Ovarian Cancer
Conditions
Keywords
DNA damage repair, replication stress
Brief summary
The purpose of this study is to evaluate the efficacy and safety of prexasertib in women with platinum-resistant or refractory recurrent ovarian cancer.
Interventions
DRUGPrexasertib
Administered IV
Sponsors
Eli Lilly and Company
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Women who have high-grade serous ovarian, primary peritoneal or fallopian tube cancer. * Cohorts 1 to 3: Have platinum-resistant disease and have documented test results assessing alterations in the BRCA1 and BRCA2 genes prior to receiving study treatment. * Cohort 1: Are BRCA negative and have received 3 or more prior lines of therapy. * Cohort 2: Are BRCA negative and have received less than 3 prior lines of therapy. * Cohort 3: Are BRCA positive and have previously received a PARP. * Cohort 4: Have primary platinum refractory disease. * Have adequate organ function. * Must be able and willing to undergo mandatory tumor biopsy.
Exclusion criteria
* Cohorts 1-3: Have previously received all of the following agents at any time in the platinum-resistant setting: gemcitabine, pegylated liposomal doxorubicin, and paclitaxel. * Have known central nervous system malignancy or metastasis. * Have previously participated in any study involving a checkpoint kinase 1 inhibitor or have hypersensitivity to the study drug or excipients. * Have at least one of the following: * history of abdominal fistula or gastrointestinal perforation * intra-abdominal abscess within last 3 months prior to the first dose of study drug * a radiographically confirmed bowel obstruction within 3 months prior to the first dose of study drug * Have a symptomatic human immunodeficiency virus infection or symptomatic activated/reactivated hepatitis A, B, or C (screening is not required). * Have a serious cardiac condition. * Have a history of prior radiotherapy to the whole pelvis. * Have chronic daily treatment with corticosteroids, excluding inhaled or topical steroids. * Have known factors that may increase the risk of infection while on study drug treatment. These may include, but are not limited to, an indwelling peritoneal catheter or open wounds. Catheters for vascular access are permitted.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieve Complete Response (CR) or Partial Response (PR): Overall Response Rate (ORR) | Baseline through Disease Progression (Up to 6 months) | Overall response rate is the best response of complete response (CR) or partial response (PR) as classified by the independent central review according to the Response Evaluation Criteria In Solid Tumors (RECIST v1.1). CR is a disappearance of all target and non-target lesions and normalization of tumor marker level. PR is an at least 30% decrease in the sum of the diameters of target lesions (taking as reference the baseline sum diameter) without progression of non-target lesions or appearance of new lesions. Overall response rate is calculated as a total number of participants with CR or PR divided by the total number of participants per cohort with at least 1 measurable lesion, multiplied by 100. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate (DCR): Percentage of Participants With a Best Overall Response of CR, PR, or Stable Disease (SD) for at Least 4 Months | Baseline through Disease Progression (up to 6 months) | DCR is defined as the number of participants who achieve a best overall response of CR, PR or SD for ≥4 months as determined by per RECIST version 1.1. CR is the disappearance of all target and non-target lesions; PR is a ≥30% decrease in sum of longest diameter of target lesions without new lesion and progression of non-target lesion; SD is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease. Disease control rate is calculated as a total number of participants with CR or PR or SD divided by the total number of participants treated, then multiplied by 100. |
| Duration of Response | Date of CR or PR to Date of Disease Progression or Death Due to Any Cause (up to 20 months) | Duration of response is defined as the time from the date measurement criteria for CR or PR (whichever is first recorded) are first met until the first date that disease is recurrent or objective progression is observed, per RECIST 1.1, or the date of death from any cause in the absence of objectively determined disease progression or recurrence. Participants known to be alive and without disease progression will be censored at the time of the last adequate tumor assessment. |
| Pharmacokinetics (PK): Maximum Plasma Concentration (Cmax) of Prexasertib | Cycle 1, Cycle 2, Cycle 4, Cycle 6 (Day 1 (End of prexasertib infusion (+15 min), 1-2 hours following end of prexasertib infusion), Cycle 2, day 1(Prior to start of prexasertib infusion) | Pharmacokinetics(PK): Maximum Plasma Concentration of Prexasertib. The same dose was administered to Cohort 1, 2, 3 and 4 and were combined for analysis. |
| Progression-Free Survival | Baseline to Disease Progression or Death from any Cause (Up to 22 months) | Progression-Free Survival (PFS) is defined as the time from the date of enrollment until the first occurrence of documented disease progression per RECIST 1.1, or death from any cause in the absence of progressive disease (PD). Participants known to be alive and without disease progression will be censored at the time of the last adequate tumor assessment. |
| Overall Survival | Baseline to Date of Death from Any Cause (Up to 26 months) | Overall survival (OS) is defined as the time from the date of enrollment until death from any cause. If the participant is alive, lost to follow-up or withdrawn from study at the time of data analysis, OS data will be censored on the last date the participant is known to be alive. |
| Percentage of Participants With at Least a 50% Reduction in CA-125 Levels From Baseline | Baseline, 4 Weeks | CA-125 response is defined as ≥50% reduction in CA-125 levels from a pretreatment sample. The response must be confirmed and maintained for ≥28 days according to GCIG criteria. Participants must have a pretreatment sample that is ≥2 times the upper limit of the reference range and obtained within 2 weeks before starting the treatment. |
Countries
Australia, Belgium, Israel, Italy, South Korea, Spain, United Kingdom, United States
Participant flow
Recruitment details
Completers included participants who died from any cause and participants who were alive and on study (either on study treatment or in long term follow-up) at study conclusion.
