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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 Breast Cancer

    Summary
    EudraCT number
    		 2006-006458-91
    Trial protocol
    		 SE   ES   DE   GB  
    Global end of trial date
    21 Dec 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Dec 2023
    First version publication date
    31 Dec 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    D0810C00008 (KU36-44)
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00494234
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca ClinicalStudy Information Center
    Sponsor organisation address
    One MedImmune Way, Gaithersburg, Maryland, United States, 20878
    Public contact
    Global Clinical Lead, AstraZeneca Clinical Study Information Center, +1 8772409479, information.center@astrazeneca.com
    Scientific contact
    Global Clinical Lead, AstraZeneca Clinical Study Information Center, +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
    02 Jul 2009
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Dec 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the study 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 participants with advanced BRCA1- or BRCA2-associated breast cancer.
    Protection of trial subjects
    The conduct of this clinical study met all local and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and are consistent with International Conference on Harmonization guideline: Good Clinical Practice, and applicable regulatory requirements. Participants signed an informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Jun 2007
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 14 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 7
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Sweden: 3
    Country: Number of subjects enrolled
    United States: 34
    Country: Number of subjects enrolled
    United Kingdom: 7
    Worldwide total number of subjects
    54
    EEA total number of subjects
    6
    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)
    50
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 13 centers in 5 countries (Australia, Germany, Sweden, UK and the USA).

    Pre-assignment
    Screening details
    		 A total of 54 participants were enrolled and received at least one dose of study drug.

    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
    Arm description
    		 Participants received two 50 mg capsules in the morning and two 50 mg capsules in the evening in 28-days cycle until confirmed disease progression, continuous treatment interruption, unacceptable toxicity or any other discontinuation criterion was met.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Olaparib
    Investigational medicinal product code
    KU-0059436
    Other name
    Lynparza
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Two 50 mg capsules in the morning and two 50 mg capsules in the evening administered orally, without interruption each day.

    Arm title
    		 Olaparib 400 mg
    Arm description
    		 Participants received eight 50 mg capsules in the morning and eight 50 mg capsules in the evening in 28-days cycle until confirmed disease progression, continuous treatment interruption, unacceptable toxicity or any other discontinuation criterion was met.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Olaparib
    Investigational medicinal product code
    KU-0059436
    Other name
    Lynparza
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Eight 50 mg capsules in the morning and eight 50 mg capsules in the evening administered orally, without interruption each day.

    Number of subjects in period 1
    		Olaparib 100 mg Olaparib 400 mg
    Started
    27
    27
    Completed
    13
    18
    Not completed
    14
    9
         Consent withdrawn by subject
    1
    -
         Disease progression
    11
    8
         Death
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Olaparib 100 mg
    Reporting group description
    		 Participants received two 50 mg capsules in the morning and two 50 mg capsules in the evening in 28-days cycle until confirmed disease progression, continuous treatment interruption, unacceptable toxicity or any other discontinuation criterion was met.

    Reporting group title
    Olaparib 400 mg
    Reporting group description
    		 Participants received eight 50 mg capsules in the morning and eight 50 mg capsules in the evening in 28-days cycle until confirmed disease progression, continuous treatment interruption, unacceptable toxicity or any other discontinuation criterion was met.

    Reporting group values
    		 Olaparib 100 mg Olaparib 400 mg Total
    Number of subjects
    		 27 27 54
    Age Categorical
    Units: Participants
        In utero
    		 0 0 0
        Preterm new born 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)
    		 24 26 50
        From 65-84 years
    		 3 1 4
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 44.7 ± 11.99 44.7 ± 9.55 -
    Gender Categorical
    Units: Participants
        Female
    		 27 27 54
        Male
    		 0 0 0
    Race
    Units: Subjects
        White
    		 25 26 51
        Black or African American
    		 1 0 1
        Asian
    		 1 1 2
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        American Indian or Alaska Native
    		 0 0 0
        Other
    		 0 0 0
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 2 2 4
        Not Hispanic or Latino
    		 4 6 10
        Unknown or not reported
    		 21 19 40

    End points

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    End points reporting groups
    Reporting group title
    Olaparib 100 mg
    Reporting group description
    		 Participants received two 50 mg capsules in the morning and two 50 mg capsules in the evening in 28-days cycle until confirmed disease progression, continuous treatment interruption, unacceptable toxicity or any other discontinuation criterion was met.

