Ovarian Cancer
Conditions
Keywords
Ovarian cancer, Trabectedin, Yondelis, Advanced Relapsed Ovarian Cancer, DOXIL, CAELYX
Brief summary
The purpose of the study is to compare the progression-free survival (PFS) of the combination of trabectedin + DOXIL with DOXIL monotherapy in patients with ovarian cancer.
Detailed description
This is a multicenter, open-label (all people know the identity of the intervention), randomized (study medication is assigned by chance), Phase 3 study comparing the combination of trabectedin + DOXIL with DOXIL monotherapy in patients with advanced ovarian cancer (who were previously treated and for whom first-line platinum-based chemotherapy regimen has failed). Approximately 650 patients will be randomly assigned to 1 of the treatment arms (DOXIL and DOXIL + trabectedin) over 2 years. At the time of randomization, patients will be stratified on the basis of platinum sensitivity of disease (sensitive or resistant) and baseline Eastern Cooperative Oncology Group performance status score (0 to 1 or 2. Safety will be evaluated on the basis of adverse events, clinical laboratory tests, physical examination, vital signs assessment and cardiovascular safety assessment. An interim analysis of overall survival will be performed in conjunction with progression-free survival analysis during the study. Treatment will be continued until disease progression occurred or until patients experienced a confirmed complete response for at least 2 cycles. Continuation of treatment in select individual patients beyond this study end date will be allowed if the investigator determined that the patient is benefiting from treatment, is eligible to receive further therapy, and consents to treatment. If disease progression has not occurred at treatment termination, then disease assessment will continue every 8 weeks until there is evidence of disease progression or death, or until the clinical data cutoff date, or until the start of first subsequent anticancer therapy, whichever is earlier.
Interventions
DRUGTrabectedin
Type=exact number, unit=mg/m2, number=1.1, form=solution, route=IV. Trabectedin will be administered over 3 hours every 3 weeks.
DRUGDOXIL
Type=exact number, unit=mg/m2, number=30, 50, form=solution, route=IV. DOXIL will be administered over 90 minutes every 4 weeks when administered alone (monotherapy) and every 3 weeks when administered with trabectedin.
DRUGDexamethasone
Type=exact number, unit=mg, number=20, form=solution, route=IV. Dexamethasone or its equivalent will be administered over 30 minutes prior to the DOXIL infusion.
Sponsors
PharmaMar
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically proven epithelial ovarian cancer, epithelial fallopian tube cancer, or primary peritoneal cancer * Prior treatment with only 1 platinum based chemotherapy regimen * Eastern Cooperative Oncology Group status of not more than 2 * Progression more than 6 months after the start of initial chemotherapy treatment
Exclusion criteria
* Treatment with more than 1 prior chemotherapy regimen * Progression within 6 months after starting initial chemotherapy * Prior exposure to anthracyclines * Unwilling or unable to have central venous catheter * Known clinically relevant central nervous system metastasis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS): Independent Radiologist Review | From the date of randomization until the date of disease progression or death, as assessed for approximately 3 years | PFS is defined as the time between randomization and disease progression or death. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | From the date of randomization until the date of death, as assessed for approximately 3 years | Overall survival was defined as the time between the randomization and death |
| Objective Response Rate (ORR) - Independent Radiologist Review | From the date of randomization until the date of disease progression or death, as assessed for approximately 3 years | Percentage of participants who achieved complete response (CR) or partial response (PR) as best overall response. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR) = Disappearance of all target lesions; Partial Response (PR)= greater than or equal to 30% decrease in the sum of the longest diameter of target lesions and Overall Response (OR) = CR + PR. |
| Duration of Response: Independent Radiologist Review | From the date of first documentation of response to the date of disease progression or death due to progressive disease, as assessed for approximately 3 years | Duration of response was defined only for participants who had complete response or partial response as best overall response. Duration of response was calculated from the date of first documentation of response (not the confirmation) to the date of disease progression or death due to progressive disease. |
| Median Area Under Curve (AUC) of Trabectedin. | Day 1 (Predose; 1.5 hour after start of infusion; 5 minutes, 2 hour and 6 to 20 hour after end of infusion); Day 8 (168 hour after end of infusion); and Day 15 (336 hour after end of infusion) at Cycles 1 and 2 | Median simulated area under the curve (AUC) of a 21 day trabectedin profile of participants (of this study) administering trabectedin and doxil, calculated using the trapezoidal rule method. Simulations were based on a dataset created of 1000 participants using the posthoc parameter estimations, derived from the population pharmacokinetic analysis dataset of Trabectedin (Participants=831, with resampling). Plasma concentration-time profiles were simulated up to 504 hour post-dosing using a rich sampling. |
| Median Maximum Plasma Concentration (Cmax) of Trabectedin. | Day 1 (Predose; 1.5 hour after start of infusion; 5 minutes, 2 hour and 6 to 20 hour after end of infusion); Day 8 (168 hour after end of infusion); and Day 15 (336 hour after end of infusion) at Cycles 1 and 2 | Median simulated maximum plasma concentration (Cmax) at 3 hour of a 21 day trabectedin profile of participants (of this study) administering trabectedin and doxil. The assessment of Cmax was based on a dataset created of 1000 participants using the posthoc parameter estimations, derived from the population pharmacokinetic analysis dataset of Trabectedin (participants=831, with resampling). Plasma concentration-time profiles were simulated up to 504 hour post-dosing using a rich sampling. |
Countries
Argentina, Australia, Belgium, Brazil, Canada, Chile, China, France, Germany, Hong Kong, Netherlands, Poland, Russia, Singapore, South Korea, Spain, Sweden, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
This study was conducted in a total of 21 countries at 124 sites worldwide.
