An Efficacy and Safety Study of Trabectedin Versus Doxorubicin-Based Chemotherapy in Participants With Translocation-Related Sarcomas (TRS)

Study Overview
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Brief Summary
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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
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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therapy in the absence of progressive disease (PD) or intolerable side effects, until the participants' consent is withdrawn or the eligibility criteria for continuing treatment are no longer fulfilled, or when a concurrent condition precludes continuation of treatment.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.

Official Title
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A Randomized, Multicenter, Phase III Trial of Trabectedin (Yondelis) Versus Doxorubicin-based Chemotherapy as First-Line Therapy in Patients With Translocation-Related Sarcomas (TRS)

Conditions
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Sarcoma

Intervention / Treatment
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* Drug: Trabectedin
* Drug: Doxorubicin
* Drug: Ifosfamide


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Trabectedin<br>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. | Drug: Trabectedin<br>* 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.<br>|
| Active Comparator: Doxorubicin plus Ifosfamide<br>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 followed by ifosfamide 6 to 9 gram (g)/m^2 every 3 weeks until disease progression. | Drug: Doxorubicin<br>* Doxorubicin 60 or 75 mg/m^2 will be given intravenously every 3 weeks until disease progression.<br>Drug: Ifosfamide<br>* Ifosfamide 6 to 9 g/m^2 will be given intravenously every 3 weeks until disease progression.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Every 6 weeks from randomization during the first 9 months and thereafter, every 9 weeks up to 20 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 6 months | 
| 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. | Every 6 weeks during first 9 months of the study and thereafter every 9 weeks up to 20 months | 
| 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. | Baseline up to End of Study (an average of 4 years) | 
| 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. | Up to 20 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sarcomas, Trabectedin, Doxorubicin, Ifosfamide, YONDELIS