Ovarian Carcinoma, Breast Cancer
Conditions
Keywords
Breast cancer, Ovarian cancer, BRCA, Triple negative, Poly(ADP ribose) polymerases, Known BRCA or Recurrent High Grade Serious/ Undifferentiated Tubo- Ovarian Carcinoma, Known BRCA or Triple Negative Breast Cancer
Brief summary
This is a Phase II, open label, non randomized correlative study of AZD2281 in patients with recurrent breast and ovarian cancer in both BRCA inherited mutation carriers and non-carriers to identify objective response rate and to assess for early markers of activity and to assess correlative markers that may provide helpful information for subsequent clinical trials. Approximately 110 patients from 7 centers in Canada will be enrolled into this study
Interventions
DRUGAZD2281
PARP inhibitor Olaparib tablets, oral
Sponsors
British Columbia Cancer Agency
AstraZeneca
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
4 parallel arms for the 2 tumour types and the BRCA mutation groups: 1. Triple negative breast Cancer with unknown BRCA mutation status: AZD2281 400 mg bid (capsules)/ 300 mg bid (tablets) administered orally 2. Known BRCA mutation positive breast cancer: AZD2281 400 mg bid (capsules)/ 300 mg bid (tablets) to be administered orally 3. High grade serous/undifferentiated tubo-ovarian carcinoma with unknown BRCA status: AZD2281 400 mg bid (capsules)/ 300 mg bid (tablets) administered orally 4. Known BRCA mutation positive ovarian cancer: AZD2281 400 mg bid (capsules)/ 300 mg bid (tablets) administered orally.
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed high grade serous and/or undifferentiated carcinoma of ovary, fallopian tube or peritoneum * Oestrogen, progesterone and HER2 negative advanced adenocarcinoma of the breast * Known BRCA positive breast cancer or ovarian cancer, that is not high grade serous or undifferentiated tubo-ovarian carcinoma. * Performance status of no more than 2.
Exclusion criteria
* Any chemotherapy, radiotherapy ( except palliative), endocrine or immunotherapy within 4 weeks prior to entry * Major surgery with 4 weeks of entering the study and must have recovered from effects of any major surgery .
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) Evaluated According to Response Evaluation Criteria In Solid Tumors (RECIST) Guidelines | Each patient with measurable disease at baseline was assessed for Objective Response from the sequence of RECIST scan data up to data cut-off, 26 March 2010. RECIST scans were performed every 8 weeks (+/- 2 weeks) from randomization. | Percentage of participants with confirmed best RECIST response of complete response (CR) or partial response (PR). Patients with a best RECIST response of CR or PR had to have a confirmed response at least 28 days later. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate (DCR) | 16 Weeks | Percentage of participants with confirmed best Response Evaluation Criteria In Solid Tumours (RECIST) response of complete response (CR), partial response (PR) orStable Disease (SD) |
| Duration of Response | RECIST tumour assessments carried out every 8 weeks from randomization (+/- 2 weeks) until data cut-off on 26 March 2010. | Duration of response is measured from the time the measurement criteria for CR or PR are met (whichever is first recorded) until the patient progresses (per RECIST criteria). If patient did not progress, they are censored at their last objective tumour assessment date. |
| Best Percentage Change From Baseline in Tumour Size | Each patient with measurable disease at baseline was assessed for best percentage change in tumour size from the sequence of RECIST scan data up to data cut-off, 26 March 2010. RECIST scans were performed every 8 weeks (+/- 2 weeks) from randomization. | The best percentage change (reduction) from baseline in tumour size (defined as the sum of the longest diameters as measured among all target lesions). |
| CA-125 Levels (Ovarian Cancer Patients Only) | 24 weeks | A response according to CA-125 has occurred if there is at least a 50% reduction in CA-125 levels from a pre-treatment sample. |
| Progression Free Survival (PFS) | RECIST tumour assessments carried out every 8 weeks from randomization (+/- 2 weeks) until data cut-off on 26 March 2010. | PFS is defined as the time from first dose to the earlier date of radiologic progression (as per Response Evaluation Criteria In Solid Tumours (RECIST) criteria or death by any cause in the absence of objective progression. |
Countries
Canada
Participant flow
Recruitment details
The first patient was enrolled on July 8, 2008 and efficacy and safety data were collected up to the data cut-off of March 26, 2010. Patients were enrolled at 6 centres in Canada. Of the 112 patients who gave informed consent 21 patients failed eligibility criteria or withdrew their consent and were not allocated to treatment.
Pre-assignment details
The study enrolled both known BRCA mutation carriers and patients with unknown BRCA status. Those with unknown status at entry had to provide a DNA sample for BRCA. One participant in arm 4 discontinued before receiving study drug and is excluded from the safety analysis set mutation analysis. Study data are summarised by confirmed mutation status.
