.89%)
         occurrences all number
    1
    14
    Blood creatinine increased
         subjects affected / exposed
    2 / 61 (3.28%)
    7 / 90 (7.78%)
         occurrences all number
    2
    12
    Blood alkaline phosphatase increased
         subjects affected / exposed
    3 / 61 (4.92%)
    6 / 90 (6.67%)
         occurrences all number
    3
    7
    Platelet count decreased
         subjects affected / exposed
    0 / 61 (0.00%)
    5 / 90 (5.56%)
         occurrences all number
    0
    9
    Neutrophil count decreased
         subjects affected / exposed
    0 / 61 (0.00%)
    6 / 90 (6.67%)
         occurrences all number
    0
    16
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 61 (1.64%)
    6 / 90 (6.67%)
         occurrences all number
    1
    9
    Weight decreased
         subjects affected / exposed
    3 / 61 (4.92%)
    7 / 90 (7.78%)
         occurrences all number
    3
    7
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 61 (4.92%)
    5 / 90 (5.56%)
         occurrences all number
    3
    12
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 61 (13.11%)
    8 / 90 (8.89%)
         occurrences all number
    8
    10
    Peripheral sensory neuropathy
         subjects affected / exposed
    2 / 61 (3.28%)
    6 / 90 (6.67%)
         occurrences all number
    2
    6
    Dizziness
         subjects affected / exposed
    3 / 61 (4.92%)
    8 / 90 (8.89%)
         occurrences all number
    4
    8
    Neuropathy peripheral
         subjects affected / exposed
    7 / 61 (11.48%)
    9 / 90 (10.00%)
         occurrences all number
    7
    10
    Dysgeusia
         subjects affected / exposed
    3 / 61 (4.92%)
    6 / 90 (6.67%)
         occurrences all number
    3
    6
    Paraesthesia
         subjects affected / exposed
    4 / 61 (6.56%)
    2 / 90 (2.22%)
         occurrences all number
    4
    3
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    16 / 61 (26.23%)
    42 / 90 (46.67%)
         occurrences all number
    19
    47
    Oedema peripheral
         subjects affected / exposed
    5 / 61 (8.20%)
    8 / 90 (8.89%)
         occurrences all number
    5
    11
    Pyrexia
         subjects affected / exposed
    4 / 61 (6.56%)
    17 / 90 (18.89%)
         occurrences all number
    5
    28
    Asthenia
         subjects affected / exposed
    6 / 61 (9.84%)
    16 / 90 (17.78%)
         occurrences all number
    6
    24
    Influenza like illness
         subjects affected / exposed
    0 / 61 (0.00%)
    6 / 90 (6.67%)
         occurrences all number
    0
    6
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    10 / 61 (16.39%)
    26 / 90 (28.89%)
         occurrences all number
    12
    35
    Thrombocytopenia
         subjects affected / exposed
    4 / 61 (6.56%)
    8 / 90 (8.89%)
         occurrences all number
    4
    9
    Neutropenia
         subjects affected / exposed
    4 / 61 (6.56%)
    8 / 90 (8.89%)
         occurrences all number
    4
    9
    Lymphopenia
         subjects affected / exposed
    0 / 61 (0.00%)
    5 / 90 (5.56%)
         occurrences all number
    0
    9
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    10 / 61 (16.39%)
    34 / 90 (37.78%)
         occurrences all number
    11
    49
    Nausea
         subjects affected / exposed
    15 / 61 (24.59%)
    44 / 90 (48.89%)
         occurrences all number
    17
    66
    Flatulence
         subjects affected / exposed
    4 / 61 (6.56%)
    2 / 90 (2.22%)
         occurrences all number
    4
    3
    Abdominal distension
         subjects affected / exposed
    6 / 61 (9.84%)
    5 / 90 (5.56%)
         occurrences all number
    6
    6
    Abdominal pain
         subjects affected / exposed
    15 / 61 (24.59%)
    26 / 90 (28.89%)
         occurrences all number
    17
    39
    Dry mouth
         subjects affected / exposed
    1 / 61 (1.64%)
    8 / 90 (8.89%)
         occurrences all number
    2
    8
    Abdominal pain upper
         subjects affected / exposed
    9 / 61 (14.75%)
    9 / 90 (10.00%)
         occurrences all number
    10
    11
    Stomatitis
         subjects affected / exposed
    3 / 61 (4.92%)
    8 / 90 (8.89%)
         occurrences all number
    3
    10
    Vomiting
         subjects affected / exposed
    9 / 61 (14.75%)
    23 / 90 (25.56%)
         occurrences all number
    12
    49
    Constipation
         subjects affected / exposed
    7 / 61 (11.48%)
    25 / 90 (27.78%)
         occurrences all number
    8
    33
    Dyspepsia
         subjects affected / exposed
    5 / 61 (8.20%)
    9 / 90 (10.00%)
         occurrences all number
    5
    16
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 61 (3.28%)
    5 / 90 (5.56%)
         occurrences all number
    2
    5
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    3 / 61 (4.92%)
    10 / 90 (11.11%)
         occurrences all number
    4
    11
    Cough
         subjects affected / exposed
    2 / 61 (3.28%)
    9 / 90 (10.00%)
         occurrences all number
    3
    13
