Trial evaluating the impact on efficacy of mifamurtide as add-on treatment to post-operative chemotherapy compared to post-operative chemotherapy alone in first-line treatment of patients with high-risk osteosarcoma (defined as metastatic osteosarcoma at diagnosis or localised osteosarcoma with poor histological response).

Multicentre, randomised, open-label, phase II trial, with 2 parallel groups. After pre-operative chemotherapy and surgery of the primary tumour and lung metastases (if applicable), patients presenting high-risk osteosarcoma (defined as metastatic osteosarcoma at diagnosis or localised osteosarcoma with poor histological response) will be randomised between 2 arms:

• Control arm: post-operative chemotherapy alone (with regimens adapted to the age of patient)
• Experimental arm : post-operative chemotherapy combined with mifamurtide

This randomised trial is part of a study recruiting all patients ≤50 years old with a newly diagnosed high-grade osteosarcoma.

Registration Criteria:

1. All newly diagnosed, biopsy-proven, high-grade osteosarcoma, whatever the initial extension of the disease

2. Age >2 years and ≤50 years;

3. Normal haematological, renal, cardiac and hepatic functions

4. Planned neoadjuvant chemotherapy as follows:

   1. Methotrexate-Etoposide-Ifosfamide (M-EI regimen) for patients ≤25 years
   2. Doxorubicin-Cisplatin-Ifosfamide (API-AI regimen) for patients 26-50 years

5. Written informed consent from patients and/or their parents/guardians before enrolment and any study-related procedure

6. Affiliation to a social insurance regimen

Inclusion Criteria:

1. Patient with a histologically proven, confirmed by experts pathologists panel (before surgery at the latest), high-grade osteosarcoma

2. Registered at diagnosis into the study

3. Primary tumour resected after pre-operative chemotherapy

4. Osteosarcoma classified as high risk because of at least one risk factor:

   1. presence of distant metastases or skip metastases at diagnosis
   2. and/or poor histological response to pre-operative chemotherapy (>10% residual viable cells on the analysis of the primary tumour surgical specimen)

5. Pre-operative chemotherapy combining

   1. Methotrexate-Etoposide-Ifosfamide (M-EI regimen) for patients ≤25 years
   2. Doxorubicin-Cisplatin-Ifosfamide (API-AI regimen) for patients 26-50 years

6. Screening laboratory values must meet the following criteria (using CTCAE v4) and should be obtained within 7 days prior to randomisation:

   1. Absolute neutrophil count ≥1.0 x 10⁹/L
   2. Platelets ≥100 x 10⁹/L
   3. Haemoglobin ≥8.0 g/mL
   4. Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤2.5 x upper limit of normal (ULN) in the absence of liver metastases or ≤5 x ULN in the presence of liver metastases
   5. Total Bilirubin ≤2 x ULN (except Gilbert Syndrome: <3.0 mg/dL) or Total Bilirubin ≤5.0 x ULN in the presence of liver metastases
   6. Creatinine clearance ≥60 mL/min/1.73 m² according to the Schwartz or Cockcroft formula according to patient's age

7. Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) done within 7 days prior to randomisation

8. Provision of dated and signed written informed consent for the randomised trial prior to any study specific procedures, sampling and analyses.

9. Patient fit to undergo protocol treatment and follow-up

10. Affiliation to a social insurance regimen

Exclusion Criteria:

1. Low grade osteosarcoma, parosteal or periosteal osteosarcoma
2. Prior history of other malignancies other than study disease (except for basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix) unless the patient has been free of the disease for at least 3 years.
3. Osteosarcoma with multiple metastases for whom complete removal is not expected to be feasible even after shrinkage with chemotherapy
4. Progressive disease at any site under initial chemotherapy, confirmed before randomisation time, and not totally resected during surgery
5. Any medical condition precluding treatment with protocol chemotherapy
6. Fractional Shortening <28% or left ventricular ejection fraction (LVEF) 50% before treatment (only for API post-operative chemotherapy) by echocardiogram or multigated acquisition (MUGA) scan
7. Pregnancy or breast-feeding
8. Hypersensitivity to the active substance or to any of the excipients
9. Concurrent use of immunodepressive treatment such as cyclosporine, tacrolimus or other calcineurin inhibitors
10. Concurrent use with high-dose non-steroidal anti-inflammatory drugs (NSAIDs, cyclooxygenase inhibitors)
11. Inflammatory or auto-immune disease, allergy or asthma requiring a chronic use of steroid treatment that cannot be stopped.
12. Patients with positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
13. Patients with positive tests for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV RNA) indicating active or chronic infection.

Individual participant data will not be shared at an individual level, they will be part of the study database including all enrolled patients.