Relapsed Ovarian Cancer, BRCA Mutation, Platinum Sensitivity
Conditions
Keywords
BRCA, ovarian, platinum, chemotherapy
Brief summary
This is a non-randomized, open-label study to assess olaparib tablets as a treatment for subjects with different homologous recombination deficiency (HRD) tumor status and with platinum-sensitive, relapsed, high-grade serous or high-grade endometrioid ovarian cancer. Subjects should have received at least 1 prior line of platinum-based chemotherapy.
Detailed description
This is a Phase II, open-label, non-randomized, multi-center study assessing the efficacy and safety of olaparib tablets 300 mg (two 150 mg tablets) given orally twice daily (bid) in subjects with platinum-sensitive or partially platinum-sensitive, relapsed, high-grade serous or high-grade endometrioid epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received at least 1 prior line of platinum-based chemotherapy. The study will assess the effectiveness of olaparib tablets as measured by the objective response rate (ORR) as determined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, in subjects with germline BRCA mutations (gBRCAm), somatic BRCA mutations (sBRCAm), or potential aberrations in homologous recombination deficiency (HRD) as determined by myChoice® HRD, as well as in subjects without identifiable HRD. This study will utilize Myriad BRACAnalysis CDx® for germline BRCA analysis and a tumor test (myChoice® HRD) for tumor BRCA analysis and HRD status. Four cohorts will be identified based upon the genetic testing described above: * Cohort 1: gBRCAm, * Cohort 2: sBRCAm and germline BRCA wild type, * Cohort 3: myChoice® HRD positive (genomic instability positive) and BRCA wild type (BRCAwt) (no BRCA mutation), * Cohort 4: myChoice® HRD negative (genomic instability negative) and BRCAwt (no BRCA mutation).
Interventions
DRUGOLAPARIB
300 mg olaparib tablets taken orally twice daily
Sponsors
AstraZeneca
Study design
Allocation
NA
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
* Provision of written signed informed consent prior to any study specific procedures; * Female subjects with histologically diagnosed relapsed high-grade serous or high-grade endometrioid ovarian cancer; * At least 1 lesion (measurable by RECIST v1.1) that can be accurately assessed at baseline by computed tomography (CT)/magnetic resonance imaging (MRI) and is suitable for repeated assessment; * Subjects must have received at least 1 prior platinum-based line of chemotherapy for ovarian cancer. Note: There is no limit on the number of lines of chemotherapy; * Subjects must be partially-platinum-sensitive (defined as progression 6 to 12 months after the end of the last platinum-based chemotherapy) or platinum sensitive (defined as progression \> 12 months after the end of the last platinum-based chemotherapy); * Subjects must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment; * ECOG performance status 0 to 1; * Subjects must have a life expectancy greater than or equal to 16 weeks; * Postmenopausal or evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 28 days of study treatment and confirmed prior to treatment on Day 1; * Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations; and * Formalin fixed, paraffin embedded tumor sample (either archival or fresh sample) from the primary or recurrent cancer must be available for central testing. If there is not written confirmation of the availability of an archived or fresh tumor sample prior to enrollment, the subject is not eligible for the study.
Exclusion criteria
* Involvement in the planning and/or conduct of the study (applies to both AstraZeneca Representative staff and/or staff at the study site); * Previous enrollment in the present study; * Exposure to any investigational product (IP) within 30 days or 5 half-lives (whichever is longer) prior to start of study treatment; * Any previous treatment with a PARP inhibitor, including olaparib; * Subjects who have platinum-resistant or refractory disease defined as progression during or within 6 months of the last platinum-based chemotherapy; * Other malignancy within the last 5 years (few exceptions apply); * Resting ECG with clinically significant abnormal findings; * Subjects receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks prior to study treatment; * Concomitant use of known strong CYP3A inhibitors or moderate CYP3A inhibitors; * Concomitant use of known strong or moderate CYP3A inducers; * Persistent toxicities (\> Common Terminology Criteria for Adverse Event \[CTCAE\] grade 2) caused by previous cancer therapy, excluding alopecia; * Subjects with MDS/AML or with features suggestive of MDS/AML; * Subjects with pneumonitis or at risk of pneumonitis; * Subjects with symptomatic uncontrolled brain metastases; * Major surgery within 2 weeks of starting study treatment, and subjects must have recovered from any effects of any major surgery; * Subjects considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease, or active, uncontrolled infection; * Breast feeding women; * Immunocompromised subjects, e.g., subjects who are known to be serologically positive for human immunodeficiency virus; * Subjects with known active hepatitis (i.e., Hepatitis B or C) due to risk of transmitting the infection through blood or other body fluids
