Osteosarcomas, like other primitive bone tumors, remain hard-to-treat malignancies, especially after failure of first-line treatments. Multiple mechanisms are initiating or rendering bone tumor cells resistant to the chemotherapies leading to the drastic reduction of treatment possibilities in case of relapses. Among the list of extra-tumoral mechanisms enabling this cancer cell resistance, hypoxia and tumor-associated macrophage modulation seem to be in the top ranks. Based on that, we generated by the past tumor data where the study of hypoxic biomarkers' expressions and the presence of protumoral macrophages were influencing the prognosis of osteosarcoma patients. In fact, the association of HIF1 hyperexpression and a high number of M2 phenotype macrophages (e.g., protumoral cells) were predictive markers of the worst outcome. We recently redone this translational approach in other bone tumors like Ewing sarcomas (EWS) showing the same prognostic tendency. Furthermore, a past pediatric phase I trial, named RAPIRI, targeting both mTor and HIF1, with combination of Sirolimus and Irinotecan, was able to provide in the relapsing bone cancers a partial response or stable disease in more than 50% of patients and particularly in patients with blood concentrations of Sirolimus between 5 and 15 µg/L. To go further and understand the potential links between macrophages and hypoxic resistant tumors, recent preliminary exploration, with an immunofluorescent assessment targeting GD2 expression on tumor cell membranes, was underlining osteosarcomas but also EWS with standard fusions and CIC-DUX4 cancers as hyperexpressing cancers for this disialoganglioside. The cell-surface molecule was highly expressed in 22 out of 32 diagnostic samples (unpublished data). This glycosphingolipid usually presenting a restricted pattern of expression on normal tissues seems to be frequently hyperexpressed in some cancers and therefore amenable to targeting by the monoclonal antibody Dinutuximab beta. The anti-GD2 effect of this drug relies on complement and immune effector cells to mediate cancer cell killing. Recent and unpublished preclinical data in our Lab (UMR-CNRS7021, Strasbourg) envisioned the proof-of-concept combining Sirolimus, Irinotecan and Dinutuximab beta in osteosarcoma models and afford sustainable results to conclude to a clear efficiency of this triple combination stopping completely osteosarcoma cell proliferation and reducing drastically their invasion in microenvironment. Gathering all those prerequisite data and, as the monoclonal therapeutic antibody (Dinutuximab beta) now is extensively evaluated in clinics in multiple indications (e.g., neuroblastomas, Ewing sarcomas and other sarcomas), we propose here a phase I/II trial with this combination of treatments targeting hypoxia and GD2 in bone tumors focusing on relapsing bone tumors with endpoints determining accurate dose to give to patients and its efficacy at 16 weeks of treatment.