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ICEBERG 3: Dose-finding Study Comparing Efficacy and Safety of a PARP Inhibitor Against Doxil in BRCA+ve Advanced Ovarian Cancer

Sponsor
AstraZeneca (Industry)
Overall Status
Completed
CT.gov ID
NCT00628251
Collaborator
(none)
97
Enrollment
24
Locations
3
Arms
121.7
Actual Duration (Months)
4
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of the study is to compare the efficacy and safety of 2 doses of drug AZD2281 against liposomal doxorubicin to see which is effective and well tolerated in treating patients with measurable BRCA1- or BRCA2-positive advanced ovarian cancer and who have failed previous platinum therapy.

Condition or Disease Intervention/Treatment Phase
Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
97 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase II, Open-Label, Randomised, Comparative, International Multicentre Study to Assess the Safety and Efficacy of Different Doses of AZD2281 Given Orally Twice Daily Versus Intravenous Liposomal Doxorubicin Given Monthly in Patients With Advanced BRCA1- or BRCA2-Associated Ovarian Cancer Who Have Failed Previous Platinum-based Chemotherapy
Actual Study Start Date :
Jul 30, 2008
Actual Primary Completion Date :
Sep 15, 2009
Actual Study Completion Date :
Sep 19, 2018

Arms and Interventions

Arm Intervention/Treatment
Experimental: 1

AZD2281 Oral 200 mg BID

Drug: AZD2281
200mg oral twice daily
Active Comparator: 2

Liposomal Doxorubicin

Drug: Liposomal Doxorubicin
50mg/m2 Monthly Intravenous
Other Names:
  • Doxil®

    		•
    Experimental: 3

    AZD2281 Oral 400 mg BID

    Drug: AZD2281
    400mg Oral twice daily
    Other Names:
  • Olaparib

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Progression Free Survival (PFS) [Tumour assessment was to be assessed at screening, every 8 weeks during the study and at the withdrawal visit, up to 56 weeks. (Data cut-off for primary analysis of PFS: 15 September 2009)]

      PFS was defined as the time to progression from the date of randomisation until the date of radiological assessment of progression per RECIST criteria or death (by any cause in the absence of progression)

    Secondary Outcome Measures

    1. Objective Response Rate (ORR) [At the time that 57 PFS events had occurred (Data cut-off for primary analysis of PFS: 15 September 2009)]

      ORR was defined according to RECIST. Complete response (CR) or partial response - (PR)- 30% decrease Patients with a best RECIST response of CR or PR had to have a confirmed response at least 28 days later.

    2. Disease Control Rate [At the time that 57 PFS events had occurred (Data cut-off for primary analysis of PFS: 15 September 2009)]

      The number of patients with confirmed CR (disappearance of all target lesions) or PR (30% decrease in the sum of the longest diameter of target lesions ) or SD ( small changes ) >4 months, divided by the number of randomised patients

    3. Overall Duration of Response [At the time that 57 PFS events had occurred (Data cut-off for primary analysis of PFS: 15 September 2009)]

      The duration of response was defined as time (months) from initial assessment of PR/CR until earliest date of objective progression or death. (Values may be underestimated as some patients had not progressed at final analysis so true duration is likely to be greater than that in database.)

    4. Best Percentage Change in Tumour Size [At the time that 57 PFS events had occurred (Data cut-off for primary analysis of PFS: 15 September 2009)]

      The percentage change (reduction) from baseline in the sum of the lengths of the longest diameter (LD) of the RECIST target lesions were objectively documented, regardless of whether the patient was still taking study medication

    5. Best Percentage Change From Baseline in CA-125 Levels [At the time that 57 PFS events had occurred (Data cut-off for primary analysis of PFS: 15 September 2009)]

      Best percentage change in cancer antigen 125 (CA-125) levels

    6. Confirmed RECIST Response and/or CA-125 Response [At the time that 57 PFS events had occurred (Data cut-off for primary analysis of PFS: 15 September 2009)]

      The percentage of patients reporting a RECIST confirmed response and/or a CA-125 response (in the absence of progression). A CA-125 response was defined as a confirmed greater or equal to 50% reduction in CA-125.

    7. Overall Survival (OS) [At the time of the cut-off for the final analysis of overall survival (30 April 2010)]

      OS was defined as time from randomisation to date of death from any cause. Patients who had not died at time of analysis were censored at last date they were known to be alive. Median OS was not calculable for olaparib groups due to an insufficient number of deaths so the percentage of participants who died are shown along with 95% confidence intervals

    8. Best Quality of Life (QoL) Response for Trial Outcome Index (TOI) [At the time that 57 PFS events had occurred (Data cut-off for primary analysis of PFS: 15 September 2009)]

      Best HRQoL response using the TOI endpoint. Improvement was defined as a change from baseline of greater than or equal to +7. The TOI score ranges from 0-100.

    9. Best QoL Response for Total Functional Analysis of Cancer Therapy - Ovarian (FACT-O) [At the time that 57 PFS events had occurred (Data cut-off for primary analysis of PFS: 15 September 2009)]

      Best HRQoL response using the total FACT-O endpoint. Improvement was defined as a change from baseline of greater than or equal to +9.