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate, Defined as the Percentage of Subjects With a Best Overall Response of Confirmed Complete Response (CR) or Partial Response (PR) | From first dose up until progression, or last evaluable assessment in the absence of progression (up to 36 months) | To determine the clinical effectiveness of olaparib treatment in each of 4 cohorts assessed using ORR according to RECIST v1.1 criteria (Investigator determined) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| CA-125 Response Rate, Defined as the Percentage of Subjects With a CA-125 Response According to GCIG Criteria Divided by the Number of Subjects Evaluable for CA-125 Response | From baseline to Day 1 of each cycle and end of study treatment visit (up to 36 months) | To determine the clinical effectiveness of olaparib treatment in each of 4 cohorts assessed using CA-125 response rate |
| Disease Control Rate Defined as the Percentage of Subjects Who Have a Best Overall Response of CR or PR or SD at Greater Than or Equal to 8 Weeks Divided by the Number of Subjects in the Efficacy Analysis Set, Prior to Any PD Event | From first dose up until progression, or last evaluable assessment in the absence of progression | To determine the clinical effectiveness of olaparib treatment in each of 4 cohorts assessed using disease control rate (DCR). DCR is defined as the percentage of subjects with a best overall response of CR or PR (at any time up to and including the defined analysis cut-off point) or who have demonstrated stable disease (SD) for at least 8 weeks from first dose, divided by the number of subjects in the efficacy analysis set. |
| Progression Free Survival | From first dose to earlier date of assessment of objective progression or death by any cause in the absence of progression (up to 36 months) | To determine the clinical effectiveness of olaparib treatment in each of 4 cohorts assessed using progression free survival |
| Duration of Response, for Those Subjects With a Confirmed Response of CR or PR | From the date of the measurement criteria for CR or PR are first met until the date of documented progression or death in the absence of disease progression (up to 36 months) | To determine the clinical effectiveness of olaparib treatment in each of 4 cohorts assessed using duration of response |
| Overall Survival | From date of first dose to date of death from any cause (up to 48 months) | To determine the clinical effectiveness of olaparib treatment in each of 4 cohorts assessed using overall survival |
| HRD Status as Per HRRm Gene Panel Assessment Will be Correlated With Clinical Outcome (ORR) for Subjects Enrolled in the 2 Cohorts With BRCAwt (Cohorts 3 and 4) | At baseline | To determine the clinical effectiveness of olaparib treatment in each of 4 cohorts assessed using HRRm gene panel status related to clinical outcome |
| Time to Any Progression | From first dose to earlier date of CA-125 progression or RECIST v1.1 progression, or death by any cause in absence of progression (up to 36 months) | To determine the clinical effectiveness of olaparib treatment in each of 4 cohorts assessed using time to any progression |
Countries
Canada, United States
Participant flow
Pre-assignment details
A total of 272 subjects enrolled. One subject did not receive treatment and was excluded from analysis (Cohort 2 patient). All participants received a dose of 300mg BID of study drug
Participants by arm
| Arm | Count |
|---|---|
| COHORT 1 germline BRCA mutant | 75 |
| COHORT 2 somatic BRCA mutant, germline BRCA wild type | 26 |
| COHORT 3 HRD positive and no BRCA mutation | 68 |
| COHORT 4 HRD negative and no BRCA mutation | 90 |
| Unassigned Cohort unassigned | 13 |
| Total | 272 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Death | 20 | 5 | 23 | 47 | 7 |
| Overall Study | Lost to Follow-up | 1 | 0 | 1 | 0 | 0 |
| Overall Study | Protocol Violation | 0 | 1 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 3 | 4 | 1 |
| Overall Study | Withdrawn from study before data cut-off | 28 | 12 | 23 | 25 | 1 |
Baseline characteristics
| Characteristic | COHORT 1 | COHORT 2 | COHORT 3 | COHORT 4 | Unassigned | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 60.7 Age Continuous STANDARD_DEVIATION 9.3 | 69.7 Age Continuous STANDARD_DEVIATION 9 | 63.2 Age Continuous STANDARD_DEVIATION 9.9 | 67.8 Age Continuous STANDARD_DEVIATION 9.5 | 69.8 Age Continuous STANDARD_DEVIATION 10 | 64.9 Age Continuous STANDARD_DEVIATION 10.1 |