Participants by arm
| Arm | Count |
|---|---|
| BRCA Positive Non-serous Ovarian Patients with non-serous ovarian cancer who have a harmful mutation in the breast cancer genes BRCA1 or BRCA2. (Serous tumors are the most common subtype of ovarian cancer; other subtypes are grouped together as non-serous in this study). | 4 |
| BRCA Positive Serous Ovarian Patients with serous ovarian cancer who have a harmful mutation in the breast cancer genes BRCA1 or BRCA2. (Serous tumors are the most common subtype of ovarian cancer). | 13 |
| BRCA Negative Non-serous Ovarian Patients with non-serous ovarian cancer who do not have a harmful mutation in the breast cancer genes BRCA1 or BRCA2 | 3 |
| BRCA Negative Serous Ovarian Patients with serous ovarian cancer who do not have a harmful mutation in the breast cancer genes BRCA1 or BRCA2 | 44 |
| BRCA Positive Non-triple Negative Breast Patients with non-Triple negative breast cancer (non-TNBC) who have a harmful mutation in the breast cancer genes BRCA1 or BRCA2. Non-TNBC are cancers that have receptors for oestrogen, progesterone or Her2 | 5 |
| BRCA Positive Triple Negative Breast Patients with Triple negative breast cancer (TNBC) who have a harmful mutation in the breast cancer genes BRCA1 or BRCA2. TNBC are cancers that don't have receptors for oestrogen, progesterone or Her2 (Some commonly used breast cancer treatments don't work for TNBC) | 5 |
| BRCA Negative Triple Negative Breast Patients with Triple negative breast cancer (TNBC) who do not have a harmful mutation in the breast cancer genes BRCA1 or BRCA2. | 16 |
| Total | 90 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 3 | 0 | 0 | 1 |
| Overall Study | Lack of Efficacy | 0 | 1 | 0 | 2 | 0 | 0 | 0 |
| Overall Study | Not Captured | 0 | 0 | 0 | 5 | 0 | 0 | 0 |
| Overall Study | Ongoing at data cut-off | 2 | 2 | 0 | 9 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | BRCA Positive Non-serous Ovarian | BRCA Positive Serous Ovarian | BRCA Negative Non-serous Ovarian | BRCA Negative Serous Ovarian | BRCA Positive Non-triple Negative Breast | BRCA Positive Triple Negative Breast | BRCA Negative Triple Negative Breast | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 60 Year STANDARD_DEVIATION 18.7 | 53.7 Year STANDARD_DEVIATION 7.3 | 60.3 Year STANDARD_DEVIATION 12.9 | 61 Year STANDARD_DEVIATION 9.5 | 49.4 Year STANDARD_DEVIATION 20.5 | 44.8 Year STANDARD_DEVIATION 15.5 | 48.8 Year STANDARD_DEVIATION 5.5 | 52.9 Year STANDARD_DEVIATION 13 |
| Sex: Female, Male Female | 4 Participants | 13 Participants | 3 Participants | 44 Participants | 5 Participants | 5 Participants | 16 Participants | 90 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 4 | 13 / 13 | 3 / 3 | 44 / 44 | 5 / 5 | 5 / 5 | 15 / 16 |
| serious Total, serious adverse events | 0 / 4 | 4 / 13 | 0 / 3 | 6 / 44 | 0 / 5 | 2 / 5 | 2 / 16 |
Outcome results
Primary
Objective Response Rate (ORR) Evaluated According to Response Evaluation Criteria In Solid Tumors (RECIST) Guidelines
Percentage of participants with confirmed best RECIST response of complete response (CR) or partial response (PR). Patients with a best RECIST response of CR or PR had to have a confirmed response at least 28 days later.
Time frame: Each patient with measurable disease at baseline was assessed for Objective Response from the sequence of RECIST scan data up to data cut-off, 26 March 2010. RECIST scans were performed every 8 weeks (+/- 2 weeks) from randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BRCA Positive Non-serous Ovarian | Objective Response Rate (ORR) Evaluated According to Response Evaluation Criteria In Solid Tumors (RECIST) Guidelines | 75 Percentage of participants |
| BRCA Positive Serous Ovarian | Objective Response Rate (ORR) Evaluated According to Response Evaluation Criteria In Solid Tumors (RECIST) Guidelines | 30.77 Percentage of participants |
| BRCA Negative Non-serous Ovarian | Objective Response Rate (ORR) Evaluated According to Response Evaluation Criteria In Solid Tumors (RECIST) Guidelines | 0 Percentage of participants |
| BRCA Negative Serous Ovarian | Objective Response Rate (ORR) Evaluated According to Response Evaluation Criteria In Solid Tumors (RECIST) Guidelines | 25.58 Percentage of participants |
| BRCA Positive Non-triple Negative Breast | Objective Response Rate (ORR) Evaluated According to Response Evaluation Criteria In Solid Tumors (RECIST) Guidelines | 0 Percentage of participants |
| BRCA Positive Triple Negative Breast | Objective Response Rate (ORR) Evaluated According to Response Evaluation Criteria In Solid Tumors (RECIST) Guidelines | 0 Percentage of participants |
| BRCA Negative Triple Negative Breast | Objective Response Rate (ORR) Evaluated According to Response Evaluation Criteria In Solid Tumors (RECIST) Guidelines | 0 Percentage of participants |
Secondary
Best Percentage Change From Baseline in Tumour Size
The best percentage change (reduction) from baseline in tumour size (defined as the sum of the longest diameters as measured among all target lesions).
