First-line Treatment of Ewing Tumours With Primary Extrapulmonary Dissemination in Patients From 2 to 50 Years (CombinaiR3)

Inclusion Criteria:

1. \- Ewing tumour histologically or cytologically confirmed, harboring a specific transcript, and with extrapulmonary metastases (including nodal extension) - histology and FISH results must be consistent, specific transcript can be obtained after inclusions.
2. \- Ewing tumour not previously treated.
3. \- Age between 2 and 50 years.
4. \- Measurable disease by cross sectional imaging (RECIST 1.1) or evaluable disease with functional metabolic, positron emission tomography scanner (PET SCAN) or other methods (e.g., cytology/histology).
5. \- General status compatible with the study treatments (LANSKY score ≥ 50%, or Karnofsky ≥ 50%, or Eastern Cooperative Oncology Group (ECOG) ≤ 2).
6. \- Adequate bone marrow function (not applicable in case of bone marrow disease).

   * Platelets ≥ 100 x 109 /L
   * Absolute Neutrophil Count (ANC) ≥ 1 x 109 /L
   * Hemoglobin ≥ 8g /dL.
7. \- Adequate liver function :

   * Aspartate Aminotransferase (AST) and Alanine Transferase (ALT) ≤ 5 x Upper Limit Normal (ULN)
   * Total Bilirubin ≤ 2 Upper Limit Normal (ULN). If total bilirubin \> 2xULN, Bilirubin Conjugated Fraction (BCF) ≤ 2 x ULN
8. \- No absolute contra-indication of Busulfan-Melphalan if radiotherapy of the primary tumour is necessary with specific attention to patient with primary spinal tumor.
9. \- Adequate cardiac and renal functions:

   * Creatinine \< 1.5 of normal for age or clearance \> 60 ml/min/1.73 m²;
   * Left Ventricular Ejection Fraction (LVEF) \> 50% and/or shortening fraction \> 28%.
10. \- No underlying disease contra-indicating the study treatments.
11. \- Patient likely compliant with the recommended study medical monitoring during and after treatments.
12. \- Patients of childbearing potential must agree to use adequate contraception for the duration of study treatments and up to 12 months for women and 6 months for men following completion of therapy.
13. \- Females of childbearing potential must have a negative serum β-human chorionic gonadotropin (HCG) pregnancy test within 10 days prior study inclusion, and/or urine pregnancy test within 48 hours before the first administration of the study treatment.
14. \- Patients covered by a health insurance system.
15. \- Patient, or patient's legal representative, informed and having signed the informed consent.

Exclusion Criteria:

1. \- Age below 2 or greater than 50 years.
2. \- Ewing tumour localized, or solely with pleural and/or lung metastases.
3. \- Concomitant disease, particularly infectious disease, likely to interfere with patient's treatment.
4. \- History of cancer, according to investigator's judgment.
5. \- Life expectancy \< 2 months.
6. \- Patient already included in another clinical trial with an investigational drug.
7. \- Pregnant or breastfeeding patient.
8. \- Person deprived of liberty or under guardianship.
9. \- Patient likely unable to comply with the study medical monitoring for geographical, social or psychological reasons.