| Race/Ethnicity, Customized AMERICAN INDIAN OR ALASKA NATIVE | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized ASIAN | 6 Participants | 3 Participants | 11 Participants | 6 Participants | 2 Participants | 28 Participants |
| Race/Ethnicity, Customized BLACK OR AFRICAN AMERICAN | 7 Participants | 0 Participants | 5 Participants | 5 Participants | 0 Participants | 17 Participants |
| Race/Ethnicity, Customized NATIVE HAWAIIAN OR OTHER PACIFIC ISLANDER | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized OTHER | 4 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 6 Participants |
| Race/Ethnicity, Customized WHITE | 58 Participants | 23 Participants | 50 Participants | 78 Participants | 11 Participants | 220 Participants |
| Sex/Gender, Customized Female | 75 Participants | 26 Participants | 68 Participants | 90 Participants | 13 Participants | 272 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 20 / 75 | 5 / 25 | 23 / 68 | 47 / 90 | 7 / 13 |
| other Total, other adverse events | 75 / 75 | 25 / 25 | 67 / 68 | 88 / 90 | 12 / 13 |
| serious Total, serious adverse events | 13 / 75 | 8 / 25 | 7 / 68 | 35 / 90 | 6 / 13 |
Outcome results
Primary
Objective Response Rate, Defined as the Percentage of Subjects With a Best Overall Response of Confirmed Complete Response (CR) or Partial Response (PR)
To determine the clinical effectiveness of olaparib treatment in each of 4 cohorts assessed using ORR according to RECIST v1.1 criteria (Investigator determined)
Time frame: From first dose up until progression, or last evaluable assessment in the absence of progression (up to 36 months)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 | Objective Response Rate, Defined as the Percentage of Subjects With a Best Overall Response of Confirmed Complete Response (CR) or Partial Response (PR) | 69.3 Percent |
| Cohort 2 | Objective Response Rate, Defined as the Percentage of Subjects With a Best Overall Response of Confirmed Complete Response (CR) or Partial Response (PR) | 64.0 Percent |
| COHORT 3 | Objective Response Rate, Defined as the Percentage of Subjects With a Best Overall Response of Confirmed Complete Response (CR) or Partial Response (PR) | 29.4 Percent |
| COHORT 4 | Objective Response Rate, Defined as the Percentage of Subjects With a Best Overall Response of Confirmed Complete Response (CR) or Partial Response (PR) | 10.1 Percent |
| Unassigned | Objective Response Rate, Defined as the Percentage of Subjects With a Best Overall Response of Confirmed Complete Response (CR) or Partial Response (PR) | 30.8 Percent |
Secondary
CA-125 Response Rate, Defined as the Percentage of Subjects With a CA-125 Response According to GCIG Criteria Divided by the Number of Subjects Evaluable for CA-125 Response
To determine the clinical effectiveness of olaparib treatment in each of 4 cohorts assessed using CA-125 response rate
Time frame: From baseline to Day 1 of each cycle and end of study treatment visit (up to 36 months)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 | CA-125 Response Rate, Defined as the Percentage of Subjects With a CA-125 Response According to GCIG Criteria Divided by the Number of Subjects Evaluable for CA-125 Response | 93.2 Percent |
| Cohort 2 | CA-125 Response Rate, Defined as the Percentage of Subjects With a CA-125 Response According to GCIG Criteria Divided by the Number of Subjects Evaluable for CA-125 Response | 70.0 Percent |
| COHORT 3 | CA-125 Response Rate, Defined as the Percentage of Subjects With a CA-125 Response According to GCIG Criteria Divided by the Number of Subjects Evaluable for CA-125 Response | 47.9 Percent |
| COHORT 4 | CA-125 Response Rate, Defined as the Percentage of Subjects With a CA-125 Response According to GCIG Criteria Divided by the Number of Subjects Evaluable for CA-125 Response | 26.6 Percent |
| Unassigned | CA-125 Response Rate, Defined as the Percentage of Subjects With a CA-125 Response According to GCIG Criteria Divided by the Number of Subjects Evaluable for CA-125 Response | 66.7 Percent |
Secondary
Disease Control Rate Defined as the Percentage of Subjects Who Have a Best Overall Response of CR or PR or SD at Greater Than or Equal to 8 Weeks Divided by the Number of Subjects in the Efficacy Analysis Set, Prior to Any PD Event
To determine the clinical effectiveness of olaparib treatment in each of 4 cohorts assessed using disease control rate (DCR). DCR is defined as the percentage of subjects with a best overall response of CR or PR (at any time up to and including the defined analysis cut-off point) or who have demonstrated stable disease (SD) for at least 8 weeks from first dose, divided by the number of subjects in the efficacy analysis set.