Time frame: Each patient with measurable disease at baseline was assessed for best percentage change in tumour size from the sequence of RECIST scan data up to data cut-off, 26 March 2010. RECIST scans were performed every 8 weeks (+/- 2 weeks) from randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BRCA Positive Non-serous Ovarian | Best Percentage Change From Baseline in Tumour Size | -44.5 Percentage |
| BRCA Positive Serous Ovarian | Best Percentage Change From Baseline in Tumour Size | -21.6 Percentage |
| BRCA Negative Non-serous Ovarian | Best Percentage Change From Baseline in Tumour Size | 33.6 Percentage |
| BRCA Negative Serous Ovarian | Best Percentage Change From Baseline in Tumour Size | -14.1 Percentage |
| BRCA Positive Non-triple Negative Breast | Best Percentage Change From Baseline in Tumour Size | -35.3 Percentage |
| BRCA Positive Triple Negative Breast | Best Percentage Change From Baseline in Tumour Size | -36.4 Percentage |
| BRCA Negative Triple Negative Breast | Best Percentage Change From Baseline in Tumour Size | 21.3 Percentage |
Secondary
CA-125 Levels (Ovarian Cancer Patients Only)
A response according to CA-125 has occurred if there is at least a 50% reduction in CA-125 levels from a pre-treatment sample.
Time frame: 24 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BRCA Positive Non-serous Ovarian | CA-125 Levels (Ovarian Cancer Patients Only) | 75 Percentage of participants |
| BRCA Positive Serous Ovarian | CA-125 Levels (Ovarian Cancer Patients Only) | 33.33 Percentage of participants |
| BRCA Negative Non-serous Ovarian | CA-125 Levels (Ovarian Cancer Patients Only) | 0 Percentage of participants |
| BRCA Negative Serous Ovarian | CA-125 Levels (Ovarian Cancer Patients Only) | 28.57 Percentage of participants |
Secondary
Disease Control Rate (DCR)
Percentage of participants with confirmed best Response Evaluation Criteria In Solid Tumours (RECIST) response of complete response (CR), partial response (PR) orStable Disease (SD)
Time frame: 16 Weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BRCA Positive Non-serous Ovarian | Disease Control Rate (DCR) | 75 Percentage of participants |
| BRCA Positive Serous Ovarian | Disease Control Rate (DCR) | 53.85 Percentage of participants |
| BRCA Negative Non-serous Ovarian | Disease Control Rate (DCR) | 0 Percentage of participants |
| BRCA Negative Serous Ovarian | Disease Control Rate (DCR) | 47.73 Percentage of participants |
| BRCA Positive Non-triple Negative Breast | Disease Control Rate (DCR) | 60 Percentage of participants |
| BRCA Positive Triple Negative Breast | Disease Control Rate (DCR) | 20 Percentage of participants |
| BRCA Negative Triple Negative Breast | Disease Control Rate (DCR) | 0 Percentage of participants |
Secondary
Duration of Response
Duration of response is measured from the time the measurement criteria for CR or PR are met (whichever is first recorded) until the patient progresses (per RECIST criteria). If patient did not progress, they are censored at their last objective tumour assessment date.
Time frame: RECIST tumour assessments carried out every 8 weeks from randomization (+/- 2 weeks) until data cut-off on 26 March 2010.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BRCA Positive Non-serous Ovarian | Duration of Response | 277 Days |
| BRCA Positive Serous Ovarian | Duration of Response | 113 Days |
| BRCA Negative Serous Ovarian | Duration of Response | 384 Days |
Secondary
Progression Free Survival (PFS)
PFS is defined as the time from first dose to the earlier date of radiologic progression (as per Response Evaluation Criteria In Solid Tumours (RECIST) criteria or death by any cause in the absence of objective progression.
Time frame: RECIST tumour assessments carried out every 8 weeks from randomization (+/- 2 weeks) until data cut-off on 26 March 2010.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BRCA Positive Non-serous Ovarian | Progression Free Survival (PFS) | 346.5 Days |
| BRCA Positive Serous Ovarian | Progression Free Survival (PFS) | 219 Days |
| BRCA Negative Non-serous Ovarian | Progression Free Survival (PFS) | 79.5 Days |
| BRCA Negative Serous Ovarian | Progression Free Survival (PFS) | 192 Days |
| BRCA Positive Non-triple Negative Breast | Progression Free Survival (PFS) | 165 Days |
| BRCA Positive Triple Negative Breast | Progression Free Survival (PFS) | 106 Days |
| BRCA Negative Triple Negative Breast | Progression Free Survival (PFS) | 54 Days |