Pre-assignment details
Only 169 participants were assigned to one of the 4 cohorts in this study. Data is not available for 3 participants who discontinued before the start of the treatment.
Participants by arm
| Arm | Count |
|---|---|
| Prexasertib Cohort 1 Participants received 105 mg/m² prexasertib as an approximately 60 (+10) minute IV infusion on Day 1 and 15 of a 28-day cycle. Participants were with platinum-resistant disease, breast cancer susceptibility gene (BRCA) negative and have received ≥3 lines of prior therapy. | 53 |
| Prexasertib Cohort 2 Participants received 105 mg/m² prexasertib as an approximately 60 (+10) minute IV infusion on Day 1 and 15 of a 28-day cycle. Participants were with platinum-resistant disease, BRCA negative and have received \<3 lines of prior therapy. | 46 |
| Prexasertib Cohort 3 Participants received 105 mg/m² prexasertib as an approximately 60 (+10) minute IV infusion on Day 1 and 15 of a 28-day cycle. Participants were with platinum-resistant disease, BRCA positive and received a prior poly ADP ribose polymerase (PARP) inhibitor. | 41 |
| Prexasertib Cohort 4 Participants received 105 mg/m² prexasertib as an approximately 60 (+10) minute IV infusion on Day 1 and 15 of a 28-day cycle. Participants were with platinum refractory disease, BRCA positive or negative, no restriction on number of lines of prior therapy. | 29 |
| Total | 169 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 1 |
| Overall Study | Physician Decision | 1 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 2 | 0 |
Baseline characteristics
| Characteristic | Prexasertib Cohort 2 | Prexasertib Cohort 3 | Prexasertib Cohort 1 | Prexasertib Cohort 4 | Total |
|---|---|---|---|---|---|
| Age, Continuous | 62.3 Years STANDARD_DEVIATION 9.4 | 59.5 Years STANDARD_DEVIATION 8.6 | 61.3 Years STANDARD_DEVIATION 9.4 | 59.0 Years STANDARD_DEVIATION 13.4 | 60.8 Years STANDARD_DEVIATION 10 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 0 Participants | 1 Participants | 0 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 40 Participants | 39 Participants | 48 Participants | 28 Participants | 155 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 2 Participants | 4 Participants | 1 Participants | 10 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 8 Participants | 4 Participants | 6 Participants | 3 Participants | 21 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 36 Participants | 37 Participants | 46 Participants | 25 Participants | 144 Participants |
| Region of Enrollment Australia | 7 Participants | 10 Participants | 14 Participants | 3 Participants | 34 Participants |
| Region of Enrollment Belgium | 1 Participants | 3 Participants | 4 Participants | 0 Participants | 8 Participants |
| Region of Enrollment Israel | 3 Participants | 7 Participants | 6 Participants | 4 Participants | 20 Participants |
| Region of Enrollment Italy | 4 Participants | 8 Participants | 4 Participants | 7 Participants | 23 Participants |
| Region of Enrollment South Korea | 5 Participants | 2 Participants | 4 Participants | 2 Participants | 13 Participants |
| Region of Enrollment Spain | 4 Participants | 4 Participants | 9 Participants | 2 Participants | 19 Participants |
| Region of Enrollment United Kingdom | 9 Participants | 4 Participants | 6 Participants | 1 Participants | 20 Participants |
| Region of Enrollment United States | 13 Participants | 3 Participants | 6 Participants | 10 Participants | 32 Participants |
| Sex: Female, Male Female | 46 Participants | 41 Participants | 53 Participants | 29 Participants | 169 Participants |
| Sex: Female, Male Male | 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 |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 53 | 1 / 46 | 1 / 41 | 1 / 29 |
| other Total, other adverse events | 53 / 53 | 44 / 46 | 39 / 41 | 28 / 29 |
| serious Total, serious adverse events | 23 / 53 | 17 / 46 | 19 / 41 | 15 / 29 |
Outcome results
Primary
Percentage of Participants Who Achieve Complete Response (CR) or Partial Response (PR): Overall Response Rate (ORR)
Overall response rate is the best response of complete response (CR) or partial response (PR) as classified by the independent central review according to the Response Evaluation Criteria In Solid Tumors (RECIST v1.1). CR is a disappearance of all target and non-target lesions and normalization of tumor marker level. PR is an at least 30% decrease in the sum of the diameters of target lesions (taking as reference the baseline sum diameter) without progression of non-target lesions or appearance of new lesions. Overall response rate is calculated as a total number of participants with CR or PR divided by the total number of participants per cohort with at least 1 measurable lesion, multiplied by 100.
