Ovarian Neoplasms
Conditions
Keywords
Advanced ovarian cancer, BRCA1 protein, BRCA2 protein, Poly(ADP ribose) polymerases
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.
Interventions
DRUGAZD2281
400mg Oral twice daily
DRUGLiposomal Doxorubicin
50mg/m2 Monthly Intravenous
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 130 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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.) |
| 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 |
| 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 |
| 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. |
| 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 |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
Australia, Belgium, Germany, Israel, Poland, Spain, Sweden, United Kingdom, United States
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 details
97 of 125 screened women with advanced BRCA 1/2 ovarian cancer who had chemotherapy were randomized
Participants by arm
| Arm | Count |
|---|---|
| Olaparib 200 mg bd Olaparib (AZD2281) 200 mg oral capsules twice daily | 32 |
| Olaparib 400 mg bd Olaparib (AZD2281) 400 mg oral capsules twice daily | 32 |
| Liposomal Doxorubicin Liposomal doxorubicin 50 mg/m2 intravenously every 4 weeks | 33 |
| Total | 97 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Ongoing Initial Study Treatment at DCO | Adverse Event | 1 | 2 | 3 |
| Ongoing Initial Study Treatment at DCO | Condition under investigation worsened | 19 | 15 | 13 |
| Ongoing Initial Study Treatment at DCO | Other | 1 | 0 | 2 |
| Ongoing Initial Study Treatment at DCO | Other reason | 0 | 1 | 6 |
| Ongoing Initial Study Treatment at DCO | Withdrawal by Subject | 1 | 2 | 1 |
| Randomised Part | Withdrawal by Subject | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Olaparib 200 mg bd | Olaparib 400 mg bd | Liposomal Doxorubicin | Total |
|---|---|---|---|---|
| Age, Continuous | 57.2 Years STANDARD_DEVIATION 8.53 | 53.8 Years STANDARD_DEVIATION 8.77 | 54.3 Years STANDARD_DEVIATION 9.32 | 55.5 Years STANDARD_DEVIATION 8.92 |
| BRCA status Deleterious BRCA1 mutation | 26 Participants | 28 Participants | 27 Participants | 81 Participants |
| BRCA status Deleterious BRCA2 mutation | 6 Participants | 4 Participants | 6 Participants | 16 Participants |
| Race/Ethnicity, Customized African-Caribbean | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Ashkenazi Jewish | 8 Participants | 10 Participants | 11 Participants | 29 Participants |
| Race/Ethnicity, Customized Not applicable | 20 Participants | 21 Participants | 19 Participants | 60 Participants |
| Race/Ethnicity, Customized Other | 4 Participants | 1 Participants | 0 Participants | 5 Participants |
| Race/Ethnicity, Customized Sephardic Jewish | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Female | 32 Participants | 32 Participants | 33 Participants | 97 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 32 / 32 | 32 / 32 | 31 / 32 |
| serious Total, serious adverse events | 5 / 32 | 6 / 32 | 5 / 32 |
Outcome results
Primary
Progression Free Survival (PFS)
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)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Olaparib 200 mg bd | Progression Free Survival (PFS) | 19 Participants |
| Olaparib 400 mg bd | Progression Free Survival (PFS) | 20 Participants |
| Liposomal Doxorubicin | Progression Free Survival (PFS) | 20 Participants |
Comparison: Analysis of olaparib 200 or 400 mg bd (n=64) versus liposomal doxorubicin (n=33). A hazard ratio \< 1 favours olaparib.p-value: 0.660495% CI: [0.51, 1.56]Regression, Cox
Comparison: Analysis of olaparib 200 (n=32) versus liposomal doxorubicin (n=33). A hazard ratio \< 1 favours olaparib.p-value: 0.779495% CI: [0.48, 1.74]Regression, Cox
Comparison: Analysis of olaparib 400 (n=32) versus liposomal doxorubicin (n=33). A hazard ratio \< 1 favours olaparib.p-value: 0.660495% CI: [0.45, 1.62]Regression, Cox
Primary
Progression Free Survival (PFS)
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)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Olaparib 200 mg bd | Progression Free Survival (PFS) | 6.5 Months |
| Olaparib 400 mg bd | Progression Free Survival (PFS) | 8.8 Months |
| Liposomal Doxorubicin | Progression Free Survival (PFS) | 7.1 Months |
Secondary
Best Percentage Change From Baseline in CA-125 Levels
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)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Olaparib 200 mg bd | Best Percentage Change From Baseline in CA-125 Levels | -37.42 Percent change |
