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    Clinical Trial Results:
    A Phase II, Open-Label, Non-Comparative, International, Multicentre Study To Assess The Efficacy And Safety Of KU-0059436 Given Orally Twice Daily In Patients With Advanced BRCA1- Or BRCA2-Associated Ovarian Cancer

    Summary
    EudraCT number
    2006-006459-10
    Trial protocol
    DE   SE   ES   GB  
    Global end of trial date
    24 Jul 2009

    Results information
    Results version number
    v1(current)
    This version publication date
    20 Jul 2018
    First version publication date
    20 Jul 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D0810C00009 (KU36-58)
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    1 Francis Crick Avenue, Cambridge Biomedical Campus, United Kingdom, CB2 1AA
    Public contact
    Gerard Lynch, AstraZeneca, ClinicalTrialTransparency@astrazeneca.com
    Scientific contact
    Gerard Lynch, AstraZeneca, ClinicalTrialTransparency@astrazeneca.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    24 Jul 2009
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Jul 2009
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Jul 2009
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of olaparib (also known as AZD2281 and KU-0059436) at two dose levels in terms of objective tumour response rate when administered orally to patients with advanced BRCA1 or BRCA2-associated ovarian cancer.
    Protection of trial subjects
    Patients could discontinue the IP at any time at the discretion of the Investigator. Patients were free to withdraw without prejudice to further treatment.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    11 Jun 2007
    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
    Spain: 1
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    United States: 42
    Country: Number of subjects enrolled
    Australia: 12
    Country: Number of subjects enrolled
    Germany: 1
    Worldwide total number of subjects
    57
    EEA total number of subjects
    3
    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)
    42
    From 65 to 84 years
    15
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The first patient was enrolled on June 11, 2007 and efficacy and safety data were collected up to the data cut-off of March 17, 2009. Patients were enrolled at 12 centres in 5 countries: Australia, Germany, Spain, Sweden and the USA.

    Pre-assignment
    Screening details
    Two cohorts of women with Breast Cancer gene 1 (BRCA1)- or BRCA2-associated ovarian cancer who had failed at least one prior chemotherapy in the advanced/metastatic setting, were planned to receive olaparib 100 mg bd (n= up to 24) or 400 mg bd (n= up to 40). Enrolment to 2 cohorts was sequential with the 400 mg bd cohort being recruited first.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    olaparib 100 mg bd
    Arm description
    olaparib (KU-0059436; AZD2281) 100 mg oral capsules, twice daily
    Arm type
    Experimental

    Investigational medicinal product name
    olaparib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    olaparib (KU-0059436; AZD2281) 100 mg oral capsules, twice daily

    Arm title
    olaparib 400 mg bd
    Arm description
    olaparib (KU-0059436; AZD2281) 400 mg oral capsules, twice daily
    Arm type
    Experimental

    Investigational medicinal product name
    olaparib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    olaparib (KU-0059436; AZD2281) 400 mg oral capsules, twice daily

    Number of subjects in period 1
    olaparib 100 mg bd olaparib 400 mg bd
    Started
    24
    33
    Completed
    7
    17
    Not completed
    17
    16
         Adverse event, serious fatal
    1
    1
         Physician decision
    -
    1
         Adverse event, non-fatal
    -
    2
         Non-compliance
    -
    1
         Intercurrent illness
    -
    1
         Lack of efficacy
    16
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    olaparib 100 mg bd
    Reporting group description
    olaparib (KU-0059436; AZD2281) 100 mg oral capsules, twice daily

    Reporting group title
    olaparib 400 mg bd
    Reporting group description
    olaparib (KU-0059436; AZD2281) 400 mg oral capsules, twice daily

    Reporting group values
    olaparib 100 mg bd olaparib 400 mg bd Total
    Number of subjects
    24 33 57
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    19 23 42
        From 65-84 years
    5 10 15
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    55.6 ( 8.02 ) 56.8 ( 10.49 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    24 33 57
        Male
    0 0 0
    BRCA mutation
    BRCA1 or BRCA2 mutations known to cause loss of gene function (clinical deleterious or suspected deleterious mutations).
    Units: Subjects
        BRCA1
    19 21 40
        BRCA2
    5 12 17

    End points

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    End points reporting groups
    Reporting group title
    olaparib 100 mg bd
    Reporting group description
    olaparib (KU-0059436; AZD2281) 100 mg oral capsules, twice daily

    Reporting group title
    olaparib 400 mg bd
    Reporting group description
    olaparib (KU-0059436; AZD2281) 400 mg oral capsules, twice daily

    Primary: Confirmed objective tumour response (according to Response Evaluation Criteria In Solid Tumors (RECIST)

