Ewing sarcoma
Conditions
Interventions
a randomized controlled trial to evaluates induction chemotherapy with VDC/IE plus regorafenib, escalation of radiotherapy dose for curative treatment, optimization of postoperative radiotherapy follo
Sponsors
Arakawa Ayumu
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 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=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
Exclusion criteria
Exclusion criteria: 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) 1.5xULN 4.Inadequate renal function defined as GFR 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| A: Induction chemotherapy EFS, B1: Radiotherapy EFS B2: Radiotherapy EFS C: Maintenance therapy EFS | — |
Secondary
| Measure | Time frame |
|---|---|
| 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 | — |
Countries
Australia, Denmark, France, Ireland, Italy, Japan, Netherlands, NewZealand, Norway, Poland, Spain, Switzerland, United Kingdom
Contacts
Public ContactAyumu Arakawa
National Cancer Center Hospital
Outcome results
None listed