| Olaparib 400 mg bd | Best Percentage Change From Baseline in CA-125 Levels | -71.19 Percent change |
| Liposomal Doxorubicin | Best Percentage Change From Baseline in CA-125 Levels | -55.8 Percent change |
Secondary
Best Percentage Change in Tumour Size
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)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Olaparib 200 mg bd | Best Percentage Change in Tumour Size | -15.90 Percent change |
| Olaparib 400 mg bd | Best Percentage Change in Tumour Size | -24.60 Percent change |
| Liposomal Doxorubicin | Best Percentage Change in Tumour Size | -14.3 Percent change |
Secondary
Best QoL Response for FACT-O Symptom Index (FOSI)
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)
Population: Evaluable for FOSI at baseline
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Olaparib 200 mg bd | Best QoL Response for FACT-O Symptom Index (FOSI) | Improved | 5 Participants |
| Olaparib 200 mg bd | Best QoL Response for FACT-O Symptom Index (FOSI) | No change | 14 Participants |
| Olaparib 200 mg bd | Best QoL Response for FACT-O Symptom Index (FOSI) | Worsened | 1 Participants |
| Olaparib 200 mg bd | Best QoL Response for FACT-O Symptom Index (FOSI) | Non-evaluable | 5 Participants |
| Olaparib 400 mg bd | Best QoL Response for FACT-O Symptom Index (FOSI) | Non-evaluable | 7 Participants |
| Olaparib 400 mg bd | Best QoL Response for FACT-O Symptom Index (FOSI) | Improved | 4 Participants |
| Olaparib 400 mg bd | Best QoL Response for FACT-O Symptom Index (FOSI) | Worsened | 9 Participants |
| Olaparib 400 mg bd | Best QoL Response for FACT-O Symptom Index (FOSI) | No change | 9 Participants |
| Liposomal Doxorubicin | Best QoL Response for FACT-O Symptom Index (FOSI) | Non-evaluable | 7 Participants |
| Liposomal Doxorubicin | Best QoL Response for FACT-O Symptom Index (FOSI) | No change | 10 Participants |
| Liposomal Doxorubicin | Best QoL Response for FACT-O Symptom Index (FOSI) | Worsened | 7 Participants |
| Liposomal Doxorubicin | Best QoL Response for FACT-O Symptom Index (FOSI) | Improved | 3 Participants |
Secondary
Best QoL Response for Total Functional Analysis of Cancer Therapy - Ovarian (FACT-O)
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)
Population: Evaluable for FACT-O at baseline
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Olaparib 200 mg bd | Best QoL Response for Total Functional Analysis of Cancer Therapy - Ovarian (FACT-O) | Improved | 3 Participants |
| Olaparib 200 mg bd | Best QoL Response for Total Functional Analysis of Cancer Therapy - Ovarian (FACT-O) | No Change | 14 Participants |
| Olaparib 200 mg bd | Best QoL Response for Total Functional Analysis of Cancer Therapy - Ovarian (FACT-O) | Worsened | 3 Participants |
| Olaparib 200 mg bd | Best QoL Response for Total Functional Analysis of Cancer Therapy - Ovarian (FACT-O) | Non-evaluable | 5 Participants |
| Olaparib 400 mg bd | Best QoL Response for Total Functional Analysis of Cancer Therapy - Ovarian (FACT-O) | Non-evaluable | 7 Participants |
| Olaparib 400 mg bd | Best QoL Response for Total Functional Analysis of Cancer Therapy - Ovarian (FACT-O) | Improved | 6 Participants |
| Olaparib 400 mg bd | Best QoL Response for Total Functional Analysis of Cancer Therapy - Ovarian (FACT-O) | Worsened | 5 Participants |
| Olaparib 400 mg bd | Best QoL Response for Total Functional Analysis of Cancer Therapy - Ovarian (FACT-O) | No Change | 11 Participants |
| Liposomal Doxorubicin | Best QoL Response for Total Functional Analysis of Cancer Therapy - Ovarian (FACT-O) | Non-evaluable | 8 Participants |
| Liposomal Doxorubicin | Best QoL Response for Total Functional Analysis of Cancer Therapy - Ovarian (FACT-O) | No Change | 11 Participants |
| Liposomal Doxorubicin | Best QoL Response for Total Functional Analysis of Cancer Therapy - Ovarian (FACT-O) | Worsened | 7 Participants |
| Liposomal Doxorubicin | Best QoL Response for Total Functional Analysis of Cancer Therapy - Ovarian (FACT-O) | Improved | 1 Participants |
Secondary
Best Quality of Life (QoL) Response for Trial Outcome Index (TOI)
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)
Population: Evaluable for TOI at baseline
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Olaparib 200 mg bd | Best Quality of Life (QoL) Response for Trial Outcome Index (TOI) | Improved | 7 Participants |