    10. Best QoL Response for FACT-O Symptom Index (FOSI) [At the time that 57 PFS events had occurred (Data cut-off for primary analysis of PFS: 15 September 2009)]

      Best HRQoL response using the FOSI endpoint. Improvement was defined as a change from baseline of greater than or equal to +3.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 130 Years
    Sexes Eligible for Study:
    Female
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Advanced ovarian cancer with positive BRCA1 or BRCA2 status

    • Progressive or recurrent disease after platinum-based chemotherapy

    • Measurable disease by RECIST

    Exclusion Criteria:

    • Previous anthracycline treatment

    • Brain metastases

    • Less than 28 days since last treatment used to treat the disease

    • Considered a poor medical risk due to a serious uncontrolled disorder

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Research Site Los Angeles California United States 90048
    2 Research Site San Francisco California United States 94115
    3 Research Site Boca Raton Florida United States 33428
    4 Research Site Boston Massachusetts United States 02115
    5 Research Site New York New York United States 10065
    6 Research Site Houston Texas United States 77030
    7 Research Site East Melbourne Australia 3002
    8 Research Site Melbourne, Parkville Australia VIC 3050
    9 Research Site Randwick Australia 2031
    10 Research Site Leuven Belgium 3000
    11 Research Site Köln Germany 50937
    12 Research Site München Germany 81377
    13 Research Site Haifa Israel 31096
    14 Research Site Ramat Gan Israel 52621
    15 Research Site Tel Aviv Israel 6423906
    16 Research Site Szczecin Poland 70-111
    17 Research Site Barcelona Spain 08035
    18 Research Site Hospitalet deLlobregat Spain 08907
    19 Research Site Lund Sweden 22185
    20 Research Site Cambridge United Kingdom CB2 0QQ
    21 Research Site Edinburgh United Kingdom EH4 2XR
    22 Research Site London United Kingdom SE1 9RT
    23 Research Site Manchester United Kingdom M20 4BX
    24 Research Site Sutton United Kingdom SM2 5PT

    Sponsors and Collaborators

    • AstraZeneca

    Investigators

    • Study Director: Jane Robertson, BSc, MBCHB, MD, AstraZeneca
    • Principal Investigator: Stan Kaye, BSc, MB, FRCP, FRCR, SMedSCi, Royal Marsden NHS Foundation Trust

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    AstraZeneca
    ClinicalTrials.gov Identifier:
    NCT00628251
    Other Study ID Numbers:
    • D0810C00012
    First Posted:
    Mar 5, 2008
    Last Update Posted:
    Dec 5, 2019
    Last Verified:
    Nov 1, 2019
    Keywords provided by AstraZeneca
    Advanced ovarian cancer
    BRCA1 protein
    BRCA2 protein
    Poly(ADP ribose) polymerases
    Additional relevant MeSH terms:
    Ovarian Neoplasms
    Carcinoma, Ovarian Epithelial
    Doxorubicin
    Liposomal doxorubicin
    Olaparib

    Study Results

    Participant Flow

    Recruitment Details First patient enrolled on 30 July 2008 and last patient on 3 March 2009 at 25 centres in 9 countries
    Pre-assignment Detail 97 of 125 screened women with advanced BRCA 1/2 ovarian cancer who had chemotherapy were randomized
    Arm/Group Title Olaparib 200 mg bd Olaparib 400 mg bd Liposomal Doxorubicin
    Arm/Group Description Olaparib (AZD2281) 200 mg oral capsules twice daily Olaparib (AZD2281) 400 mg oral capsules twice daily Liposomal doxorubicin 50 mg/m2 intravenously every 4 weeks
    Period Title: Randomised Part
    STARTED 32 32 33
    COMPLETED 32 32 32
    NOT COMPLETED 0 0 1
    Period Title: Randomised Part
    STARTED 32 32 32
    Discontinued Initial Study Treatment 22 20 25
    Crossover to Olaparib 0 0 14
    Ongoing Crossover at DCO 0 0 5
    Discontinued Crossover 0 0 9
    COMPLETED 10 12 7
    NOT COMPLETED 22 20 25

    Baseline Characteristics

    Arm/Group Title Olaparib 200 mg bd Olaparib 400 mg bd Liposomal Doxorubicin Total
    Arm/Group Description Olaparib (AZD2281) 200 mg oral capsules twice daily Olaparib (AZD2281) 400 mg oral capsules twice daily Liposomal doxorubicin 50 mg/m2 intravenously every 4 weeks Total of all reporting groups
    Overall Participants 32 32 33 97
    Age (Years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Years]
    57.2
    (8.53)
    53.8
    (8.77)
    54.3
    (9.32)
    55.5
    (8.92)
    Sex: Female, Male (Count of Participants)
    Female
    32
    100%
    32
    100%
    33
    100%
    97
    100%
    Male
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Race/Ethnicity, Customized (Number) [Number]
    African-Caribbean
    0
    0%
    0
    0%
    1
    3%
    1
    1%
    Ashkenazi Jewish
    8
    25%
    10
    31.3%
    11
    33.3%
    29
    29.9%
    Sephardic Jewish
    0
    0%
    0
    0%
    2
    6.1%
    2
    2.1%
    Not applicable
    20
    62.5%
    21
    65.6%
    19
    57.6%
    60
    61.9%
    Other
    4
    12.5%
    1
    3.1%
    0
    0%
    5
    5.2%
    BRCA status (Number) [Number]
    Deleterious BRCA1 mutation
    26
    81.3%
    28
    87.5%
    27
    81.8%
    81
    83.5%
    Deleterious BRCA2 mutation
    6
    18.8%
    4
    12.5%
    6
    18.2%
    16
    16.5%

