Phase II Prospective Multicenter Study of High-Dose Treosulfan/Melphalan as Consolidation Treatment in Newly Diagnosed High-Risk and Very High-Risk Ewing Sarcoma

Prior treatment

• Presence of concomitant bone metastases + bone marrow involvement (at least one site positive for metastatic infiltration);
• Prior or concurrent chemotherapy or radiotherapy;

Other illness

• Second malignancy;

Lab values

• Any other severe concomitant comorbiditiesthat, according to the opinion of the Investigator, makes the enrollment in the study inappropriate for the patient, in particular: o myocardial infarction/unstable angina/congestive heart failure within 6 months before enrollment, LVEF less than the lower limit of normal per local institutional standards, history of clinically significant atrial arrhythmia or any history of ventricular arrhythmia; o uncontrolled hypertension, according to age values (patients with hypertension should be under treatment on study entry to carry out blood pressure control); o cerebrovascular accident or transient ischemic attack within 6 months before enrollment, any history of peripheral arterial occlusive disease requiring revascularization, venous thromboembolism including deep venous thrombosis or pulmonary embolism within 6 months before enrolment; o uncontrolled metabolic alterations (such as hypertriglyceridemia); o severe active uncontrolled infection; o history of bleeding disorder; o history of acute pancreatitis (within 1 year before study entry) or history of chronic pancreatitis; o history of alcohol abuse;

Age

• The presence of > 5 bone lesions at age < 14 years or > 1 bone lesion at age > 14 years. Bone lesions must be confirmed by CT scan, MRI, PET scan or, in doubtful cases, by biopsy;

Other

• Pregnant or breastfeeding women;
• Neuropsychiatric, social, geographic or severe family problems that make it difficult for the patient to participate in the study.

• Primary diagnosed and histologically confirmed, localized or metastatic, Ewing sarcoma (ES) of bone or soft tissue, or ‘Ewing-like’ sarcoma but negative for EWSR1 gene rearrangement;
• Patients with disseminated ES are included if any of the following conditions are present: a) 0-5 bone lesions at age < 14 years; b) 0-1 bone lesion at age > 14 years; c) bone marrow (BM) involvement; d) Extraosseous metastases + BM involvement or + bone lesion(s) with the aforementioned age-cut-offs;
• Informed consent signed by the patient and/or by the parents/legal guardian;
• Age < 50 years. Paediatric patients (< 18 years old) must be treated in accredited centers for the treatment of paediatric cancer patients
• Registration to the protocol ≤ 45 days from diagnostic biopsy/surgery
• Karnofsky > 50% for participants > 16 years old or Lansky Play Score > 50% for paediatric participants ≤ 16 years old or ECOG ≤ 2 for adult participants;
• Adequate bone marrow function, defined as: Peripheral absolute neutrophil count (ANC) > 0.75 ×10 9 /L • Haemoglobin > 8.0 g/dL (transfusion allowed) • Platelet count > 75 × 10 9 /L (transfusion allowed)
• Adequate organ function (serum creatinine < 1.5 x upper limit of normal (ULN), calculated creatinine clearance > 60 ml/min as determined by Cockcroft-Gault or according to age and sex as determined by Schwartz’s Formula, serum bilirubin ≤ 1.5 × ULN, except for Gilbert’s Syndrome, serum lipase and amylase ≤ 1.5 × ULN, ALT and AST≤ 2.5 × ULN or ≤ 5.0 × ULN for patients with hepatic metastases, normal ventricular ejection function as LVEF > 50% and SF > 28%);
• A negative pregnancy test before enrolment and once a month during therapy for female participants of potential childbearing; for patients sexually active, it is mandatory to use an effective contraception throughout the treatment and up to 6 months beyond its end. A woman is considered of childbearing potential, i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.