| Olaparib 200 mg bd | Best Quality of Life (QoL) Response for Trial Outcome Index (TOI) | Worsened | 3 Participants |
| Olaparib 200 mg bd | Best Quality of Life (QoL) Response for Trial Outcome Index (TOI) | No change | 10 Participants |
| Olaparib 200 mg bd | Best Quality of Life (QoL) Response for Trial Outcome Index (TOI) | Non-evaluable | 5 Participants |
| Olaparib 400 mg bd | Best Quality of Life (QoL) Response for Trial Outcome Index (TOI) | No change | 10 Participants |
| Olaparib 400 mg bd | Best Quality of Life (QoL) Response for Trial Outcome Index (TOI) | Improved | 5 Participants |
| Olaparib 400 mg bd | Best Quality of Life (QoL) Response for Trial Outcome Index (TOI) | Non-evaluable | 7 Participants |
| Olaparib 400 mg bd | Best Quality of Life (QoL) Response for Trial Outcome Index (TOI) | Worsened | 7 Participants |
| Liposomal Doxorubicin | Best Quality of Life (QoL) Response for Trial Outcome Index (TOI) | Non-evaluable | 7 Participants |
| Liposomal Doxorubicin | Best Quality of Life (QoL) Response for Trial Outcome Index (TOI) | Worsened | 6 Participants |
| Liposomal Doxorubicin | Best Quality of Life (QoL) Response for Trial Outcome Index (TOI) | No change | 11 Participants |
| Liposomal Doxorubicin | Best Quality of Life (QoL) Response for Trial Outcome Index (TOI) | Improved | 3 Participants |
Secondary
Confirmed RECIST Response and/or CA-125 Response
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)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Olaparib 200 mg bd | Confirmed RECIST Response and/or CA-125 Response | 37.5 Percentage of participants |
| Olaparib 400 mg bd | Confirmed RECIST Response and/or CA-125 Response | 59.4 Percentage of participants |
| Liposomal Doxorubicin | Confirmed RECIST Response and/or CA-125 Response | 39.4 Percentage of participants |
Secondary
Disease Control Rate
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)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Olaparib 200 mg bd | Disease Control Rate | 21 Participants |
| Olaparib 400 mg bd | Disease Control Rate | 21 Participants |
| Liposomal Doxorubicin | Disease Control Rate | 19 Participants |
Secondary
Objective Response Rate (ORR)
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)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Olaparib 200 mg bd | Objective Response Rate (ORR) | Complete response | 0 Participants |
| Olaparib 200 mg bd | Objective Response Rate (ORR) | Number of Partial responders | 8 Participants |
| Olaparib 400 mg bd | Objective Response Rate (ORR) | Complete response | 0 Participants |
| Olaparib 400 mg bd | Objective Response Rate (ORR) | Number of Partial responders | 10 Participants |
| Liposomal Doxorubicin | Objective Response Rate (ORR) | Complete response | 0 Participants |
| Liposomal Doxorubicin | Objective Response Rate (ORR) | Number of Partial responders | 6 Participants |
Comparison: Analysis of olaparib 200 or 400 (n=64) versus liposomal doxorubicin (n=33).p-value: 0.129195% CI: [0.79, 7.32]Regression, Logistic
Comparison: Analysis of olaparib 200 (n=32) versus liposomal doxorubicin (n=33).p-value: 0.313195% CI: [0.55, 7.01]Regression, Logistic
Comparison: Analysis of olaparib 400 (n=32) versus liposomal doxorubicin (n=33).p-value: 0.107995% CI: [0.81, 9.76]Regression, Logistic
Secondary
Overall Duration of Response
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)
Population: Duration of response is analysed for patients experiencing a response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Olaparib 200 mg bd | Overall Duration of Response | 5.95 Months |
| Olaparib 400 mg bd | Overall Duration of Response | 6.80 Months |
| Liposomal Doxorubicin | Overall Duration of Response | 6.24 Months |
| Liposomal Doxorubicin | Overall Duration of Response | 5.49 Months |
Secondary
Overall Survival (OS)
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)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Olaparib 200 mg bd | Overall Survival (OS) | 9 Participants |
| Olaparib 400 mg bd | Overall Survival (OS) | 11 Participants |
| Liposomal Doxorubicin | Overall Survival (OS) | 13 Participants |
Comparison: Analysis of olaparib 200 or 400 (n=64) versus liposomal doxorubicin (n=33).p-value: 0.578195% CI: [0.41, 1.7]Regression, Cox
Comparison: Analysis of olaparib 200 (n=32) versus liposomal doxorubicin (n=33).p-value: 0.341795% CI: [0.27, 1.55]Regression, Cox
Comparison: Analysis of olaparib 400 (n=32) versus liposomal doxorubicin (n=33).p-value: 0.987795% CI: [0.44, 2.27]Regression, Cox