    Outcome Measures

    1. Primary Outcome
    Title Progression Free Survival (PFS)
    Description PFS was defined as the time to progression from the date of randomisation until the date of radiological assessment of progression per RECIST criteria or death (by any cause in the absence of progression)
    Time Frame Tumour assessment was to be assessed at screening, every 8 weeks during the study and at the withdrawal visit, up to 56 weeks. (Data cut-off for primary analysis of PFS: 15 September 2009)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Olaparib 200 mg bd Olaparib 400 mg bd Liposomal Doxorubicin
    Arm/Group Description Olaparib (AZD2281) 200 mg oral capsules twice daily Olaparib (AZD2281) 400 mg oral capsules twice daily Liposomal doxorubicin 50 mg/m2 intravenously every 4 weeks
    Measure Participants 32 32 33
    Count of Participants [Participants]
    19
    59.4%
    20
    62.5%
    20
    60.6%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Olaparib 200 mg bd, Olaparib 400 mg bd, Liposomal Doxorubicin
    Comments Analysis of olaparib 200 or 400 mg bd (n=64) versus liposomal doxorubicin (n=33). A hazard ratio < 1 favours olaparib.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.6604
    Comments If the observed p-value for the combined olaparib groups is <0.02 (1-sided) then the result will be regarded as statistically significant.
    Method Regression, Cox
    Comments Cox proportional hazards model with factors for treatment, BRCA (1 or 2) and platinum sensitivity (sensitive=1 or resistant/refractory=0).
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.88
    Confidence Interval (2-Sided) 95%
    0.51 to 1.56
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Olaparib 200 mg bd, Liposomal Doxorubicin
    Comments Analysis of olaparib 200 (n=32) versus liposomal doxorubicin (n=33). A hazard ratio < 1 favours olaparib.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.7794
    Comments An observed p-value of <0.005 (1-sided) will be regarded as statistically significant for a given pairwise comparison.
    Method Regression, Cox
    Comments Cox proportional hazards model with factors for treatment, BRCA (1 or 2) and platinum sensitivity (sensitive=1 or resistant/refractory=0).
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.91
    Confidence Interval () 95%
    0.48 to 1.74
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Olaparib 400 mg bd, Liposomal Doxorubicin
    Comments Analysis of olaparib 400 (n=32) versus liposomal doxorubicin (n=33). A hazard ratio < 1 favours olaparib.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.6604
    Comments An observed p-value of <0.005 (1-sided) will be regarded as statistically significant for a given pairwise comparison.
    Method Regression, Cox
    Comments Cox proportional hazards model with factors for treatment, BRCA (1 or 2) and platinum sensitivity (sensitive=1 or resistant/refractory=0).
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.86
    Confidence Interval (2-Sided) 95%
    0.45 to 1.62
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Secondary Outcome
    Title Objective Response Rate (ORR)
    Description ORR was defined according to RECIST. Complete response (CR) or partial response - (PR)- 30% decrease Patients with a best RECIST response of CR or PR had to have a confirmed response at least 28 days later.
    Time Frame At the time that 57 PFS events had occurred (Data cut-off for primary analysis of PFS: 15 September 2009)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Olaparib 200 mg bd Olaparib 400 mg bd Liposomal Doxorubicin
    Arm/Group Description Olaparib (AZD2281) 200 mg oral capsules twice daily Olaparib (AZD2281) 400 mg oral capsules twice daily Liposomal doxorubicin 50 mg/m2 intravenously every 4 weeks
    Measure Participants 32 32 33
    Complete response
    0
    0%
    0
    0%
    0
    0%
    Number of Partial responders
    8
    25%
    10
    31.3%
    6
    18.2%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Olaparib 200 mg bd, Olaparib 400 mg bd, Liposomal Doxorubicin
    Comments Analysis of olaparib 200 or 400 (n=64) versus liposomal doxorubicin (n=33).
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.1291
    Comments 2-sided p-value
    Method Regression, Logistic
    Comments Analysis was performed using logistic regression with factors for treatment, BRCA status and platinum sensitivity.
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 2.27
    Confidence Interval (2-Sided) 95%
    0.79 to 7.32
    Parameter Dispersion Type:
    Value:
    Estimation Comments An odds ratio >1 favoured olaparib
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Olaparib 200 mg bd, Liposomal Doxorubicin
    Comments Analysis of olaparib 200 (n=32) versus liposomal doxorubicin (n=33).
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.3131
    Comments 2-sided p-value
    Method Regression, Logistic
    Comments Analysis was performed using logistic regression with factors for treatment, BRCA status and platinum sensitivity.
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 1.90
    Confidence Interval (2-Sided) 95%
    0.55 to 7.01
    Parameter Dispersion Type:
    Value:
    Estimation Comments An odds ratio >1 favoured olaparib.
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Olaparib 400 mg bd, Liposomal Doxorubicin
    Comments Analysis of olaparib 400 (n=32) versus liposomal doxorubicin (n=33).
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.1079
    Comments
    Method Regression, Logistic
    Comments The analysis was performed using logistic regression with factors for treatment, BRCA status and platinum sensitivity.
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 2.69
    Confidence Interval (2-Sided) 95%
    0.81 to 9.76
    Parameter Dispersion Type:
    Value:
    Estimation Comments An odds ratio >1 favoured olaparib
    3. Secondary Outcome
    Title Disease Control Rate
    Description The number of patients with confirmed CR (disappearance of all target lesions) or PR (30% decrease in the sum of the longest diameter of target lesions ) or SD ( small changes ) >4 months, divided by the number of randomised patients
    Time Frame At the time that 57 PFS events had occurred (Data cut-off for primary analysis of PFS: 15 September 2009)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Olaparib 200 mg bd Olaparib 400 mg bd Liposomal Doxorubicin
    Arm/Group Description Olaparib (AZD2281) 200 mg oral capsules twice daily Olaparib (AZD2281) 400 mg oral capsules twice daily Liposomal doxorubicin 50 mg/m2 intravenously every 4 weeks
    Measure Participants 32 32 33
    Count of Participants [Participants]
    21
    65.6%
    21
    65.6%
    19
    57.6%
    4. Secondary Outcome
    Title Overall Duration of Response
    Description The duration of response was defined as time (months) from initial assessment of PR/CR until earliest date of objective progression or death. (Values may be underestimated as some patients had not progressed at final analysis so true duration is likely to be greater than that in database.)
    Time Frame At the time that 57 PFS events had occurred (Data cut-off for primary analysis of PFS: 15 September 2009)