Time frame: Baseline through Disease Progression (Up to 6 months)
Population: All randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Prexasertib Cohort 1 | Percentage of Participants Who Achieve Complete Response (CR) or Partial Response (PR): Overall Response Rate (ORR) | 11.3 Percentage of Participants |
| Prexasertib Cohort 2 | Percentage of Participants Who Achieve Complete Response (CR) or Partial Response (PR): Overall Response Rate (ORR) | 13.0 Percentage of Participants |
| Prexasertib Cohort 3 | Percentage of Participants Who Achieve Complete Response (CR) or Partial Response (PR): Overall Response Rate (ORR) | 12.2 Percentage of Participants |
| Prexasertib Cohort 4 | Percentage of Participants Who Achieve Complete Response (CR) or Partial Response (PR): Overall Response Rate (ORR) | 6.9 Percentage of Participants |
Secondary
Disease Control Rate (DCR): Percentage of Participants With a Best Overall Response of CR, PR, or Stable Disease (SD) for at Least 4 Months
DCR is defined as the number of participants who achieve a best overall response of CR, PR or SD for ≥4 months as determined by per RECIST version 1.1. CR is the disappearance of all target and non-target lesions; PR is a ≥30% decrease in sum of longest diameter of target lesions without new lesion and progression of non-target lesion; SD is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease. Disease control rate is calculated as a total number of participants with CR or PR or SD divided by the total number of participants treated, then multiplied by 100.
Time frame: Baseline through Disease Progression (up to 6 months)
Population: All randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Prexasertib Cohort 1 | Disease Control Rate (DCR): Percentage of Participants With a Best Overall Response of CR, PR, or Stable Disease (SD) for at Least 4 Months | 45.3 Percentage of participants |
| Prexasertib Cohort 2 | Disease Control Rate (DCR): Percentage of Participants With a Best Overall Response of CR, PR, or Stable Disease (SD) for at Least 4 Months | 32.6 Percentage of participants |
| Prexasertib Cohort 3 | Disease Control Rate (DCR): Percentage of Participants With a Best Overall Response of CR, PR, or Stable Disease (SD) for at Least 4 Months | 31.7 Percentage of participants |
| Prexasertib Cohort 4 | Disease Control Rate (DCR): Percentage of Participants With a Best Overall Response of CR, PR, or Stable Disease (SD) for at Least 4 Months | 31.0 Percentage of participants |
Secondary
Duration of Response
Duration of response is defined as the time from the date measurement criteria for CR or PR (whichever is first recorded) are first met until the first date that disease is recurrent or objective progression is observed, per RECIST 1.1, or the date of death from any cause in the absence of objectively determined disease progression or recurrence. Participants known to be alive and without disease progression will be censored at the time of the last adequate tumor assessment.
Time frame: Date of CR or PR to Date of Disease Progression or Death Due to Any Cause (up to 20 months)
Population: All randomized participants who received at least one dose of study drug and had CR or PR responses. Number of participants censored Cohort 1 = 0, Cohort 2 = 1, Cohort 3 = 0 and Cohort 4 = 0.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Prexasertib Cohort 1 | Duration of Response | 8.57 Months |
| Prexasertib Cohort 2 | Duration of Response | 3.84 Months |
| Prexasertib Cohort 3 | Duration of Response | 5.55 Months |
| Prexasertib Cohort 4 | Duration of Response | 5.31 Months |
Secondary
Overall Survival
Overall survival (OS) is defined as the time from the date of enrollment until death from any cause. If the participant is alive, lost to follow-up or withdrawn from study at the time of data analysis, OS data will be censored on the last date the participant is known to be alive.
