Leiomyosarcoma, Liposarcoma
Conditions
Keywords
Trabectedin, Yondelis, ET-743, Ecteinascidin, Anthracycline, Ifosfamide, Dexamethasone, Intravenous, Cancer, Malignant, Metastatic
Brief summary
The purpose of this study is to test the safety and effectiveness of an investigational chemotherapy agent in patients with types of advanced cancer referred to as liposarcoma or leiomyosarcoma.
Detailed description
This is an open-label (patients will know the names of the study drugs they receive), randomized (patients will be assigned by chance to receive 1 of 2 treatment schedules with trabectidin) study designed to examine the the survival, safety, and pharmacokinetics (blood levels) trabectedin when administered to patients with 2 types of cancer (Liposarcoma or Leiomyosarcoma) who have received treatment with other anti-cancer therapy (Anthracycline and/or Ifosfamide). Trabectedin (also referred to as Yondelis) is a drug being developed to treat patients with cancer. Yondelis will be administered intravenously (i.v.) via a central catheter (tube) into a central vein once a week (0.58 mg/m2 as a 3-hour infusion on Days 1, 8, and 15 of each 28-day treatment cycle) or once every 3 weeks (1.5 mg/m2 administered as a 24-hour infusion on Day 1 of every 21-day treatment cycle) until disease progression. Patients in each arm will be pretreated with 20 mg of dexamethasone i.v. 30 minutes prior to each infusion.
Interventions
DRUGYondelis
1.5 mg/m2 administered as a 24-hour i.v. infusion on Day 1 of every 21-day treatment cycle.
DRUGDexamethasone
Pretreatment with 10 mg of dexamethasone i.v. 30 minutes prior to each Yondelis infusion on Days 1, 8, and 15 of each 28-day treatment cycle.
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
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Have advanced liposarcoma or leiomyosarcoma that has metastasized (spread) * Have a pathology specimen available for centralized review * Have progressive or relapsed (reappearance of) disease, received treatment with anthracycline and/or ifosfamide before enrollment in study, and have at least one measurable tumor lesion * Have adequate bone marrow, liver and kidney function * Have Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
Exclusion criteria
* Previous exposure to Yondelis i.v. formulation, ET-743 (ecteinascidin) * Cancer that has metastasized (spread) to the central nervous system * Active viral hepatitis or chronic liver disease * Unstable cardiac (heart) condition including congestive heart failure or angina pectoris (heart pain), myocardial infarction (heart attack) within 1 year before enrollment * History of another neoplastic (malignant or nonmalignant tumor) disease (except basal cell carcinoma or cervical carcinoma adequately treated), unless in remission for 5 years or more before enrollment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Progression- Independent Review | From randomization to the first documentation of disease progression or death due to progressive disease, whichever occurs first, assessed up to 5 years | Time to Progression was defined as time between randomization and the first documentation of disease progression or death due to progressive disease. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Objective Response - Independent Review | From randomization to the first documentation of disease progression or death due to progressive disease, whichever occurs first, assessed up to 5 years | Percentage of participants with objective response based on assessment of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST). Confirmed CR defined as disappearance of all target lesions. Confirmed PR defined as greater than or equal to 30 percent decrease in sum of the longest dimensions (LD) of the target lesions taking as a reference the baseline sum LD according to RECIST. Confirmed responses are those that persist on repeat imaging study greater than or equal to 4 weeks after initial documentation of response. |
| Duration of Response - Independent Review | From randomization to the first documentation of disease progression or death due to progressive disease, whichever occurs first, assessed up to 5 years | Duration of response based on assessment of confirmed CR or confirmed PR according to RECIST. Confirmed CR defined as disappearance of all target lesions. Confirmed PR defined as greater than or equal to 30 percent decrease in sum of the LD of the target lesions taking as a reference the baseline sum LD according to RECIST. Confirmed responses are those that persist on repeat imaging study greater than or equal to 4 weeks after initial documentation of response. Kaplan-Meier estimation of response duration was used to account censored participants with ongoing response. |
| Progression-Free Survival - Independent Review | From randomization to the first documentation of disease progression or death due to progressive disease, whichever occurs first, assessed up to 5 years | The below table shows Kaplan-Meier estimate of the median time from randomization to death from any cause or first observed disease progression. |
| Overall Survival | From randomization to the first documentation of disease progression or death due to progressive disease, whichever occurs first, assessed up to 5 years | The below table shows Kaplan-Meier estimate of the median time from randomization to death from any cause or first observed disease progression. |
Countries
Australia, Belgium, Canada, France, Germany, Russia, Spain, United States
Participant flow
Recruitment details
This study evaluated the efficacy and safety of of trabectedin in participants with locally advanced or metastatic L-sarcoma whose disease had relapsed or become refractory after treatment with an anthracycline and ifosfamide. The study was conducted between 12 May 2003 and 23 April 2008 and recruited participants from 9 countries worldwide.
Pre-assignment details
In this study 271 participants were enrolled of which 270 participants (134 in the Trabectedin 1.5 mg/m2 group and 136 in the Trabectedin 0.58 mg/m2 group) were randomized as 1 participant was enrolled twice. Of these, 260 participants were treated with trabectedin including 130 participants in each treatment group.