    Reporting group title
    Olaparib 400 mg
    Reporting group description
    		 Participants received eight 50 mg capsules in the morning and eight 50 mg capsules in the evening in 28-days cycle until confirmed disease progression, continuous treatment interruption, unacceptable toxicity or any other discontinuation criterion was met.

    Primary: Confirmed Objective Response Rate (ORR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Criteria

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    End point title
    		 Confirmed Objective Response Rate (ORR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Criteria [1]
    End point description
    The ORR is the percentage of participants whose best tumour response is either complete response (CR) or partial response (PR), according to the RECIST v1.0 criteria. The CR is defined as disappearance of all target lesions (TLs). The PR is defined as at least a 30% decrease in the sum of longest diameters (LD) taking as reference the baseline sum of LD. Percentage of participants with ORR is reported. The per-protocol (PP) population included all enrolled participants who completed the trial schedule and medication regime without any major deviations to the protocol.
    End point type
    Primary
    End point timeframe
    Baseline (Days -28 to 0), Day 1 of Cycle 3, thereafter every alternate cycles until study termination or withdrawal (approximately up to 2 years)
    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: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point. NB. This must have been written by stat
    End point values
    		 Olaparib 100 mg Olaparib 400 mg
    Number of subjects analysed
    24
    26
    Units: Percentage of participants
        number (not applicable)
    25.0
    42.3
    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
    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. Those participants who were withdrawn from the study without disease progression were regarded as censored at their last evaluable RECIST assessment. Where participants had not progressed at the termination of the study, they were also regarded as censored at their last evaluable RECIST assessment. PFS was analyzed using Kaplan-Meier estimate. The PP population included all enrolled participants who completed the trial schedule and medication regime without any major deviations to the protocol.
    End point type
    Secondary
    End point timeframe
    Baseline (Days -28 to 0), Day 1 of Cycle 3, thereafter every alternate cycles until study termination or withdrawal (approximately up to 2 years)
    End point values
    		 Olaparib 100 mg Olaparib 400 mg
    Number of subjects analysed
    24
    26
    Units: Days
        median (confidence interval 95%)
    122 (67 to 167)
    193.5 (140 to 226)
    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 tumour size is defined as the sum of the longest diameters as measured among all target lesions. At each assessment, the percentage change in tumour size is defined as 100 × 1 - (sum of all target lesion diameters at visit/sum of all target lesion diameters at baseline). The PP population included all enrolled participants who completed the trial schedule and medication regime without any major deviations to the protocol.
    End point type
    Secondary
    End point timeframe
    Baseline (Days -28 to 0) through study withdrawal (approximately up to 2 years)
    End point values
    		 Olaparib 100 mg Olaparib 400 mg
    Number of subjects analysed
    24
    26
    Units: Best percentage change in tumour size
        median (confidence interval 95%)
    -10.14 (-68.9 to 286.7)
    -29.43 (-100.0 to 26.7)
    No statistical analyses for this end point

    Secondary: Clinical Benefit Rate (CBR)