Time frame: Baseline to Date of Death from Any Cause (Up to 26 months)
Population: All randomized participants who received at least one dose of study drug and had overall survival data. Number of participants censored Cohort 1 = 18, Cohort 2 = 12, Cohort 3 = 12 and Cohort 4 = 4.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Prexasertib Cohort 1 | Overall Survival | 13.04 Months |
| Prexasertib Cohort 2 | Overall Survival | 14.32 Months |
| Prexasertib Cohort 3 | Overall Survival | 11.14 Months |
| Prexasertib Cohort 4 | Overall Survival | 8.18 Months |
Secondary
Percentage of Participants With at Least a 50% Reduction in CA-125 Levels From Baseline
CA-125 response is defined as ≥50% reduction in CA-125 levels from a pretreatment sample. The response must be confirmed and maintained for ≥28 days according to GCIG criteria. Participants must have a pretreatment sample that is ≥2 times the upper limit of the reference range and obtained within 2 weeks before starting the treatment.
Time frame: Baseline, 4 Weeks
Population: All randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Prexasertib Cohort 1 | Percentage of Participants With at Least a 50% Reduction in CA-125 Levels From Baseline | 39.6 Percentage of participants |
| Prexasertib Cohort 2 | Percentage of Participants With at Least a 50% Reduction in CA-125 Levels From Baseline | 34.8 Percentage of participants |
| Prexasertib Cohort 3 | Percentage of Participants With at Least a 50% Reduction in CA-125 Levels From Baseline | 17.1 Percentage of participants |
| Prexasertib Cohort 4 | Percentage of Participants With at Least a 50% Reduction in CA-125 Levels From Baseline | 37.9 Percentage of participants |
Secondary
Pharmacokinetics (PK): Maximum Plasma Concentration (Cmax) of Prexasertib
Pharmacokinetics(PK): Maximum Plasma Concentration of Prexasertib. The same dose was administered to Cohort 1, 2, 3 and 4 and were combined for analysis.
Time frame: Cycle 1, Cycle 2, Cycle 4, Cycle 6 (Day 1 (End of prexasertib infusion (+15 min), 1-2 hours following end of prexasertib infusion), Cycle 2, day 1(Prior to start of prexasertib infusion)
Population: All randomized participants who received at least one dose of study drug and had evaluable PK data. Cohort 1, 2, 3 and 4 received the same dose and were combined per protocol.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Prexasertib Cohort 1 | Pharmacokinetics (PK): Maximum Plasma Concentration (Cmax) of Prexasertib | Cycle 1 | 668 nanograms per milliliter(ng/mL) | Geometric Coefficient of Variation 50 |
| Prexasertib Cohort 1 | Pharmacokinetics (PK): Maximum Plasma Concentration (Cmax) of Prexasertib | Cycle 2 | 718 nanograms per milliliter(ng/mL) | Geometric Coefficient of Variation 62 |
| Prexasertib Cohort 1 | Pharmacokinetics (PK): Maximum Plasma Concentration (Cmax) of Prexasertib | Cycle 4 | 678 nanograms per milliliter(ng/mL) | Geometric Coefficient of Variation 61 |
| Prexasertib Cohort 1 | Pharmacokinetics (PK): Maximum Plasma Concentration (Cmax) of Prexasertib | Cycle 6 | 672 nanograms per milliliter(ng/mL) | Geometric Coefficient of Variation 42 |
Secondary
Progression-Free Survival
Progression-Free Survival (PFS) is defined as the time from the date of enrollment until the first occurrence of documented disease progression per RECIST 1.1, or death from any cause in the absence of progressive disease (PD). Participants known to be alive and without disease progression will be censored at the time of the last adequate tumor assessment.
Time frame: Baseline to Disease Progression or Death from any Cause (Up to 22 months)
Population: All randomized participants who received at least one dose of study drug. Number of participants censored Cohort 1 = 6, Cohort 2 = 4, Cohort 3 = 4 and Cohort 4 = 4.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Prexasertib Cohort 1 | Progression-Free Survival | 3.91 Months |
| Prexasertib Cohort 2 | Progression-Free Survival | 3.71 Months |
| Prexasertib Cohort 3 | Progression-Free Survival | 3.58 Months |
| Prexasertib Cohort 4 | Progression-Free Survival | 3.71 Months |