iEuroEwing

Standard-arm (local disease)

iEuroEwing-SR part: The main goal is to conduct a randomised trial part. This will examine, whether the addition of a maintenance treatment using VinoCyc to nine cycles of VDC/IE improves EFS in patients with primary localised disease.
iEuroEwing-SR RT-part:
The main goal is to show in a randomised setting, that a higher Radiotherapy dose is not inferior regarding an acute skin toxicity CTCAE grade ≥3 under radiotherapy. A further goal is to investigate, whether a higher dose of radiation improves event-free survival since randomisation 1.

Highrisk-arm (metastatic disease)

• iEuroEwing-HR part: The main goal is to conduct a randomised trial part. This will examine, whether the addition of a maintenance treatment using VinoCyc to nine cycles of VDC/IE improves EFS in patients with primary disseminated disease.

Standard SR arm A:
Chemotherapy: The standard SR arm A consists of nine cycles of alternating VDC and IE induction, before local control and five cycles of alternating IE and VC. For patients randomised in the standard SR arm A, treatment ends with the completion of consolidation therapy.
Radiotherapy: Je nach individueller Risikoeinschätzung werden die zu einer Randomisierung zugelassenen Patienten in vier Gruppen eingeteilt (Adjuvant low risk; Adjuvant high risk; Definitiv low risk; Definitiv high risk) und innerhalb dieser Gruppe in den Standard-Arm A (A1 45 Gy, A2 50.4 Gy,A3 54 Gy and A4 59.4 Gy) oder den Experimentellen Arm-B (B1 54 Gy, B2 59.4 Gy, B3 63 Gy and B4 68.4 Gy) randomisiert.
Standard SR Arm B:
Chemotherapy:Similar to the standard SR arm A, the experimental SR arm B consists of nine cycles of alternating VDC and IE induction, before local control and five cycles of alternating IE and VC. In contrast to the standard SR arm A, patients in the experimental SR arm B receive additional maintenance therapy with VinoCyc.
Radiotherapy: Patients will be treated as decribed in the iEuroEwing-SR part. Eligible patients will undergo a randomisation for the local radiotherapy between lower radiotherapy dose in the arms A1 45 Gy, A2 50.4 Gy, A3 54 Gy and A4 59.4 Gy and the higher radiotherapy dose in the arms B1 54 Gy, B2 59.4 Gy, B3 63 Gy and B4 68.4 Gy, to the primary tumour site and/or residual tumour.

Highrisk arm-A
Chemotherapy:The standard HR arm A consists of nine cycles of alternating VDC and IE induction, before local control and five cycles of alternating IE and VC. For patients randomised in the standard HR arm A, treatment ends with the completion of consolidation therapy.
Highrisk arm-B
Chemotherapy:Similar to the standard HR arm A, the experimental HR arm B consists of nine cycles of alternating VDC and IE induction, before local control and five cycles of alternating IE and VC. In contrast to the standard HR arm A, patients in the experimental HR arm B receive additional maintenance therapy with VinoCyc.

According to the results of the EURO-E.W.I.N.G 99 and Ewing 2008 R2loctrials, a subgroup of patients with poor histological response to induction chemotherapy may be referred to a high-dose treatment with busulfan and melphalan (BuMel), with an autologous stem cell transplantation.

• Histologically (and molecularly) diagnosed primary localised (SR) or metastatic (HR) Ewing sarcoma or so called Ewing-like sarcoma ( i.e. translocation-positive small blue round cell sarcoma other than Rhabdomyosarcoma) of bone and / or soft tissue; pathological diagnosis can be performed at the investigational site
• Any sex, age over 2 and under 50 years by the date of diagnostic biopsy (Patients outside this age range may be included in the iEuroEWING registry, contact: iEuroEwing@uk-essen.de)
• Informed consent must be obtained according to national and GCP guidelines and signed prior to trial entry. Subjects and when applicable parental or legal representative(s) must understand and voluntarily provide permission to the ICF, prior to conducting any trial-related assessments / procedures. Willingness and ability to comply with
• scheduled visits and trial procedures are required.
• White blood cell (WBC) count over 2000/μl*
• Assessment of cardiac function including LVEF over 40 % and SF over 28 %*
• Serum creatinine under 1.5 X ULN*
• For patients of childbearing potential, a negative pregnancy test must be documented prior to enrolment and repeated every month during therapy. Female and male patients, who are fertile and sexually active, must agree to use an effective form of contraception from the time of signing the ICF until 6 months after the end of treatment.
• • *Parameters must be checked within the screening phase of 45 days

• Treatment of more than one cycle of chemotherapy prior to registration in the SR group
• Concurrent treatment within any other clinical trials, excluding trials with different endpoints, which, due to the nature of their endpoints, must run parallel to iEuroEwing trial, e.g. studies on antiemetics, antimycotics,
• antibiotics, strategies for psychosocial support, etc.
• Clinically significant and uncontrolled, or active cardiac disease
• Evidence of invasive fungal infection or other severe systemic infection requiring systemic / parenteral therapy
• Hypersensitivity to the active substance or other excipients contained in the investigational medical products listed in the summary of product characteristics (SmPC) or investigators brochure (IB).
• Secondary malignancy
• Pregnancy or lactation
• Female and male subjects with child-bearing potential, who avoid using highly effective contraceptive methods
• Any other medical, psychiatric or social condition which is incompatible with the protocol treatment
• Contraindications according to the respective applicable SmPCs
• Patients who receive preoperative RTX
• Patients who receive Brachytherapy
• Patients who have been diagnosed with pleural effusion
• Patients with previous RT in the same region