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    End point title
    		 Clinical Benefit Rate (CBR)
    End point description
    The CBR is defined as the percentage of participants with a RECIST tumour response of confirmed CR, PR or stable disease (SD) for ≥ 8 weeks +/- 1 week visit window. The CR is defined as disappearance of all TLs. The PR is defined as at least a 30% decrease in the sum of LD taking as reference the baseline sum of LD. Stable disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as references the smallest sum of LD since the treatment started. The PP population included all enrolled participants who completed the trial schedule and medication regime without any major deviations to the protocol.
    End point type
    Secondary
    End point timeframe
    From Day 1 of Cycle 3 through study withdrawal (approximately up to 2 years)
    End point values
    		 Olaparib 100 mg Olaparib 400 mg
    Number of subjects analysed
    24
    26
    Units: Percentage of Participants
        number (confidence interval 95%)
    70.8 (50.8 to 85.1)
    84.6 (66.5 to 93.9)
    No statistical analyses for this end point

    Secondary: Duration of Response (DoR) to Olaparib

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    End point title
    		 Duration of Response (DoR) to Olaparib
    End point description
    Duration of response is defined as the date of progression per RECIST criteria – the date when CR or PR [whichever is earliest] is confirmed + 1. The CR is defined as disappearance of all TLs. The PR is defined as at least a 30% decrease in the sum of LD taking as reference the baseline sum of LD. The PP population included all enrolled participants who completed the trial schedule and medication regime without any major deviations to the protocol. Duration of response was analyzed for those participants who had OR.
    End point type
    Secondary
    End point timeframe
    Baseline (Days -28 to 0), Day 1 of Cycle 3, thereafter every alternate cycles until study termination or withdrawal (approximately up to 2 years)
    End point values
    		 Olaparib 100 mg Olaparib 400 mg
    Number of subjects analysed
    6
    11
    Units: Days
        median (full range (min-max))
    140.5 (55 to 175)
    144.0 (92 to 393)
    No statistical analyses for this end point

    Secondary: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

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    End point title
    		 Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
    End point description
    An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug. Safety population included all participants who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Day 1 through Day 480 (maximum observed duration)
    End point values
    		 Olaparib 100 mg Olaparib 400 mg
    Number of subjects analysed
    27
    27
    Units: Participants
        Any TEAE
    27
    27
        Any TESAE
    5
    9
    No statistical analyses for this end point

    Secondary: Number of Participants With Improvement in Eastern Co-operative Oncology Group (ECOG) Performance Status Total Score From Baseline

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    End point title
    		 Number of Participants With Improvement in Eastern Co-operative Oncology Group (ECOG) Performance Status Total Score From Baseline
    End point description
    ECOG performance status is used by researchers to assess how a participant's disease is progressing. The scores are: 0=Fully Active, able to carry out work without restrictions; 1=Restricted activity and able to carry out light work or sedentary nature; 2=capable of self-care but unable to carry out work activities; 3=Capable of only limited self-care, confined to bed or chair more than 50% of waking hours; 4=Completely Disabled, and totally confined to bed or chair; 5=Dead. Change in ECOG performance status was defined as improved (less than the baseline value), no change (same as at baseline), worsened (greater than the baseline value) or missing (score is missing or was not recorded at baseline). If no measurement was recorded at Cycle 1 Day 1, the change was calculated in relation to the last recorded ECOG value prior to Day 1. The PP population included all enrolled participants who completed the trial schedule and medication regime without any major deviations to the protocol.
    End point type
    Secondary
    End point timeframe
    Screening (Days -7 to 0), Day 1 Cycle 7 (ie, after completing 6 cycles of treatment) and study withdrawal (approximately up to 2 years).
    End point values
    		 Olaparib 100 mg Olaparib 400 mg
    Number of subjects analysed
    27 [2]
    27 [3]
    Units: Participants
    number (not applicable)
        Cycle 7 Day 1 (n=11; n=15)
    1
    6
        Withdrawal visit (n=14; n=22)
    0
    2
    Notes
    [2] - Number of subjects analyzed is included in the category title
    [3] - Number of subjects analyzed is included in the category title
    No statistical analyses for this end point

    Secondary: Number of Participants With at Least 2-Grade Change from Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters

