Interest of Peri Operative CHemotherapy In Patients With CINSARC High-risk Localized Soft Tissue Sarcoma

Inclusion Criteria:

1. Diagnosis of soft-tissue sarcoma, histologically confirmed by RRePS (Réseau deRéférence en Pathologie des Sarcomes et des Viscères) network

2. According to FNCLCC grading system, grade 1, 2 or 3 tumors

3. Resectable and localized disease after appropriate extension work-up (including atleast a chest-CT)

4. 6 weeks or less between surgical excision and inclusion (if performed beforeinclusion)

5. Available archived FFPE tumor sample in sufficient quantity to allow CINSARCqualification

6. Age ≥ 18 years

7. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

8. Life expectancy of at least 12 weeks after the start of the treatment

9. Women should be post-menopaused or willing to accept the use of an effectivecontraceptive regimen during the treatment period and at least 12 months (ifosfamidetreatment) or 6 months (dacarbazine treatment) after the end of the treatmentperiod. All non-menopaused women should have a negative pregnancy test within 72hours prior to registration. Men should accept to use an effective contraceptionduring treatment period and at least 3 months after the end of the study treatment.

10. Signed written informed consent

11. Patient affiliated to a Social Health Insurance in France.

Exclusion Criteria:

1. Soft-tissue sarcoma with the following histological subtypes: well-differentiatedliposarcomas, alveolar soft-part sarcoma, dermatofibrosarcoma protuberans,clear-cell sarcoma, epithelioid sarcoma, alveolar or embryonal rhabdomyosarcoma

2. Primitive cutaneous, retroperitoneal, uterus or visceral STS

3. Metastatic disease

4. Previous or ongoing treatment for the sarcoma (with the exception of surgicalexcision)

5. Contra-indication for Doxorubicin, Ifosfamide and Dacarbazine treatments

6. Prior therapy with ifosfamide or cyclophosphamide or other nitrogen mustards, andprior therapy with anthracyclines

7. Prior mediastinal/cardiac radiotherapy

8. History or presence of clinically relevant cardiovascular abnormalities such asuncontrolled hypertension, congestive heart failure NYHA classification of 3,unstable angina or poorly controlled arrhythmia, myocardial infarction within 6months prior to study entry

9. Prior or concurrent malignant disease diagnosed or treated in the last 2 yearsexcept for adequately treated in situ carcinoma of the cervix, basal or squamousskin cell carcinoma, or in situ transitional bladder cell carcinoma

10. Active, uncontrolled bacterial, viral, or fungal infections, requiring systemictherapy

11. Known infection with HIV, hepatitis B, or hepatitis C

12. Women who are breastfeeding, pregnant or who plan to become pregnant while in thetrial

13. Concomitant disease or condition that could interfere with the conduct of the study,or that would, in the opinion of the investigator, pose an unacceptable risk to thesubject in this study

14. Patient who has forfeited his/her freedom by administrative or legal award or who isunder legal protection (curatorship and guardianship, protection of justice)

15. Patient unable to comply with the protocol for any reason.

ADDITIONAL CRITERIA FOR THE RANDOMIZED PHASE III STUDY

1. High-risk CINSARC signature

2. Acceptable hematologic function (within 72 hours prior randomization): Absoluteneutrophil count (ANC) ≥ 1.5 G/L, Platelet count ≥ 100 G/L and Hemoglobin > 9g/dL

3. Acceptable renal function within 72 hours prior randomization: Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 60 mL/min (by the Cockcroft and Gaultformula)

4. Acceptable liver function: Bilirubin ≤ 1.5 x upper limit of normal (ULN), AST (SGOT)and ALT (SGPT) ≤ 2.5 x ULN

5. Normal LVEF (>50%) measured by echocardiography or isotopic ventriculography