    Outcome Measure Data

    Analysis Population Description
    Duration of response is analysed for patients experiencing a response.
    Arm/Group Title Olaparib 200 mg bd Olaparib 400 mg bd Olaparib 200 mg bd + Olaparib 400 mg bd, Liposomal Doxorubicin
    Arm/Group Description Olaparib (AZD2281) 200 mg oral capsules twice daily Olaparib (AZD2281) 400 mg oral capsules twice daily Olaparib (AZD2281) 200 or 400 mg oral capsules twice daily Liposomal doxorubicin 50 mg/m2 intravenously every 4 weeks
    Measure Participants 8 10 18 6
    Median (95% Confidence Interval) [Months]
    5.95
    6.80
    6.24
    5.49
    5. Secondary Outcome
    Title Best Percentage Change in Tumour Size
    Description The percentage change (reduction) from baseline in the sum of the lengths of the longest diameter (LD) of the RECIST target lesions were objectively documented, regardless of whether the patient was still taking study medication
    Time Frame At the time that 57 PFS events had occurred (Data cut-off for primary analysis of PFS: 15 September 2009)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Olaparib 200 mg bd Olaparib 400 mg bd Liposomal Doxorubicin
    Arm/Group Description Olaparib (AZD2281) 200 mg oral capsules twice daily Olaparib (AZD2281) 400 mg oral capsules twice daily Liposomal doxorubicin 50 mg/m2 intravenously every 4 weeks
    Measure Participants 32 32 33
    Median (Full Range) [Percent change]
    -15.90
    -24.60
    -14.3
    6. Secondary Outcome
    Title Best Percentage Change From Baseline in CA-125 Levels
    Description Best percentage change in cancer antigen 125 (CA-125) levels
    Time Frame At the time that 57 PFS events had occurred (Data cut-off for primary analysis of PFS: 15 September 2009)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Olaparib 200 mg bd Olaparib 400 mg bd Liposomal Doxorubicin
    Arm/Group Description Olaparib (AZD2281) 200 mg oral capsules twice daily Olaparib (AZD2281) 400 mg oral capsules twice daily Liposomal doxorubicin 50 mg/m2 intravenously every 4 weeks
    Measure Participants 30 31 33
    Median (Full Range) [Percent change]
    -37.42
    -71.19
    -55.8
    7. Secondary Outcome
    Title Confirmed RECIST Response and/or CA-125 Response
    Description The percentage of patients reporting a RECIST confirmed response and/or a CA-125 response (in the absence of progression). A CA-125 response was defined as a confirmed greater or equal to 50% reduction in CA-125.
    Time Frame At the time that 57 PFS events had occurred (Data cut-off for primary analysis of PFS: 15 September 2009)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Olaparib 200 mg bd Olaparib 400 mg bd Liposomal Doxorubicin
    Arm/Group Description Olaparib (AZD2281) 200 mg oral capsules twice daily Olaparib (AZD2281) 400 mg oral capsules twice daily Liposomal doxorubicin 50 mg/m2 intravenously every 4 weeks
    Measure Participants 32 32 33
    Number [Percentage of participants]
    37.5
    117.2%
    59.4
    185.6%
    39.4
    119.4%
    8. Secondary Outcome
    Title Overall Survival (OS)
    Description OS was defined as time from randomisation to date of death from any cause. Patients who had not died at time of analysis were censored at last date they were known to be alive. Median OS was not calculable for olaparib groups due to an insufficient number of deaths so the percentage of participants who died are shown along with 95% confidence intervals
    Time Frame At the time of the cut-off for the final analysis of overall survival (30 April 2010)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Olaparib 200 mg bd Olaparib 400 mg bd Liposomal Doxorubicin
    Arm/Group Description Olaparib (AZD2281) 200 mg oral capsules twice daily Olaparib (AZD2281) 400 mg oral capsules twice daily Liposomal doxorubicin 50 mg/m2 intravenously every 4 weeks
    Measure Participants 32 32 33
    Count of Participants [Participants]
    9
    28.1%
    11
    34.4%
    13
    39.4%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Olaparib 200 mg bd, Olaparib 400 mg bd, Liposomal Doxorubicin
    Comments Analysis of olaparib 200 or 400 (n=64) versus liposomal doxorubicin (n=33).
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.5781
    Comments 2-sided p-value
    Method Regression, Cox
    Comments Analysis was performed using a Cox proportional hazards model with factors for treatment, BRCA status and platinum sensitivity.
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.82
    Confidence Interval (2-Sided) 95%
    0.41 to 1.70
    Parameter Dispersion Type:
    Value:
    Estimation Comments A hazard ratio of <1 favoured olaparib.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Olaparib 200 mg bd, Liposomal Doxorubicin
    Comments Analysis of olaparib 200 (n=32) versus liposomal doxorubicin (n=33).
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.3417
    Comments 2-sided p-value
    Method Regression, Cox
    Comments Analysis was performed using a Cox proportional hazards model with factors for treatment, BRCA status and platinum sensitivity.
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.66
    Confidence Interval (2-Sided) 95%
    0.27 to 1.55
    Parameter Dispersion Type:
    Value:
    Estimation Comments A hazard ratio of <1 favoured olaparib.
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Olaparib 400 mg bd, Liposomal Doxorubicin
    Comments Analysis of olaparib 400 (n=32) versus liposomal doxorubicin (n=33).
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.9877
    Comments 2-sided p-value
    Method Regression, Cox
    Comments Analysis was performed using a Cox proportional hazards model with factors for treatment, BRCA status and platinum sensitivity.
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.01
    Confidence Interval (2-Sided) 95%
    0.44 to 2.27
    Parameter Dispersion Type:
    Value:
    Estimation Comments A hazard ratio of <1 favoured olaparib.
    9. Secondary Outcome
    Title Best Quality of Life (QoL) Response for Trial Outcome Index (TOI)
    Description Best HRQoL response using the TOI endpoint. Improvement was defined as a change from baseline of greater than or equal to +7. The TOI score ranges from 0-100.
    Time Frame At the time that 57 PFS events had occurred (Data cut-off for primary analysis of PFS: 15 September 2009)

