Phase Ib / Regorafenib With Conventional Chemotherapy/Newly Diagnosed Patients/ Multimetastatic Ewing Sarcoma

New drug efficacy in ES has been disappointing in the last decades and no new drugs have been successfully introduced up to now in front line treatment. Among the tested drugs, early clinical data suggest that strategies using multi-targeted tyrosine kinase inhibitors (TKI) with anti-angiogenic activities are among the most efficient and may be beneficial in the treatment of patients with ES. Several TKI have been and are currently being tested as single-agent in patients with relapsed/refractory ES with encouraging results in phase II trials. Regorafenib has shown promising activity in Ewing sarcoma relapse setting, Nevertheless, regorafenib has never been combined with the intensive chemotherapy VDC/IE schedule and therefore this combination needs to be evaluated in order to avoid dose reduction of the current standard treatment and hence its efficacy. The current clinical trial has been therefore designed to test the feasibility of regorafenib with ES conventional chemotherapy. It consists of a phase Ib that will only recruit patients with multi-metastatic (other than lungs/pleura only) ES, that present the highest unmet medical need (2 year EFS: 33%, similar to patients with relapse/refractory ES).