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    End point title
    		 Number of Participants With at Least 2-Grade Change from Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters
    End point description
    Number of participants with at least 2-grade change from baseline to worst toxicity grade in clinical laboratory parameters are reported. Laboratory parameters included hematology, clinical chemistry, and urinalysis. Safety population included all participants who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Day 1 through Day 480 (maximum observed duration)
    End point values
    		 Olaparib 100 mg Olaparib 400 mg
    Number of subjects analysed
    27
    27
    Units: Participants
        Haemoglobin
    2
    3
        White blood cells
    5
    11
        Absolute neutrophil count
    3
    6
        Lymphocytes
    3
    2
        Platelets
    0
    2
        Activated partial thromboplastin time
    1
    2
        Alanine aminotransferase
    2
    3
        Aspartate aminotransferase
    3
    1
        Alkaline phosphatase
    1
    0
        Gamma glutamyl transferase
    4
    2
        Albumin
    1
    0
        Total bilirubin
    0
    4
        Sodium (decrease)
    1
    0
        Potassium (increase)
    0
    1
        Creatinine
    0
    2
        Glucose (increase)
    2
    2
        Glucose (decrease)
    3
    3
        Calcium (decrease)
    3
    3
        Amylase
    1
    0
        Lipase
    2
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Clinically Significant Changes in Vital Signs from Baseline

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    End point title
    		 Number of Participants With Clinically Significant Changes in Vital Signs from Baseline
    End point description
    Number of participants with clinically significant changes in vital signs are reported. Vital sign parameters included body temperature, blood pressure, and pulse rate. Safety population included all participants who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Day 1 through Day 480 (maximum observed duration)
    End point values
    		 Olaparib 100 mg Olaparib 400 mg
    Number of subjects analysed
    27
    27
    Units: Participants
        Tachycardia
    1
    0
        Supraventricular arrhythmia
    1
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 to 480 (maximum observed duration)
    Adverse event reporting additional description
    The safety population included all participants who received at least one dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    12.0
    Reporting groups
    Reporting group title
    Olaparib 100 mg
    Reporting group description
    		 Participants received two 50 mg capsules in the morning and two 50 mg capsules in the evening in 28-days cycle until confirmed disease progression, continuous treatment interruption, unacceptable toxicity or any other discontinuation criterion was met.

    Reporting group title
    Olaparib 400 mg
    Reporting group description
    		 Participants received eight 50 mg capsules in the morning and eight 50 mg capsules in the evening in 28-days cycle until confirmed disease progression, continuous treatment interruption, unacceptable toxicity or any other discontinuation criterion was met.