    Outcome Measure Data

    Analysis Population Description
    Evaluable for TOI at baseline
    Arm/Group Title Olaparib 200 mg bd Olaparib 400 mg bd Liposomal Doxorubicin
    Arm/Group Description Olaparib (AZD2281) 200 mg oral capsules twice daily Olaparib (AZD2281) 400 mg oral capsules twice daily Liposomal doxorubicin 50 mg/m2 intravenously every 4 weeks
    Measure Participants 32 32 33
    Improved
    7
    21.9%
    5
    15.6%
    3
    9.1%
    No change
    10
    31.3%
    10
    31.3%
    11
    33.3%
    Worsened
    3
    9.4%
    7
    21.9%
    6
    18.2%
    Non-evaluable
    5
    15.6%
    7
    21.9%
    7
    21.2%
    10. Secondary Outcome
    Title Best QoL Response for Total Functional Analysis of Cancer Therapy - Ovarian (FACT-O)
    Description Best HRQoL response using the total FACT-O endpoint. Improvement was defined as a change from baseline of greater than or equal to +9.
    Time Frame At the time that 57 PFS events had occurred (Data cut-off for primary analysis of PFS: 15 September 2009)

    Outcome Measure Data

    Analysis Population Description
    Evaluable for FACT-O at baseline
    Arm/Group Title Olaparib 200 mg bd Olaparib 400 mg bd Liposomal Doxorubicin
    Arm/Group Description Olaparib (AZD2281) 200 mg oral capsules twice daily Olaparib (AZD2281) 400 mg oral capsules twice daily Liposomal doxorubicin 50 mg/m2 intravenously every 4 weeks
    Measure Participants 32 32 33
    Improved
    3
    9.4%
    6
    18.8%
    1
    3%
    No Change
    14
    43.8%
    11
    34.4%
    11
    33.3%
    Worsened
    3
    9.4%
    5
    15.6%
    7
    21.2%
    Non-evaluable
    5
    15.6%
    7
    21.9%
    8
    24.2%
    11. Secondary Outcome
    Title Best QoL Response for FACT-O Symptom Index (FOSI)
    Description Best HRQoL response using the FOSI endpoint. Improvement was defined as a change from baseline of greater than or equal to +3.
    Time Frame At the time that 57 PFS events had occurred (Data cut-off for primary analysis of PFS: 15 September 2009)