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    End point title
    Confirmed objective tumour response (according to Response Evaluation Criteria In Solid Tumors (RECIST) [1]
    End point description
    Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by CT/MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease from baseline in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
    End point type
    Primary
    End point timeframe
    Baseline, every 8 also at study termination or initiation of confounding anti-cancer therapy.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There are no statistical analyses in this study as it was exploratory.
    End point values
    olaparib 100 mg bd olaparib 400 mg bd
    Number of subjects analysed
    22 [2]
    31 [3]
    Units: Participants
        PP Analysis Set
    3
    11
        ITT Analysis Set
    3
    11
    Notes
    [2] - Number analysed refers to PP Analysis Set
    [3] - Number analysed refers to PP Analysis Set
    No statistical analyses for this end point

    Secondary: Clinical Benefit (CB)

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    End point title
    Clinical Benefit (CB)
    End point description
    Clinical Benefit (CB) is defined as the percentage of patients with a RECIST tumour response of confirmed complete response, partial response or stable disease for ≥8 weeks)
    End point type
    Secondary
    End point timeframe
    End of study
    End point values
    olaparib 100 mg bd olaparib 400 mg bd
    Number of subjects analysed
    22
    31
    Units: Percentage of participants
    number (confidence interval 95%)
        PP Analysis Set
    45.5 (26.9 to 65.3)
    71.0 (53.4 to 83.9)
    No statistical analyses for this end point

    Secondary: Duration of response

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    End point title
    Duration of response
    End point description
    Duration of response to olaparib
    End point type
    Secondary
    End point timeframe
    End of study
    End point values
    olaparib 100 mg bd olaparib 400 mg bd
    Number of subjects analysed
    22
    31
    Units: Days
    median (full range (min-max))
        PP Analysis Set
    242 (169 to 288)
    301 (126 to 506)
    No statistical analyses for this end point

    Secondary: Best percentage change in tumour size

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    End point title
    Best percentage change in tumour size
    End point description
    The best % change (reduction) from baseline in tumour size (defined as the sum of the longest diameters as measured among all target lesions).
    End point type
    Secondary
    End point timeframe
    End of study
    End point values
    olaparib 100 mg bd olaparib 400 mg bd
    Number of subjects analysed
    22
    31
    Units: Percent change
    median (full range (min-max))
        PP Analysis Set
    -5.1 (-85.7 to 66.1)
    -25.8 (-100.0 to 150.0)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS)

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    End point title
    Progression-Free Survival (PFS)
    End point description
    Progression-Free Survival (PFS) is defined as the time from first dose to the earlier date of radiologic progression (as per RECIST criteria) or death by any cause in the absence of objective progression.
    End point type
    Secondary
    End point timeframe
    End of study
    End point values
    olaparib 100 mg bd olaparib 400 mg bd
    Number of subjects analysed
    22
    31
    Units: Days
    median (confidence interval 95%)
        PP Analysis Set
    62.5 (56 to 113)
    226 (105 to 338)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline, every visit until 30 days after last dose.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    olaparib 100 mg bd
    Reporting group description
    olaparib (KU-0059436; AZD2281) 100 mg oral capsules, twice daily

    Reporting group title
    olaparib 400 mg bd
    Reporting group description
    olaparib (KU-0059436; AZD2281) 400 mg oral capsules, twice daily

