Targeting Microenvironment and Cellular Immunity in Sarcomas Weekly Trabectedin Combined With Metronomic Cyclophosphamide

Inclusion Criteria: 1. Patients with soft-tissue sarcoma histologically confirmed by central review 2. Metastatic or unresectable locally advanced disease, 3. Age ≥ 18 years, 4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2, 5. Life expectancy \> 3 months, 6. Measurable disease according to RECIST v1.1 outside any previously irradiated field, 7. For patients included in phase II study, progressive disease according to RECIST v1.1 criteria diagnosed on the basis of two CT scan or MRI obtained at an interval less than 6 months in the period of 12 months prior to inclusion and confirmed by central review, 8. Previous use of Anthracyclines, 9. Have provided tissue from an archival tissue sample, 10. At least three weeks since last chemotherapy, immunotherapy or any other pharmacological treatment and/or radiotherapy, 11. Adequate hematological, renal, metabolic and hepatic function: 1. Hemoglobin ≥ 9 g/dl (patients may have received prior red blood cell \[RBC\] transfusion, if clinically indicated); absolute neutrophil count (ANC) ≥ 1.5 x 10\^9/l, and platelet count ≥ 100 x 10\^9/l 2. Alanine aminotransferase (ALT), aspartate aminotransferase (AST)\< or = 2.5 x upper limit of normality (ULN) ( \< or = 5 in case of extensive liver involvement) and alkaline phosphatase (AP) \< or = 2.5 x ULN 3. Total bilirubin \< or = ULN. 4. Albumin ≥ 25 g/l 5. Serum Creatinine \< or =1.5 x ULN or calculated creatinine clearance (CrCl) ≥ 30 ml/min (according to Cockroft formula). 6. Creatine Phosphokinase (CPK) \< or = 2.5 x ULN 12. Women of childbearing potential must have a negative serum pregnancy test before study entry. Both women and men must agree to use a medically acceptable method of contraception throughout the treatment period and for six months after discontinuation of treatment. Acceptable methods of contraception include intrauterine device (IUD), oral contraceptive, subdermal implant and double barrier, 13. No prior or concurrent malignant disease diagnosed or treated in the last 2 years except for adequately treated in situ carcinoma of the cervix, basal or squamous skin cell carcinoma, or in situ transitional bladder cell carcinoma, 14. Recovery to grade ≤ 1 from any adverse event (AE) derived from previous treatment (excluding alopecia of any grade and non-painful peripheral neuropathy grade ≤ 2) according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 4.0), 15. Patients with a French social security in compliance with the Law relating to biomedical research (Article 1121-11 of French Public Health Code), 16. Voluntarily signed and dated written informed consent prior to any study specific procedure. Exclusion Criteria: 1. Previous treatment with Trabectedin, 2. Currently active bacterial or fungus infection (\> grade 2 CTC \[CTCAE\] HIV1, HIV2, hepatitis B or hepatitis C infections, 3. History of chronic alcohol use and/or cirrhosis, 4. The following unstable cardiac conditions are not allowed: * Congestive heart failure * Angina pectoris * Myocardial infarction within 1 year before registration * Uncontrolled arterial hypertension defined as blood pressure ≥ 150/100 mmHg despite optimal medical therapy * Arrhythmias clinically significant 5. Patients unable to receive corticotherapy, 6. Known central nervous system malignancy (CNS), 7. Men or women of childbearing potential who are not using an effective method of contraception as previously described; women who are pregnant or breast feeding, 8. Participation to a study involving a medical or therapeutic intervention in the last 30 days, 9. Previous enrolment in the present study, 10. Patient unable to follow and comply with the study procedures because of any geographical, social or psychological reasons, 11. Known hypersensitivity to any involved study drug or any of its formulation components. 12. Recent vaccination (in the last 2 weeks before inclusion) for yellow fever.