Paediatrics, Recurrent/refractory Ewing sarcoma Cancer
Conditions
Interventions
Current intervention as of 10/01/2025:
At trial entry, patients will be randomised to one of the available chemotherapy regimens:
1. High dose Ifosfamide (IFOS): 4 cycles of 21 days, additional cycle
Sponsors
University of Birmingham (UK)
Eligibility
Sex/Gender
All
Age
2 Years to 110 Years
Inclusion criteria
Inclusion criteria: Current participant inclusion criteria (since 03-May-2023) as of 10/01/2025: 1. Histologically confirmed Ewing or Ewing-like sarcoma of the bone or soft tissues. Histological confirmation either at initial diagnosis or disease progression. 2. Radiological evidence of disease progression during or after completion of the first or any subsequent line of treatment. 3. Age = 2 years*. 4. Eligible for randomisation between at least two open study arms. 5. Adequate renal function is defined as GFR =60 ml/min/1.73m2. If GFR is calculated and is 18 years of age should have BP =150/90 mm Hg at screening. 3. Urine dipstick <2+ for proteinuria. If =2+ proteinuria on dipstick, a spot urine protein:creatinine ratio test must be < CTCAE grade 2 Proteinuria. Previous participant inclusion criteria as of 14/12/2018: 1. Histologically confirmed ES. 2. Disease progression (during or after completion of first line treatment) or any subsequent recurrence OR Refractory disease, defined by progression during first line treatment or within 12 weeks of its completion. Disease progression will be based on RECIST criteria. The appearance of new bone lesions on bone scan will require confirmation with cross-sectional imaging. 3. Soft tissue disease component evaluable by cross-sectional imaging (RECIST). Patients with bone disease without a measurable soft tissue component or bone marrow disease only will be eligible for the study but will not contribute to the phase II primary outcome measure. 4. Age =4 years and <50 years. 5. Patient assessed as medically fit to receive cytotoxic chemotherapy. 6. Documented negative pregnancy test for female patients of childbearing potential. 7. Patient agrees to use effective contraception during therapy and for 12 months after last trial treatment, where applicable. 8. Written informed consent from the patient and/or parent/legal guardian. Previous participant inclusion criteria: 1. Histologically confirmed Ewing sarcoma 2. Disease recurrence after completion of first-line treatment 3. Refractory disease, defined by progression during first-line treatment or within 12 weeks of its completion 4. Soft tis
Exclusion criteria
Exclusion criteria: Current participant exclusion criteria (since 03-May-2023) as of 10/01/2025: 1. Absolute Neutrophil Count (ANC) 480 msec). 2. History of aneurysm 3. Arterial Thromboembolism in previous 6 months 4. Gastrointestinal or non-gastrointestinal fistula. 5. Gastrointestinal bleeding or active haemoptysis within the previous 3 weeks 6. Major surgery within the previous 3 weeks 7. Previous treatment with tyrosine kinase inhibitors 8. Radiographic evidence of intratumoral cavitation, encasement, or invasion of a major blood vessel, or proximity to major blood vessels with the potential risk of severe haemorrhage associated with tumor shrinkage/necrosis after lenvatinib therapy. Previous participant exclusion criteria as of 14/12/2018: 1. Bone marrow infiltration resulting in Absolute Neutrophil Count (ANC) <1.0 x 109/L or platelets <75 x 109/L. 2. Cytotoxic chemotherapy or other investigational medicinal product (IMP) within previous two weeks. 3. Myeloablative therapy within previous eight weeks. 4. Radiotherapy to target lesion within previous six weeks. 5. Pregnant or breastfeeding women. 6. Follow-up not possible due to social, geographic or psychological reasons. 7. Previous randomisation into the rEECur trial Additional criteria for specific arms: 1. Patients with a contraindication to any IMP may be entered into the study but may not be randomised to receive an arm that contains a contraindicated IMP. They will be eligible for trial entry as long as they can be randomised between a minimum of two study arms. 2. Patients who are unable to receive one or more IMPs due to local or national funding arrangements will be eligible for trial entry as long as they can be randomised between a minimum of two study arms. 3. Patients and investigators may decline randomisation to one or more trial regimens but will be eligible for trial entry as long as they can be randomised between a minimum of two study arms. 4. Patients who have previously received one of the trial regimens off-trial may not be randomised to receive that chemotherapy regimen again. However, patients who have received cyclophosphamide during first line therapy may be
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Current primary outcome measure as of 10/01/2025: Event-free survival time (EFS) Previous primary outcome measure: Phase II: Objective Response Rate (ORR) will be measured by cross-sectional imaging according to RECIST criteria Phase III: Progression-Free Survival (PFS) is defined as the time from randomisation until the first event (progression, recurrence following response or death without progression or recurrence). Second malignancy is not classified as an event for progression-free survival. For those patients who do not experience events during the trial, progression-free survival times will be censored at the date of their last available trial assessment. | — |
Secondary
| Measure | Time frame |
|---|---|
| Current secondary outcome measure as of 10/01/2025: 1. Objective imaging response (OR) according to RECIST 1.1 criteria after 2 and 4 cycles of IFOS and IFOS-L, and at the end of trial treatment for all arms 2. Progression-free survival time (PFS) 3. Overall survival time (OS) 4. Toxicity, defined by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v4.0 5. PET-CT response after 4 cycles (this sub-study is now closed and being analysed) 6. Quality of life (QoL) 7. Days spent in hospital Previous secondary outcome measure: 1. Overall Survival (OS) is defined as the time from randomisation to death, irrespective of the cause. Surviving patients will be censored at their last follow-up date. OS will only be analysed for the first randomisation for each patient (re-randomisations will not be considered). Analysis methods will be as per PFS. 2. Adverse events and toxicity: Safety data will be summarised by arm for all treated patients using appropriate tabulations and descriptive statistics. Exploratory standard statistical tests will be performed to compare the arms. 3. Quality of Life (QoL) will be assessed at the following time points: baseline, following chemotherapy cycle 2, following chemotherapy cycle 4 using =18 years: EORTC QLQ-C30, <18 years: PedsQL™ Generic Core Scales and Multidimensional Fatigue Score 4. Days spent in hthe ospital while on trial treatment or due to trial treatment. The number (range) and proportion (with confidence intervals) of days in hospital will be presented for each arm and overall. Exploratory standard statistical tests will be performed to compare the arms. | — |
Countries
Australia, Belgium, Czech Republic, Denmark, England, Finland, France, Germany, Hungary, Italy, Netherlands, New Zealand, Northern Ireland, Norway, Poland, Scotland, Spain, Sweden, Switzerland, United Kingdom, Wales
Outcome results
None listed