Liposarcomas are soft tissue sarcomas most frequent. We distinguish three subtypes on the basis of their histological and cytogenetic characteristics: well-differentiated liposarcoma / dedifferentiated, myxoid liposarcoma and / or round cell liposarcoma and pleomorphic. Dedifferentiated liposarcomas (LDD) represent 20% of liposarcomas and are characterized by well-differentiated component associated with a contingent sarcomatous differentiation and fat-usually high grade. The LDD are most often rétropértionéal seat. Thus, their development is very long asymptomatic. At diagnosis, tumor volume is often very important making surgical removal impossible in a high proportion of cases. Operable tumors have also a risk of local recurrence by about 50% and about 20% metastatic. Chemotherapy is the only treatment of these advanced forms. However, the currently available drugs (adriamycin, ifosfamide) have only very limited effectiveness. Progression-free survival of patients does not exceed 2 months. The LDD is characterized cytogenetically by the constant presence of two amplicons (1p32 and 6q23) respectively targeting genes MAP3K5 and JUN. These two genes encode proteins involved in the signaling pathway Jun N-terminal kinase (JNK). Activation of JNK is involved in the loss of adipose differentiation and tumor aggressiveness of LDD. The plitidepsin is a drug capable of inducing apoptosis of tumor cells carrying a functional activation of the JNK pathway. This drug has such a pro-apoptotic and anti-proliferative in vitro models of LDD. plitidepsin could represent the treatment of choice for patients with advanced LDD. The objective of this study is to evaluate the anti-tumor activity of plitidepsin patients with locally advanced dedifferentiated liposarcomas and / or metastatic.

Inclusion Criteria:

1. Voluntarily signed and dated written informed consent prior to any study specific procedure.

2. Histologically confirmed DLPS by central review.

3. Metastatic or unresectable locally advanced disease

4. Progressive disease according to RECIST v1.1 criteria diagnosed on the basis of two CT scan obtained at an interval less than 3 months and confirmed by central review

5. At least one prior anthracycline-containing chemotherapy regimen

6. Age ≥ 18 years.

7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1.

8. Measurable disease according to RECIST v1.1 outside any previously irradiated field.

9. 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) ≥ 1.2 x 109/l, and platelet count ≥ 100 x 109/l.
   2. Alkaline phosphatase (AP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) 2.5 x upper limit of normality (ULN) (5 in case of extensive skeletal involvement for AP exclusively).
   3. Total bilirubin 1.5 x ULN.
   4. Albumin > 25 g/l.
   5. Calculated creatinine clearance (CrCl) ≥ 40 ml/min (according to cockroft and Gault formula).
   6. Creatine phosphokinase (CPK) ≤ 2.5 x ULN.

10. Troponin I ≤ ULN

11. No prior or concurrent malignant disease in the last 5 years except for adequately treated in situ carcinoma of the cervix, basal or squamous skin cell carcinoma, or in situ transitional bladder cell carcinoma.

12. At least three weeks since last chemotherapy (six weeks in case of nitrosoureas and mitomycin C), immunotherapy or any other pharmacological treatment and/or radiotherapy.

13. 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).

14. Left ventricular ejection fraction (LVEF) by echocardiogram (ECHO) or multiple gated acquisition (MUGA) within normal limits.

15. 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.

16. Patients with a french social security in compliance with the French law relating to biomedical research

Exclusion Criteria:

1. Previous treatment with plitidepsin.

2. More than three prior lines of therapy for advanced disease.

3. Concomitant diseases/conditions:

   1. History or presence of unstable angina, myocardial infarction, congestive heart failure or clinically significant valvular heart disease. Symptomatic arrhythmia or any arrhythmia requiring ongoing treatment, and/or prolonged QT-QTc grade > 1.
   2. Previous mediastinal radiotherapy.
   3. Previous treatment with anthracyclines at cumulative doses in excess of 450 mg/m2 doxorubicin equivalent.
   4. Symptomatic arrhythmia or any arrhythmia requiring ongoing treatment, and/or prolonged QT-QTc grade > 1.
   5. Active uncontrolled infection.
   6. Myopathy or persistent CPK elevations > 2.5 x ULN in two different determinations performed with one week apart.
   7. Any other major illness that, in the Investigator's judgment, will substantially increase the risk associated with the patient's participation in this study.

4. Evidence of progressive or symptomatic central nervous system (CNS) or leptomeningeal metastases.

5. 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.

6. Tumor tissue sample not available for pathological review and/or JNK immunochemistry testing.

7. Participation in a clinical study and / or receipt of an investigational drug during the last 30 days.

8. Previous enrolment in the present study.

9. Patient unable to follow and comply with the study procedures because of any geographical, social or psychological reasons.

10. Known hypersensitivity to any involved study drug or any of its formulation components