    Serious adverse events
    olaparib 100 mg bd olaparib 400 mg bd
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 24 (29.17%)
    12 / 33 (36.36%)
         number of deaths (all causes)
    10
    11
         number of deaths resulting from adverse events
    Vascular disorders
    Deep Vein Thrombosis
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 33 (3.03%)
         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
    Oedema Peripheral
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary Embolism
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Failure
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental Status Changes
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Humerus Fracture
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood Pressure Increased
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac Failure Congestive
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Encephalopathy
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 33 (3.03%)
         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
    Neutropenia
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Intestinal Obstruction
         subjects affected / exposed
    0 / 24 (0.00%)
    2 / 33 (6.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 24 (4.17%)
    2 / 33 (6.06%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 24 (4.17%)
    2 / 33 (6.06%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal Pain
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large Intestinal Obstruction
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Obstruction
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal Perforation
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small Intestinal Obstruction
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile Duct Stone
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 33 (3.03%)
         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 / 24 (4.17%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Failure Acute
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    olaparib 100 mg bd olaparib 400 mg bd
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 24 (95.83%)
    33 / 33 (100.00%)
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    13 / 24 (54.17%)
    17 / 33 (51.52%)
         occurrences all number
    13
    17
    Oedema Peripheral
         subjects affected / exposed
    1 / 24 (4.17%)
    6 / 33 (18.18%)
         occurrences all number
    1
    6
    Pyrexia
         subjects affected / exposed
    2 / 24 (8.33%)
    2 / 33 (6.06%)
         occurrences all number
    2
    2
    Asthenia
         subjects affected / exposed
    0 / 24 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Reproductive system and breast disorders
    Pelvic Pain
         subjects affected / exposed
    2 / 24 (8.33%)
    2 / 33 (6.06%)
         occurrences all number
    2
    2
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    4 / 24 (16.67%)
    0 / 33 (0.00%)
         occurrences all number
    4
    0
    Cough
         subjects affected / exposed
    3 / 24 (12.50%)
    1 / 33 (3.03%)
         occurrences all number
    3
    1
    Dyspnoea Exertional
         subjects affected / exposed
    0 / 24 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Oropharyngeal Pain
         subjects affected / exposed
    1 / 24 (4.17%)
    2 / 33 (6.06%)
         occurrences all number
    1
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 24 (4.17%)
    4 / 33 (12.12%)
         occurrences all number
    1
    4
    Depression
         subjects affected / exposed
    2 / 24 (8.33%)
    3 / 33 (9.09%)
         occurrences all number
    2
    3
    Anxiety
         subjects affected / exposed
    1 / 24 (4.17%)
    2 / 33 (6.06%)
         occurrences all number
    1
    2
    Investigations
    Waist Circumference Increased
         subjects affected / exposed
    4 / 24 (16.67%)
    0 / 33 (0.00%)
         occurrences all number
    4
    0
    Haemoglobin Urine
         subjects affected / exposed
    3 / 24 (12.50%)
    0 / 33 (0.00%)
         occurrences all number
    3
    0
    Blood Urine Present
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Gamma-Glutamyltransferase Increased
         subjects affected / exposed
    0 / 24 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 24 (4.17%)
    4 / 33 (12.12%)
         occurrences all number
    1
    4
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 24 (16.67%)
    7 / 33 (21.21%)
         occurrences all number
    4
    7
    Neuropathy Peripheral
         subjects affected / exposed
    4 / 24 (16.67%)
    1 / 33 (3.03%)
         occurrences all number
    4
    1
    Dizziness
         subjects affected / exposed
    2 / 24 (8.33%)
    3 / 33 (9.09%)
         occurrences all number
    2
    3
    Dysgeusia
         subjects affected / exposed
    2 / 24 (8.33%)
    1 / 33 (3.03%)
         occurrences all number
    2
    1
    Sinus Headache
         subjects affected / exposed
    1 / 24 (4.17%)
    2 / 33 (6.06%)
         occurrences all number
    1
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 24 (12.50%)
    7 / 33 (21.21%)
         occurrences all number
    3
    7
    Lymphopenia
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Thrombocytopenia
         subjects affected / exposed
    3 / 24 (12.50%)
    1 / 33 (3.03%)
         occurrences all number
    3
    1
    Neutropenia
         subjects affected / exposed
    2 / 24 (8.33%)
    3 / 33 (9.09%)
         occurrences all number
    2
    3
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    15 / 24 (62.50%)
    21 / 33 (63.64%)
         occurrences all number
    15
    21
    Diarrhoea
         subjects affected / exposed
    7 / 24 (29.17%)
    12 / 33 (36.36%)
         occurrences all number
    7
    12
    Abdominal Pain
         subjects affected / exposed
    4 / 24 (16.67%)
    9 / 33 (27.27%)
         occurrences all number
    4
    9
    Vomiting
         subjects affected / exposed
    6 / 24 (25.00%)
    11 / 33 (33.33%)
         occurrences all number
    6
    11
    Constipation
         subjects affected / exposed
    6 / 24 (25.00%)
    4 / 33 (12.12%)
         occurrences all number
    6
    4
    Abdominal Distension
         subjects affected / exposed
    4 / 24 (16.67%)
    6 / 33 (18.18%)
         occurrences all number
    4
    6
    Dyspepsia
         subjects affected / exposed
    4 / 24 (16.67%)
    4 / 33 (12.12%)
         occurrences all number
    4
    4
    Abdominal Pain Upper