    Serious adverse events
    		 Olaparib 100 mg Olaparib 400 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 27 (18.52%)
    9 / 27 (33.33%)
         number of deaths (all causes)
    3
    6
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 27 (3.70%)
         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
    Allergic transfusion reaction
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 27 (0.00%)
    3 / 27 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 27 (7.41%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory disorder
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Purpura
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 27 (3.70%)
         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 acute
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 27 (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
    		 Olaparib 100 mg Olaparib 400 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 27 (100.00%)
    26 / 27 (96.30%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    4 / 27 (14.81%)
    1 / 27 (3.70%)
         occurrences all number
    4
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    17 / 27 (62.96%)
    19 / 27 (70.37%)
         occurrences all number
    19
    25
    Oedema peripheral
         subjects affected / exposed
    4 / 27 (14.81%)
    6 / 27 (22.22%)
         occurrences all number
    4
    6
    Influenza like illness
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    2
    Asthenia
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    2
    Chest pain
         subjects affected / exposed
    1 / 27 (3.70%)
    2 / 27 (7.41%)
         occurrences all number
    1
    2
    Pyrexia
         subjects affected / exposed
    2 / 27 (7.41%)
    3 / 27 (11.11%)
         occurrences all number
    2
    3
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 27 (0.00%)
         occurrences all number
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea exertional
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    2
    Pleural effusion
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 27 (0.00%)
         occurrences all number
    2
    0
    Dyspnoea
         subjects affected / exposed
    9 / 27 (33.33%)
    1 / 27 (3.70%)
         occurrences all number
    9
    1
    Cough
         subjects affected / exposed
    8 / 27 (29.63%)
    4 / 27 (14.81%)
         occurrences all number
    8
    5
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    7 / 27 (25.93%)
    2 / 27 (7.41%)
         occurrences all number
    7
    2
    Depression
         subjects affected / exposed
    3 / 27 (11.11%)
    1 / 27 (3.70%)
         occurrences all number
    3
    1
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 27 (11.11%)
    0 / 27 (0.00%)
         occurrences all number
    3
    0
    Weight increased
         subjects affected / exposed
    0 / 27 (0.00%)
    3 / 27 (11.11%)
         occurrences all number
    0
    3
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 27 (0.00%)
         occurrences all number
    2
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 27 (22.22%)
    10 / 27 (37.04%)
         occurrences all number
    9
    23
    Peripheral sensory neuropathy
         subjects affected / exposed
    3 / 27 (11.11%)
    0 / 27 (0.00%)
         occurrences all number
    3
    0
    Hypoaesthesia
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    2
    Lethargy
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    2
    Migraine
         subjects affected / exposed
    1 / 27 (3.70%)
    3 / 27 (11.11%)
         occurrences all number
    1
    5
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 27 (11.11%)
    5 / 27 (18.52%)
         occurrences all number
    3
    5
    Neutropenia
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    2
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    15 / 27 (55.56%)
    14 / 27 (51.85%)
         occurrences all number
    19
    17
    Dyspepsia
         subjects affected / exposed
    2 / 27 (7.41%)
    5 / 27 (18.52%)
         occurrences all number
    2
    5
    Abdominal pain
         subjects affected / exposed
    2 / 27 (7.41%)
    5 / 27 (18.52%)
         occurrences all number
    2
    5
    Diarrhoea
         subjects affected / exposed
    4 / 27 (14.81%)
    8 / 27 (29.63%)
         occurrences all number
    5
    10
    Constipation
         subjects affected / exposed
    8 / 27 (29.63%)
    6 / 27 (22.22%)
         occurrences all number
    8
    6
    Vomiting
         subjects affected / exposed
    6 / 27 (22.22%)
    10 / 27 (37.04%)
         occurrences all number
    8
    16
    Flatulence
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    3
    Abdominal pain upper
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    3
    Abdominal pain lower
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 27 (0.00%)
         occurrences all number
    2
    0
    Toothache
         subjects affected / exposed
    2 / 27 (7.41%)
    1 / 27 (3.70%)
         occurrences all number
    2
    1
    Stomatitis
         subjects affected / exposed
    3 / 27 (11.11%)
    1 / 27 (3.70%)
         occurrences all number
    3
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 27 (3.70%)
    2 / 27 (7.41%)
         occurrences all number
    1
    2
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 27 (3.70%)
    2 / 27 (7.41%)
         occurrences all number
    1
    2
    Skin lesion
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    2
    Renal and urinary disorders
    Urinary tract pain
         subjects affected / exposed
    2 / 27 (7.41%)
    1 / 27 (3.70%)
         occurrences all number
    2
    1
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    7 / 27 (25.93%)
    2 / 27 (7.41%)
         occurrences all number
    7
    2
    Back pain
         subjects affected / exposed
    6 / 27 (22.22%)
    1 / 27 (3.70%)
         occurrences all number
    6
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 27 (7.41%)
    2 / 27 (7.41%)
         occurrences all number
    2
    3
    Bone pain
         subjects affected / exposed
    1 / 27 (3.70%)
    2 / 27 (7.41%)
         occurrences all number
    2
    2
    Muscular weakness
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 27 (0.00%)
         occurrences all number
    2
    0
    Arthralgia
         subjects affected / exposed
    6 / 27 (22.22%)
    4 / 27 (14.81%)
         occurrences all number
    7
    4
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    4
    Sinusitis
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 27 (0.00%)
         occurrences all number
    2
    0
    Bronchitis
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    2
    Oral candidiasis
         subjects affected / exposed
    2 / 27 (7.41%)
    1 / 27 (3.70%)
         occurrences all number
    2
    1
    Urinary tract infection
         subjects affected / exposed
    2 / 27 (7.41%)
    3 / 27 (11.11%)
         occurrences all number
    2
    3
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 27 (14.81%)
    2 / 27 (7.41%)
         occurrences all number
    5
    3
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    5 / 27 (18.52%)
    3 / 27 (11.11%)
         occurrences all number
    5
    3
    Hypokalaemia
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    2