    Outcome Measure Data

    Analysis Population Description
    Evaluable for FOSI at baseline
    Arm/Group Title Olaparib 200 mg bd Olaparib 400 mg bd Liposomal Doxorubicin
    Arm/Group Description Olaparib (AZD2281) 200 mg oral capsules twice daily Olaparib (AZD2281) 400 mg oral capsules twice daily Liposomal doxorubicin 50 mg/m2 intravenously every 4 weeks
    Measure Participants 32 32 33
    Improved
    5
    15.6%
    4
    12.5%
    3
    9.1%
    No change
    14
    43.8%
    9
    28.1%
    10
    30.3%
    Worsened
    1
    3.1%
    9
    28.1%
    7
    21.2%
    Non-evaluable
    5
    15.6%
    7
    21.9%
    7
    21.2%
    12. Primary Outcome
    Title Progression Free Survival (PFS)
    Description PFS was defined as the time to progression from the date of randomisation until the date of radiological assessment of progression per RECIST criteria or death (by any cause in the absence of progression)
    Time Frame Tumour assessment was to be assessed at screening, every 8 weeks during the study and at the withdrawal visit, up to 56 weeks. (Data cut-off for primary analysis of PFS: 15 September 2009)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Olaparib 200 mg bd Olaparib 400 mg bd Liposomal Doxorubicin
    Arm/Group Description Olaparib (AZD2281) 200 mg oral capsules twice daily Olaparib (AZD2281) 400 mg oral capsules twice daily Liposomal doxorubicin 50 mg/m2 intravenously every 4 weeks
    Measure Participants 32 32 33
    Median (95% Confidence Interval) [Months]
    6.5
    8.8
    7.1

