Study on Leiomyosarcoma, Liposarcomas and Synovial Sarcoma With Trabectedin

Study Overview
=================
Brief Summary
-----------------
Two arm, randomized, open-label study, to determine the best time to secondary resistance between responding patients who discontinue treatment and resumed Trabectedin at the time of progression versus patients who continued treatment until progression. T

Detailed Description
-----------------
This is an Italian, multicenter, randomized, open-label , two arm, study, to determine the best time to secondary resistance between responding patients who discontinue treatment and resumed Trabectedin at the time of progression versus patients who continued treatment until progression. The aim is to evaluate the best clinical practice for responding patients as Trabectedin has an acceptable safety profile with no evidence of cumulative toxicity. After signing informed consent and being assessed for eligibility criteria , eligible patients will start the trabectedin treatment. All the patients who will complete 6 cycles of treatment without disease progression will be be randomized to continue Trabectedin versus treatment interruption followed by re-challenge at progression. Patients randomized to discontinue treatment will be candidate to other 6 cycles of treatment and if they do not progress, to another interruption. The treatment will be resumed again at progression for other 6 cycles and this scheme of treatment will be proposed until progression under Trabectedin. The study will be conducted in Italy in approximately 12 centers, in order to recruit 330 evaluable patients over a 4 year period. The follow-up will last approximately 3 years.

Official Title
-----------------
Time to Secondary Resistance to Trabectedin After Interruption Versus Continuation in Responding Patients With Liposarcoma, Leiomyosarcoma and Synovial Sarcoma

Conditions
-----------------
Leiomyosarcoma, Liposarcoma, Synovial Sarcoma

Intervention / Treatment
-----------------
* Drug: Trabectedin discontinuation
* Drug: Trabectedin continuation


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: The patient or legal representative must be able to read and understand the informed consent form and must have been willing to give written informed consent and any locally required authorization before any study-specific procedures, including screening evaluations, sampling, and analyses Diagnosis of well differentiated/dedifferentiated liposarcoma, mixoid round cell liposarcoma, leiomyosarcoma or synovial sarcoma Persistent or locally relapsed and/or metastatic disease Pathology specimens available for centralized review (central review is not mandatory prior to start the treatment, but within a month from screening, tumor sample must be sent to central pathology reviewer for a retrospective diagnosis confirmation). Age ≥ 18 years Adequate bone marrow function Adequate organ function, Eastern Cooperative Oncology Group Performance Status ≤ 2 One or more previous systemic treatments with anthracyclines with or without ifosfamide (unless one or both are clinically contraindicated) Measurable disease. Patient who received radiotherapy within 3 weeks form the treatment start, can be included as long there is a measurable lesion outside of the irradiation field A minimum of 3 weeks since any previous chemotherapy treatment Recovery from toxic effects of prior therapies to (Grade 1 or lower) Female patients of child-bearing potential must have negative pregnancy test within 7 days before initiation each cycle of chemotherapy. Post-menopausal women must be amenorrhoeic for at least 12 months to be considered of non-childbearing potential. Male and female patients of reproductive potential must agree to employ an effective method of birth control throughout the study. Exclusion Criteria: Pregnant or breast-feeding women Prior exposure to Trabectedin Peripheral neuropathy, Grade 2 or higher History of other malignancies (except basal cell carcinoma or cervical carcinoma in situ, adequately treated), unless in remission from 5 years or more and judged of negligible potential of relapse Known central nervous system metastases Active viral hepatitis or chronic liver disease Unstable cardiac condition, including congestive heart failure or angina pectoris, myocardial infarction within six months before enrollment, uncontrolled arterial hypertension or arrhythmia Active major infection Previous treatment with any other investigational or not investigational agents within 14 days of first day of study drug dosing Known history of human immunodeficiency virus infection Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation of the study drugs Other serious concomitant illnesses or any condition that may interfere with the subject's participation in the study or evaluation of the study results

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, open-label , two arm study All the patients who will complete 6 cycles of treatment without disease progression will be be randomized to continue Trabectedin versus treatment interruption followed by re-challenge at progression. Patients randomized to discontinue treatment will be candidate to other 6 cycles of treatment and if they do not progress, to another interruption. The treatment will be resumed again at progression for other 6 cycles and this scheme of treatment will be proposed until progression under Trabectedin.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Trabectedin continuation<br>All the patients who will complete 6 cycles of trabectedin without disease progression, will continue trabectedin until progressive disease, unacceptable toxicity, patient or investigator decision | Drug: Trabectedin continuation<br>* Patients who did not progressed after 6 cycles of trabectedin will continue the treatment until Progressive Disease or unacceptable toxicity<br>* Other names: Treatment continuation;|
| Experimental: Trabectedin discontinuation<br>All the patients who will complete 6 cycles of trabectedin without disease progression , will discontinue trabectedin. The treatment will be resumed again at progression for other 6 cycles and this scheme of treatment will be proposed until progression under trabectedin. | Drug: Trabectedin discontinuation<br>* Patients who did not progressed after 6 cycles of trabectedin will stop the treatment and resume drug in case of progression for other 6 cycles. The treatment will be resumed again at progression for other 6 cycles and this scheme of treatment will be proposed until progression under trabectedin.<br>* Other names: Treatment discontinuation;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time secondary resistance to Trabectedin | Time secondary resistance to Trabectedin is the time from the first trabectedin dose to progression not amenable to treatment with Trabectedin, or death, whichever occurs first | Week 18 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall Survival is the time from the first trabectedin dose to death for any cause | month 6,month 12, month 18, month 24, months 30, month 36, month 42, month 48, month 54, month 60 | 
| Incidence of adverse event | Adverse events are evaluate from the first trabectedin dose throughout the study according to CTCAE 5.0 | Week 9, week 18, week 27, week 36, week 45, week 54, week 63, week 72, week 81 | 
| Progression free survival | Time from the first trabectedin dose to time of onset of progression disease | Week 9, week 18, week 27, week 36, week 45, week 54, week 63, week 72, week 81 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
trabectedin, soft tissue sarcoma