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    3 / 61 (4.92%)
    12 / 90 (13.33%)
         occurrences all number
    4
    15
    Pruritus
         subjects affected / exposed
    4 / 61 (6.56%)
    9 / 90 (10.00%)
         occurrences all number
    4
    11
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 61 (1.64%)
    8 / 90 (8.89%)
         occurrences all number
    1
    8
    Anxiety
         subjects affected / exposed
    2 / 61 (3.28%)
    9 / 90 (10.00%)
         occurrences all number
    2
    10
    Depression
         subjects affected / exposed
    0 / 61 (0.00%)
    5 / 90 (5.56%)
         occurrences all number
    0
    6
    Musculoskeletal and connective tissue disorders
    Flank pain
         subjects affected / exposed
    4 / 61 (6.56%)
    3 / 90 (3.33%)
         occurrences all number
    4
    3
    Myalgia
         subjects affected / exposed
    3 / 61 (4.92%)
    6 / 90 (6.67%)
         occurrences all number
    5
    6
    Pain in extremity
         subjects affected / exposed
    4 / 61 (6.56%)
    8 / 90 (8.89%)
         occurrences all number
    4
    10
    Muscle spasms
         subjects affected / exposed
    2 / 61 (3.28%)
    6 / 90 (6.67%)
         occurrences all number
    2
    9
    Arthralgia
         subjects affected / exposed
    11 / 61 (18.03%)
    19 / 90 (21.11%)
         occurrences all number
    11
    25
    Back pain
         subjects affected / exposed
    13 / 61 (21.31%)
    24 / 90 (26.67%)
         occurrences all number
    13
    28
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 61 (3.28%)
    12 / 90 (13.33%)
         occurrences all number
    2
    21
    Influenza
         subjects affected / exposed
    0 / 61 (0.00%)
    6 / 90 (6.67%)
         occurrences all number
    0
    8
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 61 (1.64%)
    8 / 90 (8.89%)
         occurrences all number
    1
    15
    Decreased appetite
         subjects affected / exposed
    4 / 61 (6.56%)
    24 / 90 (26.67%)
         occurrences all number
    5
    29

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Oct 2014
    Information in Section 1.4.1.1 Myelodysplastic syndrome/acute myeloid leukaemia, Table 1 Study Schedule, and Section 4.2 Treatment period were updated to ensure protocol consistency and correct typo.
    28 Feb 2015
    The study is sized based on the number of events required to detect superiority at the time of the primary PFS analysis. To ensure that the type I error is controlled at the 2.5% 1-sided level overall, the significance level was previously allocated between the interim and final PFS analyses, taking account of correlation between them. Removal of the interim superiority analysis as per FDA recommendation means that a 2.5% significance level can be allocated to the primary PFS analysis and therefore the number of PFS events required at the time of the primary PFS analysis is slightly reduced. Removal of the superiority analysis at the time of the interim analysis as per FDA recommendation, therefore OS and PFS2 will not be analysed at this time. To change the type of analysis used for EORTC QLQ-C30 global QoL score to MMRM analysis of adjusted mean change from baseline, which is independent of minimal important differences (MID) values that are not well-defined and is suitable for analysing continuous responses measured repeatedly over time. The MMRM statistical analysis will be based on actual scores, rather than pre-selected MIDs, and will analyse data from all time points. A supportive analysis of global HRQoL improvement rate will be conducted using the ‘generic’ cut off of 10% change from baseline as suggested in Osoba et al 2005. To provide additional data on the QT study that has been conducted. To ensure that the patient can start treatment within 8 weeks of their last chemotherapy dose. Due to the screening period, the original text meant that patients would have had to start treatment within 7 weeks of their last chemotherapy dose, this was not the intention. Extending this window by 7 days makes it clearer for the investigators and reduces the risk of protocol deviations.
    30 Aug 2019
    Updated with Regulatory Agency identifiers. Updated the study period based on the current study status. Clarification provided for patient continuing to receive treatment as open labelled drug via manual supply outside of the study setting once the IVRS/IWRS has been closed. Included this new section to clarify the SAEs reporting post 30-day follow-up period. Clarification text added on how safety reporting is performed in study. Clarification text provided on overdose. Clarification provided on the timing of follow-up for pregnancy, occurring during study treatment. Clarification provided on the dose reduction scenarios during study treatment period. Latest information on management of study drug related toxicity were added. Provide solution on the medication supply when achieving study closure.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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