    Adverse Events

    Time Frame
    Adverse Event Reporting Description AEs reported = all events up to OS data cut-off. After PFS data cut-off, AEs only collected for olaparib and cross-over groups. The safety profile of these 2 groups at OS was consistent with that at time of PFS. One patient was recorded as crossing over to olaparib but not receiving cross-over treatment.
    Arm/Group Title Olaparib 200 mg bd Olaparib 400 mg bd Liposomal Doxorubicin
    Arm/Group Description Olaparib (AZD2281) 200 mg oral capsules twice daily Olaparib (AZD2281) 400 mg oral capsules twice daily Liposomal doxorubicin 50 mg/m2 intravenously every 4 weeks
    All Cause Mortality
    Olaparib 200 mg bd Olaparib 400 mg bd Liposomal Doxorubicin
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    Olaparib 200 mg bd Olaparib 400 mg bd Liposomal Doxorubicin
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 5/32 (15.6%) 6/32 (18.8%) 5/32 (15.6%)
    Gastrointestinal disorders
    Vomiting 0/32 (0%) 0/32 (0%) 1/32 (3.1%)
    Abdominal Pain Lower 0/32 (0%) 0/32 (0%) 1/32 (3.1%)
    Constipation 1/32 (3.1%) 0/32 (0%) 0/32 (0%)
    Intestinal Obstruction 1/32 (3.1%) 1/32 (3.1%) 0/32 (0%)
    Nausea 0/32 (0%) 0/32 (0%) 1/32 (3.1%)
    Small Intestinal Obstruction 0/32 (0%) 1/32 (3.1%) 0/32 (0%)
    Subileus 0/32 (0%) 1/32 (3.1%) 0/32 (0%)
    General disorders
    Fatigue 1/32 (3.1%) 0/32 (0%) 1/32 (3.1%)
    Pyrexia 0/32 (0%) 1/32 (3.1%) 0/32 (0%)
    Hepatobiliary disorders
    Cholelithiasis 0/32 (0%) 0/32 (0%) 1/32 (3.1%)
    Infections and infestations
    Bacteraemia 0/32 (0%) 1/32 (3.1%) 0/32 (0%)
    Injury, poisoning and procedural complications
    Overdose 0/32 (0%) 0/32 (0%) 0/32 (0%)
    Haemoglobin Decreased 0/32 (0%) 1/32 (3.1%) 0/32 (0%)
    Metabolism and nutrition disorders
    Hypokalaemia 0/32 (0%) 0/32 (0%) 0/32 (0%)
    Hyponatraemia 0/32 (0%) 0/32 (0%) 0/32 (0%)
    Musculoskeletal and connective tissue disorders
    Back Pain 0/32 (0%) 0/32 (0%) 0/32 (0%)
    Intervertebral Disc Degeneration 0/32 (0%) 1/32 (3.1%) 0/32 (0%)
    Musculoskeletal Chest Pain 1/32 (3.1%) 0/32 (0%) 0/32 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Myelodysplastic Syndrome 1/32 (3.1%) 0/32 (0%) 0/32 (0%)
    Nervous system disorders
    Cerebrovascular Accident 2/32 (6.3%) 0/32 (0%) 0/32 (0%)
    Syncope 1/32 (3.1%) 0/32 (0%) 1/32 (3.1%)
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea 0/32 (0%) 0/32 (0%) 1/32 (3.1%)
    Vascular disorders
    Deep Vein Thrombosis 0/32 (0%) 0/32 (0%) 1/32 (3.1%)
    Other (Not Including Serious) Adverse Events
    Olaparib 200 mg bd Olaparib 400 mg bd Liposomal Doxorubicin
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 32/32 (100%) 32/32 (100%) 31/32 (96.9%)
    Blood and lymphatic system disorders
    Anaemia 4/32 (12.5%) 11/32 (34.4%) 2/32 (6.3%)
    Neutropenia 2/32 (6.3%) 3/32 (9.4%) 6/32 (18.8%)
    Leukopenia 5/32 (15.6%) 2/32 (6.3%) 1/32 (3.1%)
    Thrombocytopenia 2/32 (6.3%) 0/32 (0%) 1/32 (3.1%)
    Cardiac disorders
    Palpitations 0/32 (0%) 2/32 (6.3%) 1/32 (3.1%)
    Eye disorders
    Dry Eye 0/32 (0%) 0/32 (0%) 2/32 (6.3%)
    Gastrointestinal disorders
    Nausea 19/32 (59.4%) 25/32 (78.1%) 18/32 (56.3%)
    Stomatitis 0/32 (0%) 1/32 (3.1%) 19/32 (59.4%)
    Vomiting 11/32 (34.4%) 16/32 (50%) 10/32 (31.3%)
    Abdominal Pain 12/32 (37.5%) 8/32 (25%) 12/32 (37.5%)
    Constipation 9/32 (28.1%) 6/32 (18.8%) 12/32 (37.5%)
    Diarrhoea 8/32 (25%) 12/32 (37.5%) 10/32 (31.3%)
    Dyspepsia 5/32 (15.6%) 7/32 (21.9%) 7/32 (21.9%)
    Abdominal Distension 3/32 (9.4%) 3/32 (9.4%) 5/32 (15.6%)
    Dry Mouth 0/32 (0%) 4/32 (12.5%) 3/32 (9.4%)
    Flatulence 2/32 (6.3%) 4/32 (12.5%) 2/32 (6.3%)
    Gastrooesophageal Reflux Disease 1/32 (3.1%) 3/32 (9.4%) 2/32 (6.3%)
    Haemorrhoids 1/32 (3.1%) 1/32 (3.1%) 3/32 (9.4%)
    Abdominal Discomfort 0/32 (0%) 2/32 (6.3%) 0/32 (0%)
    Abdominal Pain Upper 1/32 (3.1%) 2/32 (6.3%) 2/32 (6.3%)
    Ascites 2/32 (6.3%) 0/32 (0%) 0/32 (0%)
    Dysphagia 0/32 (0%) 1/32 (3.1%) 2/32 (6.3%)
    Gastritis 0/32 (0%) 2/32 (6.3%) 0/32 (0%)
    Intestinal Obstruction 0/32 (0%) 0/32 (0%) 2/32 (6.3%)
    Mouth Ulceration 0/32 (0%) 0/32 (0%) 2/32 (6.3%)
    Oral Pain 1/32 (3.1%) 0/32 (0%) 2/32 (6.3%)
    Salivary Hypersecretion 0/32 (0%) 2/32 (6.3%) 0/32 (0%)
    General disorders
