All included patients will receive standard Ewing sarcoma (ES) treatment concomitant with regorafenib.~Standard ES treatment consists of: induction chemotherapy (VDC/IE) and local treatment (surgery/radiotherapy), followed by consolidation chemotherapy (VC/IE)/ Bu-Mel (according to physician and patient choice).~Regorafenib will be administered during induction chemotherapy (VDC/IE) and during consolidation chemotherapy with conventional chemotherapy (VC/IE) but not Bu-Mel therapy~Conventional chemotherapy will be administered at the recommended dose (100%) and only regorafenib will be escalated/de-escalated, starting at DL0:~DL1: 82 mg/m^2 once daily for 21 days/28 days (max 160mg) (100% of the RP2D)~DL0 (starting dose): 66 mg/m^2 once daily for 21 days/28 days (max 120mg) (80% of the RP2D)~DL-1: 50 mg/m^2 once daily for 21 days/28 days (max 80mg) (60% of the RP2D) Regorafenib will be stopped 2 weeks before planned surgery of the primary tumor and reintroduced when adequate wound healing is obtained, concomitant with consolidation VC/IE chemotherapy.~Regorafenib will only be given concomitant to radiotherapy in case the primary tumor is located in the extremities. In case of primary tumors located in the pelvis, abdomen, thorax, spine, brain, head or neck, regorafenib will be stopped at least 1 week before start of radiotherapy.
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).