International Clinical Research Programme to Improve Outcomes in Newly Diagnosed Ewing SarcomaTrial 1 (INTER-EWING-1)
INTER-EWING-1 (INTER-EWING-1)
Arakawa Ayumu
National Cancer Center Hospital
5-1-1 Tsukiji, Chuo-ku
+81-3-3542-2511
aarakawa@ncc.go.jp
Arakawa Ayumu
National Cancer Center Hospital
5-1-1 Tsukiji, Chuo-ku
+81-3-3542-2511
ncch2411_office@ml.res.ncc.go.jp
Recruiting
May. 01, 2026
90
Interventional
randomized controlled trial
open(masking not used)
no treatment control/standard of care control
parallel assignment
treatment purpose
Study entry
1.Any histologically and genetically confirmed Ewing sarcoma of bone or soft tissue, or round cell sarcomas which are Ewings like but negative for EWSR1-Fli gene rearrangement
2.Age >=2 years
3.Written informed consent from the patient and or the parent legal guardia
Randomisation A
1.Entered into the INTER-EWING-1 study
2.Metastatic disease
3.Adequate liver function defined as total bilirubin<=2 xULN and alanine aminotransferase (ALT) or aspartate aminotransferase (AST) <=5 xULN (total bilirubin is allowed up to 3xULN if Gilberts syndrome is documented)
4.Adequate cardiac function as evidenced by left ventricular ejection fraction (LVEF) >=50% or fractional shortening >= 28% at baseline as determined by echocardiography
5.Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as a BP <95th percentile for age and height at screening and no change in antihypertensive medications within 1 week prior to randomisation. Patients over 18 years old should have BP <=150/90 mm Hg
6.No prior treatment for Ewing sarcoma other than surgery
7.Medically fit to receive treatment
8.Documented negative pregnancy test for female patients of childbearing potential
9.Patient agrees to use contraception during therapy and for 12 months after last trial treatment (female) or 6 months after last trial treatment (males),where applicable
10.Written informed consent from the patient and/or the parent legal guardian
Radiotherapy Randomisations B1 and B2
1.Entered into the INTER-EWING-1 study
2.Received induction/consolidation chemotherapy with standard VDC/IE/VC regimen (patients who have received VAI/BuMel as part of consolidation therapy will also be eligible)
3.Patient assessed as medically fit to receive the radiotherapy
4.Documented negative pregnancy test for female patients of childbearing potential
5.Patient agrees to use contraception during therapy and for 12 months after last trial treatment (females) o r 6 months after last trial treatment (males), where patient is sexually active
6.Written informed consent from the patient and/or the parent/legal guardian
Randomisation B1
1.Patients requiring definitive radical radiotherapy to primary tumour site as sole local therapy following discussion by local multidisciplinary team
This includes patients who have undergone an R2 resection of the primary tumour (macroscopic residual tumour), requiring definitive radical radiotherapy
Randomisation B2
1.Patients requiring post-operative radiotherapy following discussion by local multidisciplinary team at the multidisciplinary team meeting
Randomisation C
1.Entered into the INTER-EWING-1 study
2.Received induction/ consolidation chemotherapy with standardVDC/IE/VC regimen (patients who have received VAI/BuMel as part of consolidation therapy will also be eligible)
3.Have responded to induction treatment and not progressed
4.Medically fit to receive treatment
5.Absence of severe vincristine neuropathy i.e. requiring discontinuation of vincristine treatment
6.Adequate liver function: bilirubin <3 x ULN and ALT or AST < 5 x ULN
7.Documented negative pregnancy test for female patients of childbearing potential
8.Patient agrees to use contraception during therapy and for 12 months after last trial treatment (females) or 6 months after last trial treatment (males), where patient is sexually active
9.Written informed consent from the patient and/or the parent legal guardian
Study entry
1.Previous malignancy
2.Follow-up not possible due to social, geographic or psychological reasons
Randomisation A Induction chemotherapy randomisation
1.Localised tumour
2.Absolute Neutrophil Count (ANC) < 0.75 x 109/L or platelets < 75 x 109/L
3.International Normalized Ratio (INR) and Partial Thromboplastin Time (PTT) >1.5xULN
4.Inadequate renal function defined as GFR <60 ml/min/1.73 m2
5.A clinically significant ECG abnormality, including a marked prolonged QTc interval (e.g. a repeated demonstration of a QTc 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 of randomisation)
6.Arterial/venous thromboembolism in the previous 6 months
7.Radiographic evidence of intratumoural cavitation, encasement, or invasion of a major blood vessel, or proximity to major blood vessels with potential risk of severe haemorrhage associated with tumour shrinkage/necrosis after regorafenib therapy
8.Gastrointestinal malabsorption or any other condition that in the opinion of the investigator might affect the absorption of regorafenib
9.Major surgical procedure or significant traumatic injury within 4 weeks prior to randomisation
10.Urinary outflow obstruction that cannot be relieved prior to starting treatment
11.Uncontrolled significant inter-current illness or active infection
12.Any anticoagulant therapy
13.Pre-existing medical condition precluding treatment
14.Known contraindication or hypersensitivity to any of the treatments or excipients
15.Active inflammation of the urinary bladder (cystitis)
16.Pregnant or breastfeeding women
Radiotherapy Randomisations B1 and B2
1.Previous radiotherapy to the same site
2.Pregnant or breastfeeding women
3.BuMel high dose chemotherapy within previous 10 weeks
Randomisation B1 Definitive radical radiotherapy dose finding randomisation
1.Patients who have had a R1 or R0 surgical resection of their tumour
2.Previous high dose chemotherapy including busulfan when specified dose constraints to critical organs cannot be met
Randomisation B2 Post-operative radiotherapy dose finding randomisation
1.R2 resection (macroscopic residual tumour)
2.Patients with a primary tumour of the limb that has been treated by surgery with wide resection (R0 and all tissues involved by the pre-chemotherapy tumour volume have been completely resected) and have good histological response (< 10% viable cells) and small tumour volume (< 200 mls at diagnosis)
Randomisation C Maintenance chemotherapy randomisation
1. Urinary outflow obstruction that cannot be relieved prior to starting treatment
2. Uncontrolled significant inter-current illness or active infection
3. Active inflammation of the urinary bladder (cystitis)
4. Known contraindication or hypersensitivity to any of the treatments or excipients
5. Pregnant or breastfeeding women
2age old over
No limit
Both
Ewing sarcoma
a randomized controlled trial to evaluates induction chemotherapy with VDC/IE plus regorafenib, escalation of radiotherapy dose for curative treatment, optimization of postoperative radiotherapy following surgery, and the addition of maintenance therapy with vinorelbine plus cyclophosphamide after completion of intensive therapy.
A: Induction chemotherapy: OS, Toxicity, QoL, Histological response (if surgery is
performed)
B1: Radiotherapy LFFS, OS, Toxicity, Achievement of local control, Acute
post-radiotherapy toxicity, Late toxicity, QoL
B2: Radiotherapy LFFS, OS, Toxicity, Achievement of local control, Acute
post-radiotherapy toxicity, Late toxicity, QoL
C: Maintenance therapy OS, Toxicity, QoL
Japan Agency for Medical Research and Development
National Cancer Center Hospital Certified Review Board
5-1-1 Tsukiji, Chuo-ku, Tokyo
+81-3-3542-2511
ncch-irb@ml.res.ncc.go.jp
Approval
Sept. 15, 2025
United Kingdom/France/Italy/Netherlands/Spain/Australia/Poland/Norway/Denmark/Ireland/Switzerland/NewZealand