         subjects affected / exposed
    3 / 24 (12.50%)
    3 / 33 (9.09%)
         occurrences all number
    3
    3
    Abdominal Discomfort
         subjects affected / exposed
    1 / 24 (4.17%)
    3 / 33 (9.09%)
         occurrences all number
    1
    3
    Abdominal Pain Lower
         subjects affected / exposed
    0 / 24 (0.00%)
    3 / 33 (9.09%)
         occurrences all number
    0
    3
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    1 / 24 (4.17%)
    3 / 33 (9.09%)
         occurrences all number
    1
    3
    Gastrointestinal Pain
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Ascites
         subjects affected / exposed
    0 / 24 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Gastritis
         subjects affected / exposed
    0 / 24 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Rectal Haemorrhage
         subjects affected / exposed
    0 / 24 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Salivary Hypersecretion
         subjects affected / exposed
    0 / 24 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Stomatitis
         subjects affected / exposed
    1 / 24 (4.17%)
    2 / 33 (6.06%)
         occurrences all number
    1
    2
    Intestinal obstruction
         subjects affected / exposed
    0 / 24 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    5 / 24 (20.83%)
    5 / 33 (15.15%)
         occurrences all number
    5
    5
    Dry Skin
         subjects affected / exposed
    2 / 24 (8.33%)
    1 / 33 (3.03%)
         occurrences all number
    2
    1
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 24 (16.67%)
    2 / 33 (6.06%)
         occurrences all number
    4
    2
    Back Pain
         subjects affected / exposed
    4 / 24 (16.67%)
    2 / 33 (6.06%)
         occurrences all number
    4
    2
    Muscle Spasms
         subjects affected / exposed
    0 / 24 (0.00%)
    4 / 33 (12.12%)
         occurrences all number
    0
    4
    Pain In Extremity
         subjects affected / exposed
    0 / 24 (0.00%)
    3 / 33 (9.09%)
         occurrences all number
    0
    3
    Flank Pain
         subjects affected / exposed
    0 / 24 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Joint Swelling
         subjects affected / exposed
    0 / 24 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Myalgia
         subjects affected / exposed
    1 / 24 (4.17%)
    2 / 33 (6.06%)
         occurrences all number
    1
    2
    Infections and infestations
    Urinary Tract Infection
         subjects affected / exposed
    5 / 24 (20.83%)
    2 / 33 (6.06%)
         occurrences all number
    5
    2
    Upper Respiratory Tract Infection
         subjects affected / exposed
    2 / 24 (8.33%)
    3 / 33 (9.09%)
         occurrences all number
    2
    3
    Oral Herpes
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Cellulitis
         subjects affected / exposed
    0 / 24 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Herpes Zoster
         subjects affected / exposed
    0 / 24 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Nasopharyngitis
         subjects affected / exposed
    0 / 24 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Sinusitis
         subjects affected / exposed
    0 / 24 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    2 / 24 (8.33%)
    4 / 33 (12.12%)
         occurrences all number
    2
    4
    Hypomagnesaemia
         subjects affected / exposed
    1 / 24 (4.17%)
    4 / 33 (12.12%)
         occurrences all number
    1
    4
    Anorexia
         subjects affected / exposed
    1 / 24 (4.17%)
    3 / 33 (9.09%)
         occurrences all number
    1
    3
    Hyperkalaemia
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Decreased Appetite
         subjects affected / exposed
    1 / 24 (4.17%)
    2 / 33 (6.06%)
         occurrences all number
    1
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Sep 2007
    Section 4 Objectives. A second dose group (100 mg bd) was introduced. After completion of the 400 mg bd dose group (40 patients), up to 24 patients (at least 6 of each BRCA type) were to be treated with 100 mg bd. The statistics section (5.7.3) was changed to provide justification for the amended sample size with the addition of the new cohort of patients. Section 5.3.1 Inclusion criteria. Inclusion criteria 2, 3 and 7 were each expanded for clarification. Section 5.3.2 Exclusion criteria. Exclusion criteria 4, 5 and 6 were each expanded for clarification. Section 5.3.2 Exclusion criteria. Exclusion criterion 2 was modified. This criterion cross-refers to the section concerning restrictions in concomitant medication which was also changed. Some previously restricted drugs were to be allowed (specifically, fluvoxamine, fluconazole, fluoxetine, amiodarone, paroxetine, quinidine). Section 5.3.4 Discontinuation of patients from treatment. The original protocol stated that patients were to be discontinued from treatment if they had significant disease progression. The amendment clarified that the definition of progressive disease should be based on imaging / RECIST criteria and not mainly on tumour markers (if possible). Section 2.3.1.1 Independent Data Monitoring Committee. An IDMC was introduced. The original protocol stated that ineligible patients would not be replaced. This was revised to state that ineligible patients who gave informed consent but never received study drug (screening failures) would be replaced.
    20 Mar 2008
    Section 4.2 Secondary objectives. The secondary endpoint Time to progression (TTP) was changed to progression-free survival (PFS). Section 5.1 Study Design. Design was revised such that after cycle 6 all patients who were benefiting from treatment with olaparib were to continue on treatment and return to site for visits every 2 months. Another column was added to Table 2 to specify data to be collected at these visits. Section 5.1 Study Design. Blood sampling for peripheral blood mononuclear cells (PBMCs) was discontinued for new patients entering the study. The section “procedures in case of pregnancy” was updated.
    22 May 2008
    All ongoing patients in the 100 mg bd dose group were offered the option to move to the 400 mg bd dose immediately or when the investigator considered that disease progression had occurred.
    11 Feb 2009
    This amendment defined the end of study as 12 months post-LPI, or after approval of amendment 4, whichever was the later.

    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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