Sarcoma
Conditions
Keywords
Sarcomas, Trabectedin, Doxorubicin, Ifosfamide, YONDELIS
Brief summary
The purpose of this study is to evaluate the efficacy and safety of trabectedin compared to standard doxorubicin in participants with advanced translocation-related sarcomas (cancer of connective tissue cells) (TRS).
Detailed description
This is a randomized (study drug assigned by chance), multicenter (when more than one hospital or medical school team work on a medical research study), Phase 3 trial to evaluate the efficacy and safety of trabectedin as compared to standard doxorubicin in participants with advanced TRS. Participants will be randomized in a 1:1 ratio to either of the 2 treatment groups, that is, trabectedin or doxorubicin plus ifosfamide group. Participants in trabectedin group will receive trabectedin 1.5 milligram per square meter (mg/m\^2) given as a 24-hour continuous intravenous infusion (a fluid or a medicine delivered into a vein by way of a needle) every 3 weeks and in doxorubicin plus ifosfamide group participants will receive doxorubicin 60 or 75 mg/m\^2 intravenously every 3 weeks followed by ifosfamide 6 to 9 gram (g)/m\^2 every 3 weeks. Participants in either treatment arm will continue receiving therapy in the absence of progressive disease (PD) or intolerable side effects, until the participants' consent is withdrawn or the eligibility criteria for continuing treatment are no longer fulfilled, or when a concurrent condition precludes continuation of treatment. Efficacy will be assessed primarily by evaluating progression-free survival (PFS). Participants' safety will be monitored throughout the trial.
Interventions
DRUGTrabectedin
Trabectedin 1.5 milligram per square meter (mg/m\^2) will be given as 24-hour continuous intravenous infusion every 3 weeks until disease progression.
DRUGDoxorubicin
Doxorubicin 60 or 75 mg/m\^2 will be given intravenously every 3 weeks until disease progression.
DRUGIfosfamide
Ifosfamide 6 to 9 g/m\^2 will be given intravenously every 3 weeks until disease progression.
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
* Pathological diagnosis of translocation-related sarcomas (TRS) including the following subtypes: alveolar soft part sarcoma, angiomatoid fibrous histiocytoma, clear cell sarcoma, desmoplastic small round cell tumor, low grade endometrial stromal sarcoma (prior hormone therapy allowed), low grade fibromyxoid sarcoma, myxoid chondrosarcoma, myxoid/round cell liposarcoma (MRCL) and synovial sarcoma * Participants must have unresectable locally advanced or metastatic progressive disease prior to enrolment * Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0-2 * Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) within normal limits according to institutional standards, as shown by echocardiography or scintigraphy multiple-gated acquisition scan \[MUGA\] * Measurable disease as defined by the radiological (computed tomography \[CT\] scan and magnetic resonance imaging \[MRI\]) Response Evaluation Criteria in Solid Tumors (RECIST v.1.0) guidelines
Exclusion criteria
* Known hypersensitivity to any components of the intravenous formulation of trabectedin or the comparators * Prior chemotherapy treatment or irradiation of the lesion if only one target lesion is available * Brain metastases and/or leptomeningeal metastases, even if treated * Pregnant or lactating women or men and women of reproductive potential who are not using effective contraceptive methods * History of another neoplastic disease (except basal cell carcinoma or cervical carcinoma in situ adequately treated) unless in remission for five years or more
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression - Free Survival (PFS) | Every 6 weeks from randomization during the first 9 months and thereafter, every 9 weeks up to 20 months | The PFS was assessed as median number of days from the date of randomization until the first documented sign of disease progression (increase in disease; radiographic, clinical, or both) or death due to any cause, whichever occurred earlier. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 6-month Progression - Free Survival | 6 months | Percentage of participants survived for 6 months from the start of study treatment without progression of disease. Progression of the disease was associated with increasing symptoms, including pain from new or progressing lesions. Delay in disease progression generally represents a clinical benefit to the participant. |
| Percentage of Participants With Objective Response | Every 6 weeks during first 9 months of the study and thereafter every 9 weeks up to 20 months | Tumor response was assessed according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria: Partial Response (PR)=at least 30% reduction in the sum of the longest dimensions (LD) of all target lesions in reference to the baseline sum LD, Complete Response (CR) =Disappearance of all non-target lesions. Percentage of participants with objective tumor response was determined by the number of participants with PR or CR divided by the total number of response-evaluable participants. |
| Overall Survival | Baseline up to End of Study (an average of 4 years) | Overall survival defined as time from the date of randomization to the date of death. For participants who were alive at the time of analysis, overall survival was censored at the last contact date. |
| Duration of Response (DOR) | Up to 20 months | The DOR is defined as the time from date of first documentation of response (CR or PR, whichever comes first) to the date of documented PD or death. PR=at least 30% reduction in the sum of the longest dimensions (LD) of all target lesions in reference to the baseline sum LD, CR =Disappearance of all non-target lesions. |