    Fatigue 12/32 (37.5%) 21/32 (65.6%) 14/32 (43.8%)
    Asthenia 6/32 (18.8%) 11/32 (34.4%) 4/32 (12.5%)
    Mucosal Inflammation 0/32 (0%) 0/32 (0%) 7/32 (21.9%)
    Pyrexia 1/32 (3.1%) 4/32 (12.5%) 4/32 (12.5%)
    Chills 0/32 (0%) 1/32 (3.1%) 3/32 (9.4%)
    Oedema Peripheral 2/32 (6.3%) 3/32 (9.4%) 2/32 (6.3%)
    Pain 0/32 (0%) 1/32 (3.1%) 2/32 (6.3%)
    Immune system disorders
    Drug Hypersensitivity 0/32 (0%) 0/32 (0%) 2/32 (6.3%)
    Infections and infestations
    Urinary Tract Infection 5/32 (15.6%) 11/32 (34.4%) 4/32 (12.5%)
    Upper Respiratory Tract Infection 5/32 (15.6%) 2/32 (6.3%) 2/32 (6.3%)
    Influenza 3/32 (9.4%) 2/32 (6.3%) 1/32 (3.1%)
    Nasopharyngitis 2/32 (6.3%) 2/32 (6.3%) 3/32 (9.4%)
    Bronchitis 1/32 (3.1%) 1/32 (3.1%) 2/32 (6.3%)
    Gastroenteritis 0/32 (0%) 0/32 (0%) 2/32 (6.3%)
    Intertrigo Candida 0/32 (0%) 0/32 (0%) 2/32 (6.3%)
    Rhinitis 0/32 (0%) 2/32 (6.3%) 0/32 (0%)
    Tinea Pedis 0/32 (0%) 0/32 (0%) 2/32 (6.3%)
    Tonsillitis 0/32 (0%) 2/32 (6.3%) 0/32 (0%)
    Viral Infection 2/32 (6.3%) 2/32 (6.3%) 1/32 (3.1%)
    Body Temperature Increased 1/32 (3.1%) 3/32 (9.4%) 0/32 (0%)
    Weight Decreased 2/32 (6.3%) 2/32 (6.3%) 2/32 (6.3%)
    Metabolism and nutrition disorders
    Decreased Appetite 5/32 (15.6%) 5/32 (15.6%) 8/32 (25%)
    Hypomagnesaemia 2/32 (6.3%) 1/32 (3.1%) 1/32 (3.1%)
    Musculoskeletal and connective tissue disorders
    Back Pain 3/32 (9.4%) 6/32 (18.8%) 5/32 (15.6%)
    Arthralgia 3/32 (9.4%) 0/32 (0%) 2/32 (6.3%)
    Pain In Extremity 1/32 (3.1%) 3/32 (9.4%) 3/32 (9.4%)
    Flank Pain 2/32 (6.3%) 0/32 (0%) 0/32 (0%)
    Groin Pain 1/32 (3.1%) 0/32 (0%) 2/32 (6.3%)
    Muscle Spasms 2/32 (6.3%) 2/32 (6.3%) 0/32 (0%)
    Musculoskeletal Chest Pain 0/32 (0%) 1/32 (3.1%) 2/32 (6.3%)
    Musculoskeletal Pain 2/32 (6.3%) 1/32 (3.1%) 2/32 (6.3%)
    Myalgia 2/32 (6.3%) 2/32 (6.3%) 1/32 (3.1%)
    Nervous system disorders
    Headache 8/32 (25%) 9/32 (28.1%) 8/32 (25%)
    Dizziness 2/32 (6.3%) 7/32 (21.9%) 3/32 (9.4%)
    Dysgeusia 5/32 (15.6%) 5/32 (15.6%) 0/32 (0%)
    Neuropathy Peripheral 2/32 (6.3%) 3/32 (9.4%) 2/32 (6.3%)
    Memory Impairment 2/32 (6.3%) 1/32 (3.1%) 1/32 (3.1%)
    Psychiatric disorders
    Insomnia 3/32 (9.4%) 4/32 (12.5%) 2/32 (6.3%)
    Anxiety 2/32 (6.3%) 1/32 (3.1%) 2/32 (6.3%)
    Renal and urinary disorders
    Pollakiuria 1/32 (3.1%) 2/32 (6.3%) 0/32 (0%)
    Respiratory, thoracic and mediastinal disorders
    Cough 6/32 (18.8%) 6/32 (18.8%) 5/32 (15.6%)
    Dyspnoea 2/32 (6.3%) 2/32 (6.3%) 4/32 (12.5%)
    Oropharyngeal Pain 4/32 (12.5%) 1/32 (3.1%) 2/32 (6.3%)
    Dyspnoea Exertional 0/32 (0%) 2/32 (6.3%) 0/32 (0%)
    Productive Cough 0/32 (0%) 2/32 (6.3%) 0/32 (0%)
    Skin and subcutaneous tissue disorders
    Palmar-Plantar Erythrodysaesthesia Syndrome 0/32 (0%) 0/32 (0%) 20/32 (62.5%)
    Rash 3/32 (9.4%) 3/32 (9.4%) 14/32 (43.8%)
    Alopecia 3/32 (9.4%) 4/32 (12.5%) 7/32 (21.9%)
    Erythema 0/32 (0%) 0/32 (0%) 6/32 (18.8%)
    Pruritus 0/32 (0%) 0/32 (0%) 5/32 (15.6%)
    Blister 0/32 (0%) 0/32 (0%) 4/32 (12.5%)
    Dry Skin 1/32 (3.1%) 0/32 (0%) 4/32 (12.5%)
    Skin Hyperpigmentation 0/32 (0%) 0/32 (0%) 3/32 (9.4%)
    Exfoliative Rash 0/32 (0%) 0/32 (0%) 2/32 (6.3%)
    Vascular disorders
    Hypertension 0/32 (0%) 7/32 (21.9%) 1/32 (3.1%)
    Hot Flush 4/32 (12.5%) 1/32 (3.1%) 1/32 (3.1%)
    Hypotension 2/32 (6.3%) 0/32 (0%) 1/32 (3.1%)

    Limitations/Caveats

    The AEs reported include all events up to the OS data cut-off. After the PFS data cut-off, AEs were only collected for the olaparib and cross-over groups. The safety profile of these 2 groups at OS was consistent with that at the time of PFS.

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    No publication of the study results may be made until publication of the results of the multi-centre study or 2 years after study completion, whichever is the sooner

    Results Point of Contact

    Name/Title Paula del Rosario
    Organization AstraZeneca
    Phone +44 7884 735492
    Email ClinicalTrialTransparency@astrazeneca.com
    Responsible Party:
    AstraZeneca
    ClinicalTrials.gov Identifier:
    NCT00628251
    Other Study ID Numbers:
    • D0810C00012
    First Posted:
    Mar 5, 2008
    Last Update Posted:
    Dec 5, 2019
    Last Verified:
    Nov 1, 2019