Internationale, randomisierte klinische Studie für Patienten mit rezidiviertem oder nicht auf die Standardbehandlung ansprechendem Ewing-Sarkom

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 cycles at clinician's discretion.
2. High dose Ifosfamide and Lenvatinib (IFOS-L): 4 cycles of 21 days, additional IFOS cycles at clinician?s discretion. Lenvatinib capsules are taken once daily continuously throughout and for up to 2 years in total.

Local disease control measures are encouraged where possible. However, these should be delayed if possible until the completion of protocol-defined treatment (4 cycles of IFOS) or completion of 4 IFOS cycles for patients on IFOS-L.

Stem cell harvesting may be carried out in patients for whom high-dose therapy is planned. However, if an alternative chemotherapy regimen is planned for stem cell mobilisation, it should be delayed if possible until completion of protocol-defined treatment, (i.e after completion of IFOS-L or, 6 cycles of
CE or, 4 cycles of IFOS) or as a minimum must be delayed until after the response assessment following cycle 4. Patients who continue to receive Lenvatinib (see section 7.2.3.5) should not receive chemotherapy other than ifosfamide at the protocol-defined dose. If these are planned, lenvatinib must be permanently discontinued prior to treatment.

Myeloablative therapy may be given at the discretion of the treating physician after 6 cycles of CE or after 4 cycles of IFOS. High-dose therapy may not be given simultaneously with lenvatinib. If high-dose therapy is planned, lenvatinib must be permanently discontinued beforehand.





Previous intervention:
At trial entry patients will be randomised to one of four chemotherapy regimens:
1. Topotecan and cyclophosphamide (TC): 6 cycles. Additional cycles may

Gender: Both
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 <90 ml/min/1.73m2, an isotopic GFR should be performed to confirm adequate renal function.
6. Patient assessed as medically fit to receive trial treatment
7. Date of planned randomisation within 4 weeks of baseline imaging.
8. Documented negative pregnancy test for female patients of childbearing potential.
9. Patient agrees to use effective contraception during therapy and for 12 months after the last trial treatment, where applicable.
10. Written informed consent from the patient and/or parent/legal guardian.
* Trial sites in Austria will only recruit patients aged =2 years<30 years due to the conditional approval issued by their ethics committee.

Additional criteria for the CE arm (This treatment arm has been closed to recruitment since 15-Aug-2024. Therefore, this criterion no longer applies):
Carboplatin is contraindicated in patients with actively bleeding tumours. Therefore, patients with actively bleeding tumours are not eligible for CE randomisation.

Additional criteria for the IFOS-L arm:
1. Adequate liver function: bilirubin <3 x ULN and ALT or AST < 5 x ULN
2. Left ventricular ejection fraction =50% at baseline as determined by echocardiography.
2. Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as: a. BP <95th percentile for sex, age, and height. Subjects >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: Current participant exclusion criteria (since 03-May-2023) as of 10/01/2025:
1. 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 the previous two weeks.
3. Myeloablative therapy within the previous eight weeks.
4. Radiotherapy to target lesion within the previous six weeks.
5. Pregnant or breastfeeding women.
6. Pre-existing medical condition that would necessitate a dose modification during cycle 1 as described in section 7.
7. Any central neurotoxicity with previous ifosfamide treatment
8. Clinical evidence of nephrotic syndrome
9. Follow-up is not possible due to social, geographic or psychological reasons.
10. Previous randomisation into the rEECur trial
11. Patients with a contraindication or hypersensitivity to any IMP may not be randomised to receive an arm that contains the contraindicated IMP.
12. Patients who have previously received one of the trial regimens off-trial may not be randomised to receive that regimen again. Patients who have had ifosfamide during first-line therapy may receive the IFOS or IFOS-L arm. There is no requirement for a minimum time between receiving first-line ifosfamide and entry to rEECur.

Additional exclusion criteria for the IFOS-L arm:
1. Clinically significant ECG abnormality, including a marked baseline prolonged QT or QTc interval (eg, a repeated demonstration of a QTc interval >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