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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 participants), up to 24 participants (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 participants. 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 1, 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 participants from treatment. The original protocol stated that participants 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.
    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. Blood sampling for peripheral blood mononuclear cells (PBMCs) was discontinued for new participants entering the study. Section 5.1 Study Design. Biochemistry assessments for amylase and lipase were added. Section 5.3 Selection of study population. The participant number was reduced (64 to 52), sites were added, and the recruitment period was lengthened. The statistics section (5.7.3) was changed to provide justification for the amended sample size. Section 5.3.2 Exclusion criteria. Exclusion criterion 3 was modified.
    04 Jun 2008
    Section 5.3 Selection of study population. The sample size was increased from ‘up to 26’ to ‘up to 27’ per cohort. Section 5.3.4 Discontinuation of participants from treatment or assessment. Participants in the 100 mg bd dose cohort could move to 400 mg bd, at the investigator’s discretion, if they had clinically significant progressive disease. Section 5.7.4 Interim analyses. Flexibility was added to the protocol to allow for a potential increase in dose in cohort 2 (100 mg bd). Informal interim monthly reviews of withdrawal rates from each cohort were introduced and if a statistically significantly higher withdrawal rate in the 100 mg bd dose group was observed, then participants in the 100 mg bd dose group were to be allowed to move to the 400 mg bd dose, at the investigator’s discretion.
    11 Feb 2009
    This amendment defined the end of study as 6 months post-LPI, or after approval of amendment 4, whichever was the later.
    19 Aug 2010
    1. The sponsor of the study was changed from KuDOS Pharmaceuticals Ltd., to AstraZeneca AB, with a change of address. The protocol was updated accordingly. 2. The sponsor project manager was changed. The protocol was updated accordingly. 3. Removed text specific to the previous protocol amendment (number 4) regarding visits done before the protocol was approved. 4. Updated the exclusion criteria to include 2 methods of contraception in combination rather than 1. 5. Updated the summary of Phase I data.
    26 Jul 2021
    Synopsis, Sections 3.1.1 Presentation of KU-0059436, 3.1.3 Packaging/Labelling of KU-0059436, 3.2 Dose, Route and Schedule of KU-0059436 Administration, 5.3 Table 3 Schedule of Assessments, and 6.1.3.5 Overdose and NEW Sections 3.3.3 Dose Modifications During the Continued Access Phase and 5.3.5 Patients in the Continued Access Phase: Addition of language regarding transition from capsule form to tablet form for those participants in continued access phase, including labelling, follow up, overdose and recommended capsule doses to equivalent tablet doses. Section 3.1.2 Storage/Stability of KU-0059436 Removal of text regarding KU-0059436 needing to be protected from light. Section 3.5.1 Medications That May NOT be Administered: Updated language on live/bacterial vaccines not being permitted while taking KU-0059436 (olaparib). Section 3.5.4 Contraception: Added language on contraception and length of time on contraception. Section 6.1.3.7 KU-0059436 (Olaparib) Adverse Events of Special Interest: Updated safety language regarding adverse events of special interest.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The plasma concentration data was analysed using a population approach and polyadenosine 5’ diphosphoribose polymerase (PARP) inhibition data had already been obtained from Study D0810C00002. Hence no PK and PARP inhibition data are included.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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