rEECur: International Randomised Controlled Trial of Chemotherapy for the Treatment of Recurrent and Primary Refractory Ewing Sarcoma

Prior treatment

• Any central neurotoxicity with previous ifosfamide treatment.
• For IFOS/IFOS-L randomisation only: Arterial Thromboembolism in previous 6 months.
• For IFOS/IFOS-L randomisation only: Gastrointestinal bleeding or active haemoptysis within previous 3 weeks.
• For IFOS/IFOS-L randomisation only: Major surgery within previous 3 weeks.
• For IFOS/IFOS-L randomisation only: Previous treatment with tyrosine kinase inhibitors.
• Previous randomisation into the rEECur trial.
• 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.
• Cytotoxic chemotherapy or other investigational medicinal product (IMP) within previous two weeks.
• Radiotherapy to target lesion within previous six weeks.

Other illness

• Pre-existing medical condition that would necessitate a dose modification during cycle 1 as described in section 7 of the protocol.
• For CE randomisation only: Carboplatin is contraindicated in patients with actively bleeding tumours. Therefore, patients with actively bleeding tumours are not eligible for the CE randomisation.
• For IFOS/IFOS-L randomisation only: History of aneurysm.
• For IFOS/IFOS-L randomisation only: Gastrointestinal or non-gastrointestinal fistula.
• Clinical evidence of nephrotic syndrome.
• For IFOS/IFOS-L randomisation only: Radiographic evidence of intratumoral cavitation, encasement, or invasion of a major blood vessel, or proximity to major blood vessels with potential risk of severe haemorrhage associated with tumor shrinkage/necrosis after lenvatinib therapy.
• Patients with a contraindication or hypersensitivity to any IMP may not be randomised to receive an arm that contains the contraindicated IMP.

Lab values

• Absolute Neutrophil Count (ANC) <1.0 x 109/L or platelets <75 x 109/L.
• For IFOS/IFOS-L randomisation only: Clinically significant ECG abnormality, including a marked baseline prolonged QT or QTc interval (eg, a repeated demonstration of a QTc interval >480 msec).

Other

• Follow-up not possible due to social, geographic or psychological reasons.
• Pregnant or breastfeeding women.

• Histologically confirmed Ewing or Ewing-like sarcoma of the bone or soft tissues. Histological confirmation either at initial diagnosis or disease progression.
• Patient agrees to use effective contraception during therapy and for 12 months after last trial treatment, where applicable.
• For IFOS/IFOS-L randomisation only: Adequate liver function: bilirubin <3 x ULN and ALT or AST < 5 x ULN.
• For IFOS/IFOS-L randomisation only: Left ventricular ejection fraction ≥50% at baseline as determined by echocardiography.
• For IFOS/IFOS-L randomisation only: 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.
• For IFOS/IFOS-L randomisation only: Urine dipstick <2+ for proteinuria. If ≥2+ proteinuria on dipstick, a spot urine protein:creatinine ratio test must be < CTCAE grade 2 Proteinuria.
• Written informed consent from the patient and/or parent/legal guardian.
• Radiological evidence of disease progression during or after completion of first or any subsequent line of treatment.
• Age ≥ 2 years (* Trial sites in Austria will only recruit patients aged ≥2 years<30 years due to the conditional approval issued by their ethics committee).
• Eligible for randomisation between at least two open study arms.
• Adequate renal function 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.
• Patient assessed as medically fit to receive trial treatment.
• Date of planned randomisation within 4 weeks of baseline imaging.
• Documented negative pregnancy test for female patients of childbearing potential.