Pre-assignment details
672 participants were randomized (337 in trabectedin + DOXIL arm and 335 in DOXIL arm) and out of which 9 participants were not treated. 663 participants received treatment ie, 330 participants received DOXIL and 333 received trabectedin + DOXIL.
Participants by arm
| Arm | Count |
|---|---|
| DOXIL 50 mg/m2 DOXIL administered as a 90-minute intravenous (IV) infusion, every 4 weeks | 335 |
| Trabectedin/DOXIL 30 mg/m2 DOXIL administered as a 90-minute IV infusion followed by 1.1 mg/m2 trabectedin as a 3-hour IV infusion, every 3 weeks | 337 |
| Total | 672 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 40 | 71 |
| Overall Study | Complete Response (Confirmed) | 14 | 24 |
| Overall Study | Death | 8 | 8 |
| Overall Study | Disease Progression | 180 | 142 |
| Overall Study | Lost to Follow-up | 0 | 2 |
| Overall Study | Other | 43 | 32 |
| Overall Study | Withdrawal by Subject | 50 | 58 |
Baseline characteristics
| Characteristic | DOXIL | Total | Trabectedin/DOXIL |
|---|---|---|---|
| Age, Continuous | 58.2 years STANDARD_DEVIATION 10.75 | 57.5 years STANDARD_DEVIATION 10.63 | 56.8 years STANDARD_DEVIATION 10.48 |
| Region of Enrollment Argentina | 5 participants | 7 participants | 2 participants |
| Region of Enrollment Australia | 5 participants | 7 participants | 2 participants |
| Region of Enrollment Belgium-Luxemburg | 12 participants | 25 participants | 13 participants |
| Region of Enrollment Brazil | 12 participants | 21 participants | 9 participants |
| Region of Enrollment Canada | 22 participants | 56 participants | 34 participants |
| Region of Enrollment Chile | 1 participants | 3 participants | 2 participants |
| Region of Enrollment China | 37 participants | 73 participants | 36 participants |
| Region of Enrollment France | 0 participants | 2 participants | 2 participants |
| Region of Enrollment Germany | 6 participants | 19 participants | 13 participants |
| Region of Enrollment Hong Kong | 10 participants | 25 participants | 15 participants |
| Region of Enrollment Italy | 3 participants | 7 participants | 4 participants |
| Region of Enrollment Netherlands | 4 participants | 5 participants | 1 participants |
| Region of Enrollment Poland | 47 participants | 86 participants | 39 participants |
| Region of Enrollment Republic Of Korea | 17 participants | 28 participants | 11 participants |
| Region of Enrollment Russia | 52 participants | 108 participants | 56 participants |
| Region of Enrollment Singapore | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Spain | 8 participants | 17 participants | 9 participants |
| Region of Enrollment Sweden | 6 participants | 14 participants | 8 participants |
| Region of Enrollment Taiwan | 7 participants | 9 participants | 2 participants |
| Region of Enrollment United Kingdom | 18 participants | 38 participants | 20 participants |
| Region of Enrollment United States Of America | 63 participants | 121 participants | 58 participants |
| Sex: Female, Male Female | 335 Participants | 672 Participants | 337 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 333 / 333 | 318 / 330 |
| serious Total, serious adverse events | 133 / 333 | 102 / 330 |
Outcome results
Primary
Progression-Free Survival (PFS): Independent Radiologist Review
PFS is defined as the time between randomization and disease progression or death.