Time frame: From first dose up until progression, or last evaluable assessment in the absence of progression
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 | Disease Control Rate Defined as the Percentage of Subjects Who Have a Best Overall Response of CR or PR or SD at Greater Than or Equal to 8 Weeks Divided by the Number of Subjects in the Efficacy Analysis Set, Prior to Any PD Event | 96.0 Percent |
| Cohort 2 | Disease Control Rate Defined as the Percentage of Subjects Who Have a Best Overall Response of CR or PR or SD at Greater Than or Equal to 8 Weeks Divided by the Number of Subjects in the Efficacy Analysis Set, Prior to Any PD Event | 100.0 Percent |
| COHORT 3 | Disease Control Rate Defined as the Percentage of Subjects Who Have a Best Overall Response of CR or PR or SD at Greater Than or Equal to 8 Weeks Divided by the Number of Subjects in the Efficacy Analysis Set, Prior to Any PD Event | 79.4 Percent |
| COHORT 4 | Disease Control Rate Defined as the Percentage of Subjects Who Have a Best Overall Response of CR or PR or SD at Greater Than or Equal to 8 Weeks Divided by the Number of Subjects in the Efficacy Analysis Set, Prior to Any PD Event | 75.3 Percent |
| Unassigned | Disease Control Rate Defined as the Percentage of Subjects Who Have a Best Overall Response of CR or PR or SD at Greater Than or Equal to 8 Weeks Divided by the Number of Subjects in the Efficacy Analysis Set, Prior to Any PD Event | 92.3 Percent |
Secondary
Duration of Response, for Those Subjects With a Confirmed Response of CR or PR
To determine the clinical effectiveness of olaparib treatment in each of 4 cohorts assessed using duration of response
Time frame: From the date of the measurement criteria for CR or PR are first met until the date of documented progression or death in the absence of disease progression (up to 36 months)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 | Duration of Response, for Those Subjects With a Confirmed Response of CR or PR | 9.4 Months |
| Cohort 2 | Duration of Response, for Those Subjects With a Confirmed Response of CR or PR | 14.7 Months |
| COHORT 3 | Duration of Response, for Those Subjects With a Confirmed Response of CR or PR | 10.0 Months |
| COHORT 4 | Duration of Response, for Those Subjects With a Confirmed Response of CR or PR | 5.3 Months |
| Unassigned | Duration of Response, for Those Subjects With a Confirmed Response of CR or PR | 7.5 Months |
Secondary
HRD Status as Per HRRm Gene Panel Assessment Will be Correlated With Clinical Outcome (ORR) for Subjects Enrolled in the 2 Cohorts With BRCAwt (Cohorts 3 and 4)
To determine the clinical effectiveness of olaparib treatment in each of 4 cohorts assessed using HRRm gene panel status related to clinical outcome
Time frame: At baseline
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 | HRD Status as Per HRRm Gene Panel Assessment Will be Correlated With Clinical Outcome (ORR) for Subjects Enrolled in the 2 Cohorts With BRCAwt (Cohorts 3 and 4) | 11.1 Percent |
| Cohort 2 | HRD Status as Per HRRm Gene Panel Assessment Will be Correlated With Clinical Outcome (ORR) for Subjects Enrolled in the 2 Cohorts With BRCAwt (Cohorts 3 and 4) | 32.1 Percent |
| COHORT 3 | HRD Status as Per HRRm Gene Panel Assessment Will be Correlated With Clinical Outcome (ORR) for Subjects Enrolled in the 2 Cohorts With BRCAwt (Cohorts 3 and 4) | 8.3 Percent |
| COHORT 4 | HRD Status as Per HRRm Gene Panel Assessment Will be Correlated With Clinical Outcome (ORR) for Subjects Enrolled in the 2 Cohorts With BRCAwt (Cohorts 3 and 4) | 10.5 Percent |
Secondary
Overall Survival
To determine the clinical effectiveness of olaparib treatment in each of 4 cohorts assessed using overall survival
Time frame: From date of first dose to date of death from any cause (up to 48 months)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 | Overall Survival | NA Months |
| Cohort 2 | Overall Survival | NA Months |
| COHORT 3 | Overall Survival | NA Months |
| COHORT 4 | Overall Survival | 23.8 Months |
| Unassigned | Overall Survival | 18 Months |
Secondary
Progression Free Survival
To determine the clinical effectiveness of olaparib treatment in each of 4 cohorts assessed using progression free survival
Time frame: From first dose to earlier date of assessment of objective progression or death by any cause in the absence of progression (up to 36 months)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 | Progression Free Survival | 11 Months |
| Cohort 2 | Progression Free Survival | 10.8 Months |
| COHORT 3 | Progression Free Survival | 7.2 Months |
| COHORT 4 | Progression Free Survival | 5.4 Months |
| Unassigned | Progression Free Survival | 9.2 Months |
Secondary
Time to Any Progression
To determine the clinical effectiveness of olaparib treatment in each of 4 cohorts assessed using time to any progression
Time frame: From first dose to earlier date of CA-125 progression or RECIST v1.1 progression, or death by any cause in absence of progression (up to 36 months)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 | Time to Any Progression | 10.9 Months |
| Cohort 2 | Time to Any Progression | 11.1 Months |
| COHORT 3 | Time to Any Progression | 7.2 Months |
| COHORT 4 | Time to Any Progression | 5.3 Months |
| Unassigned | Time to Any Progression | 7.3 Months |