Countries
France, Germany, Spain, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Trabectedin Trabectedin 1.5 milligram per square meter (mg/m\^2) given as 24-hour continuous intravenous infusion every 3 weeks until disease progression. | 61 |
| Doxorubicin Plus Ifosfamide Doxorubicin (as a monotherapy) 75 mg per m\^2 will be given intravenously every 3 weeks or Doxorubicin 60 mg per m\^2 will be given intravenously every 3 weeks along with ifosfamide 6 to 9 gram (g)/m\^2 every 3 weeks until disease progression. | 60 |
| Total | 121 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 11 | 6 |
| Overall Study | Death | 3 | 0 |
| Overall Study | Other | 6 | 17 |
| Overall Study | Participant refusal | 3 | 4 |
| Overall Study | Physician Decision | 16 | 17 |
| Overall Study | Progressive disease | 22 | 13 |
| Overall Study | Randomized but not treated | 0 | 3 |
Baseline characteristics
| Characteristic | Trabectedin | Doxorubicin Plus Ifosfamide | Total |
|---|---|---|---|
| Age, Customized >=18 to <=49 years | 33 participants | 30 participants | 63 participants |
| Age, Customized >=50 to <=65 years | 19 participants | 21 participants | 40 participants |
| Age, Customized >=65 years | 9 participants | 9 participants | 18 participants |
| Sex: Female, Male Female | 25 Participants | 22 Participants | 47 Participants |
| Sex: Female, Male Male | 36 Participants | 38 Participants | 74 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 55 / 61 | 52 / 57 |
| serious Total, serious adverse events | 24 / 61 | 16 / 57 |
Outcome results
Primary
Progression - Free Survival (PFS)
The PFS was assessed as median number of days from the date of randomization until the first documented sign of disease progression (increase in disease; radiographic, clinical, or both) or death due to any cause, whichever occurred earlier.
Time frame: Every 6 weeks from randomization during the first 9 months and thereafter, every 9 weeks up to 20 months
Population: Efficacy population included all participants randomly assigned to either treatment arm with externally confirmed pathological and molecular diagnosis of translocation-related sarcomas (TRS)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trabectedin | Progression - Free Survival (PFS) | 19.6 months |
| Doxorubicin Plus Ifosfamide | Progression - Free Survival (PFS) | 8.3 months |
Secondary
6-month Progression - Free Survival
Percentage of participants survived for 6 months from the start of study treatment without progression of disease. Progression of the disease was associated with increasing symptoms, including pain from new or progressing lesions. Delay in disease progression generally represents a clinical benefit to the participant.
Time frame: 6 months
Population: Efficacy population included all participants randomly assigned to either treatment arm with externally confirmed pathological and molecular diagnosis of TRS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Trabectedin | 6-month Progression - Free Survival | 66.7 percentage of participants |
| Doxorubicin Plus Ifosfamide | 6-month Progression - Free Survival | 78.3 percentage of participants |
Secondary
Duration of Response (DOR)
The DOR is defined as the time from date of first documentation of response (CR or PR, whichever comes first) to the date of documented PD or death. PR=at least 30% reduction in the sum of the longest dimensions (LD) of all target lesions in reference to the baseline sum LD, CR =Disappearance of all non-target lesions.
Time frame: Up to 20 months
Population: Efficacy population included all participants randomly assigned to either treatment arm with externally confirmed pathological and molecular diagnosis of TRS. 'N' (number of participants analyzed) signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trabectedin | Duration of Response (DOR) | NA days |
| Doxorubicin Plus Ifosfamide | Duration of Response (DOR) | NA days |
Secondary
Overall Survival
Overall survival defined as time from the date of randomization to the date of death. For participants who were alive at the time of analysis, overall survival was censored at the last contact date.
Time frame: Baseline up to End of Study (an average of 4 years)
Population: Efficacy population included all participants randomly assigned to either treatment arm with externally confirmed pathological and molecular diagnosis of TRS.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trabectedin | Overall Survival | 46.6 months |
| Doxorubicin Plus Ifosfamide | Overall Survival | 33.5 months |
Secondary
Percentage of Participants With Objective Response
Tumor response was assessed according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria: Partial Response (PR)=at least 30% reduction in the sum of the longest dimensions (LD) of all target lesions in reference to the baseline sum LD, Complete Response (CR) =Disappearance of all non-target lesions. Percentage of participants with objective tumor response was determined by the number of participants with PR or CR divided by the total number of response-evaluable participants.
Time frame: Every 6 weeks during first 9 months of the study and thereafter every 9 weeks up to 20 months
Population: Efficacy population included all participants randomly assigned to either treatment arm with externally confirmed pathological and molecular diagnosis of TRS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Trabectedin | Percentage of Participants With Objective Response | 5.9 percentage of participants |
| Doxorubicin Plus Ifosfamide | Percentage of Participants With Objective Response | 27.0 percentage of participants |