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

Inclusion Criteria:

1. Any histologically and genetically confirmed Ewing sarcoma of bone or soft tissue, or round cell sarcomas which are 'Ewing's-like' but negative for EWSR1 gene rearrangement
2. Metastatic disease
3. Age ≥2 years and \<50 years (from second birthday to 49 years 364 days)
4. Patient assessed as medically fit to receive the Ewing sarcoma standard multimodal treatment and regorafenib, including:

   * Absolute Neutrophil Count (ANC) ≥ 0.75x10\^9/L, platelets ≥ 75x10\^9/L.
   * Alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤ 5×ULN
   * Bilirubin ≤ 2×ULN
   * Creatinine \< 2x ULN or creatinine clearance \>60 ml/min/1.73 m\^2
   * International normalized ratio (INR)/ Partial thromboplastin time (PTT). INR and PTT ≤ 1.5 x ULN. INR \& PTT ≤ 1.5xULN
5. Adequate cardiac function as evidenced by left ventricular ejection fraction (LVEF) ≥50%) at baseline, as determined by echocardiography
6. Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as: a BP \<95th percentile for sex, age, and height at screening (as per National Heart Lung and Blood Institute \[NHLBI\] guidelines) and no change in antihypertensive medications within 1 week prior to Cycle 1 Day 1. Patients \>18 years old should have BP ≤ 150/90 mmHg.
7. No prior treatment for Ewing sarcoma other than surgery
8. Negative pregnancy test for female patients of childbearing potential within 7 days prior to study registration.
9. Patient agrees to use highly effective contraception during therapy and for 12 months after last trial treatment (females) or 6 months after last trial treatment (males), where applicable
10. Subject must be able to swallow and retain oral medication.
11. Written informed consent from the patient and/or the parent/legal guardian, according to local, regional or national regulation prior to any study specific procedures.
12. Patients must be affiliated to a social security system or beneficiary of the same, as per local regulatory requirements (France only)

Exclusion Criteria:

1. Localized tumor or metastatic disease to lung/pleura only.
2. Contra-indication to the Ewing sarcoma standard multimodal treatment
3. Pregnant or breastfeeding women or intending to become pregnant during the study.
4. Follow-up not possible due to social, geographic or psychological reasons
5. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter absorption of oral drugs
6. A clinically significant ECG abnormality, including a marked prolonged QTcF interval (eg, a repeated demonstration of a QTcF interval \>480 msec) Clinically significant, uncontrolled heart disease (including history of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal arrhythmias, or conduction abnormality, unstable angina, active coronary artery disease and myocardial infarction within 6 months before randomization.) Uncontrolled hypertension (systolic pressure \>150 mmHg or diastolic pressure \> 90 mmHg on repeated measurement) despite optimal medical management
7. Previous arterial or venous thromboembolisms Grade ≥ 3 per CTCAE v5.0
8. Hypersensitivity to any active substance or to any excipients
9. Radiographic evidence of encasement or invasion of a major blood vessel or of intratumoral cavitation
10. Major surgical procedure or significant traumatic injury within 28 days before starting study treatment
11. Non-healing wound, ulcer or bone fracture.
12. Uncontrolled systemic or local infection requiring systemic treatment
13. Any anticoagulant therapy (risk of hemorrhage with Regorafenib)
14. Interstitial lung disease with ongoing signs and symptoms.
15. Known prior history of HBV, HCV, HIV
16. Any other medical or other condition that, in the opinion of the investigator(s), would preclude the subject's participation in this clinical study