Participants by arm
| Arm | Count |
|---|---|
| Trabectedin 1.5 mg/m2 Participants received trabectedin as a 24-hour intravenous (IV) infusion at a starting dose of 1.5 mg/m2 on Day 1 of each 21-day treatment cycle, with 20 mg dexamethasone administered IV 30 min before each trabectedin infusion. | 136 |
| Trabectedin 0.58 mg/m2 Participants received trabectedin as a 3-hour intravenous (IV) infusion at a starting dose of 0.58 mg/m2 on Days 1, 8, and 15 of each 28-day treatment cycle, with 10 mg dexamethasone administered IV 30 min before each trabectedin infusion | 134 |
| Total | 270 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 12 | 10 |
| Overall Study | Death | 2 | 3 |
| Overall Study | Disease Progression | 93 | 94 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Other | 2 | 4 |
| Overall Study | randomized but not treated | 6 | 4 |
| Overall Study | Subject Ineligible To Continue | 2 | 1 |
| Overall Study | Treatment Switch | 0 | 13 |
| Overall Study | Withdrawal by Subject | 18 | 5 |
Baseline characteristics
| Characteristic | Trabectedin 0.58 mg/m2 | Total | Trabectedin 1.5 mg/m2 |
|---|---|---|---|
| Age, Continuous | 53.4 years STANDARD_DEVIATION 10.7 | 53.1 years STANDARD_DEVIATION 10.32 | 52.8 years STANDARD_DEVIATION 9.95 |
| Region of Enrollment Australia | 1 participants | 4 participants | 3 participants |
| Region of Enrollment Belgium | 2 participants | 3 participants | 1 participants |
| Region of Enrollment Canada | 11 participants | 24 participants | 13 participants |
| Region of Enrollment France | 12 participants | 17 participants | 5 participants |
| Region of Enrollment Germany | 0 participants | 2 participants | 2 participants |
| Region of Enrollment Italy | 3 participants | 8 participants | 5 participants |
| Region of Enrollment Russia | 13 participants | 28 participants | 15 participants |
| Region of Enrollment Spain | 0 participants | 3 participants | 3 participants |
| Region of Enrollment United States Of America | 92 participants | 181 participants | 89 participants |
| Sex: Female, Male Female | 78 Participants | 170 Participants | 92 Participants |
| Sex: Female, Male Male | 56 Participants | 100 Participants | 44 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 129 / 130 | 128 / 130 |
| serious Total, serious adverse events | 48 / 130 | 41 / 130 |
Outcome results
Primary
Time to Progression- Independent Review
Time to Progression was defined as time between randomization and the first documentation of disease progression or death due to progressive disease.
Time frame: From randomization to the first documentation of disease progression or death due to progressive disease, whichever occurs first, assessed up to 5 years
Population: All participants who were randomly assigned to one of the two schedules, independent of whether they received trabectedin or not.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trabectedin 1.5 mg/m2 | Time to Progression- Independent Review | 3.7 months |
| Trabectedin 0.58 mg/m2 | Time to Progression- Independent Review | 2.3 months |
p-value: 0.030295% CI: [0.554, 0.974]Log Rank
Secondary
Duration of Response - Independent Review
Duration of response based on assessment of confirmed CR or confirmed PR according to RECIST. Confirmed CR defined as disappearance of all target lesions. Confirmed PR defined as greater than or equal to 30 percent decrease in sum of the LD of the target lesions taking as a reference the baseline sum LD according to RECIST. Confirmed responses are those that persist on repeat imaging study greater than or equal to 4 weeks after initial documentation of response. Kaplan-Meier estimation of response duration was used to account censored participants with ongoing response.
Time frame: From randomization to the first documentation of disease progression or death due to progressive disease, whichever occurs first, assessed up to 5 years
Population: All participants who were randomly assigned to one of the two schedules, independent of whether they received trabectedin or not. Participants with confirmed response only were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trabectedin 1.5 mg/m2 | Duration of Response - Independent Review | 7.5 Months |
| Trabectedin 0.58 mg/m2 | Duration of Response - Independent Review | NA Months |
Secondary
Overall Survival
The below table shows Kaplan-Meier estimate of the median time from randomization to death from any cause or first observed disease progression.
Time frame: From randomization to the first documentation of disease progression or death due to progressive disease, whichever occurs first, assessed up to 5 years
Population: All participants who were randomly assigned to one of the two schedules, independent of whether they received trabectedin or not.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trabectedin 1.5 mg/m2 | Overall Survival | 13.9 months |
| Trabectedin 0.58 mg/m2 | Overall Survival | 11.8 months |
p-value: 0.19295% CI: [0.653, 1.09]Log Rank
Secondary
Percentage of Participants Objective Response - Independent Review
Percentage of participants with objective response based on assessment of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST). Confirmed CR defined as disappearance of all target lesions. Confirmed PR defined as greater than or equal to 30 percent decrease in sum of the longest dimensions (LD) of the target lesions taking as a reference the baseline sum LD according to RECIST. Confirmed responses are those that persist on repeat imaging study greater than or equal to 4 weeks after initial documentation of response.
Time frame: From randomization to the first documentation of disease progression or death due to progressive disease, whichever occurs first, assessed up to 5 years
Population: All participants who were randomly assigned to one of the two schedules, independent of whether they received trabectedin or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Trabectedin 1.5 mg/m2 | Percentage of Participants Objective Response - Independent Review | 5.1 Percentage of participants |
| Trabectedin 0.58 mg/m2 | Percentage of Participants Objective Response - Independent Review | 1.5 Percentage of participants |
Secondary
Progression-Free Survival - Independent Review
The below table shows Kaplan-Meier estimate of the median time from randomization to death from any cause or first observed disease progression.
Time frame: From randomization to the first documentation of disease progression or death due to progressive disease, whichever occurs first, assessed up to 5 years
Population: All participants who were randomly assigned to one of the two schedules, independent of whether they received trabectedin or not.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trabectedin 1.5 mg/m2 | Progression-Free Survival - Independent Review | 3.3 months |
| Trabectedin 0.58 mg/m2 | Progression-Free Survival - Independent Review | 2.3 months |
p-value: 0.041895% CI: [0.574, 0.992]Log Rank