Time frame: From the date of randomization until the date of disease progression or death, as assessed for approximately 3 years
Population: All Measurable Analysis Participants: All randomized participants who had measurable disease at baseline as assessed by the independent radiology review. Measurable disease is defined as having at least 1 lesion measured with a diameter of ≥20 mm using conventional techniques or of ≥10 mm using a spiral computerized tomography scan.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| DOXIL | Progression-Free Survival (PFS): Independent Radiologist Review | 5.8 Months |
| Trabectedin/DOXIL | Progression-Free Survival (PFS): Independent Radiologist Review | 7.3 Months |
p-value: 0.01995% CI: [0.65, 0.96]Log Rank
Secondary
Duration of Response: Independent Radiologist Review
Duration of response was defined only for participants who had complete response or partial response as best overall response. Duration of response was calculated from the date of first documentation of response (not the confirmation) to the date of disease progression or death due to progressive disease.
Time frame: From the date of first documentation of response to the date of disease progression or death due to progressive disease, as assessed for approximately 3 years
Population: All Responders (CR/PR) Analysis Participants: all participants who achieved CR or PR as best overall response during the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| DOXIL | Duration of Response: Independent Radiologist Review | 7.7 Months |
| Trabectedin/DOXIL | Duration of Response: Independent Radiologist Review | 7.9 Months |
p-value: 0.820395% CI: [0.62, 1.46]Log Rank
Secondary
Median Area Under Curve (AUC) of Trabectedin.
Median simulated area under the curve (AUC) of a 21 day trabectedin profile of participants (of this study) administering trabectedin and doxil, calculated using the trapezoidal rule method. Simulations were based on a dataset created of 1000 participants using the posthoc parameter estimations, derived from the population pharmacokinetic analysis dataset of Trabectedin (Participants=831, with resampling). Plasma concentration-time profiles were simulated up to 504 hour post-dosing using a rich sampling.
Time frame: Day 1 (Predose; 1.5 hour after start of infusion; 5 minutes, 2 hour and 6 to 20 hour after end of infusion); Day 8 (168 hour after end of infusion); and Day 15 (336 hour after end of infusion) at Cycles 1 and 2
Population: Blood samples for pharmacokinetic analysis were collected from 86 participants of this study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DOXIL | Median Area Under Curve (AUC) of Trabectedin. | 74.24 ng*h/mL |
Secondary
Median Maximum Plasma Concentration (Cmax) of Trabectedin.
Median simulated maximum plasma concentration (Cmax) at 3 hour of a 21 day trabectedin profile of participants (of this study) administering trabectedin and doxil. The assessment of Cmax was based on a dataset created of 1000 participants using the posthoc parameter estimations, derived from the population pharmacokinetic analysis dataset of Trabectedin (participants=831, with resampling). Plasma concentration-time profiles were simulated up to 504 hour post-dosing using a rich sampling.
Time frame: Day 1 (Predose; 1.5 hour after start of infusion; 5 minutes, 2 hour and 6 to 20 hour after end of infusion); Day 8 (168 hour after end of infusion); and Day 15 (336 hour after end of infusion) at Cycles 1 and 2
Population: Blood samples for pharmacokinetic analysis were collected from 86 participants of this study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DOXIL | Median Maximum Plasma Concentration (Cmax) of Trabectedin. | 13394 pg/mL |
Secondary
Objective Response Rate (ORR) - Independent Radiologist Review
Percentage of participants who achieved complete response (CR) or partial response (PR) as best overall response. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR) = Disappearance of all target lesions; Partial Response (PR)= greater than or equal to 30% decrease in the sum of the longest diameter of target lesions and Overall Response (OR) = CR + PR.
Time frame: From the date of randomization until the date of disease progression or death, as assessed for approximately 3 years
Population: All Randomized Analysis Participants: all participants who were randomized to this study, independent of whether they received study medication or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DOXIL | Objective Response Rate (ORR) - Independent Radiologist Review | 18.8 Percentage of participants |
| Trabectedin/DOXIL | Objective Response Rate (ORR) - Independent Radiologist Review | 27.6 Percentage of participants |
p-value: 0.00895% CI: [1.144, 2.367]Fisher Exact
Secondary
Overall Survival
Overall survival was defined as the time between the randomization and death
Time frame: From the date of randomization until the date of death, as assessed for approximately 3 years
Population: All Randomized Analysis Participants: all participants who were randomized to this study, independent of whether they received study medication or not
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| DOXIL | Overall Survival | 18.9 Months |
| Trabectedin/DOXIL | Overall Survival | 22.2 Months |
p-value: 0.083595% CI: [0.72, 1.02]Log Rank