International clinical research programme to improve outcomes in newly diagnosed Ewing sarcoma – Trial 1

Study Entry: INTER-EWING-1 includes a study entry point where all patients with Ewing sarcoma (ES) may give consent for the analysis of their biological samples and/or undergo additional scans, alongside the collection of very basic patient characteristics, a treatment summary, and follow-up data for events. Treatment questions Patients may be entered into more than one treatment question following study entry. Separate consent is required for study entry and for each trial question. Newly diagnosed patients should, where possible, be entered into the INTER-EWING-1 study at the time of initial diagnosis prior to receiving any chemotherapy. However, patients may enter the study at any point of the treatment pathway as long as they are eligible. Screening assessments A histologically confirmed diagnosis of ES is required for Study Entry. The majority of screening assessments for subsequent randomisations are standard of care, and will include blood tests, urine tests, physical exam, and scans (e.g. CT, MRI, PET-CT). Induction chemotherapy for newly diagnosed patients (Randomisation A): This section will be updated after the recommended phase II dose has been established from the externally sponsored phase Ib study (ClinicalTrials.gov Identifier: NCT05830084, EudraCT No: 2022-002874-10). Patients will be randomised to receive either Vincristine - Doxorubicin - Cyclophosphamide / Ifosfamide - Etoposide (VDC/IE) without regorafenib or VDC/IE with regorafenib. Randomisation B: Where a patient is deemed suitable for radiotherapy and is eligible, radiotherapy randomisation should be considered. Radiotherapy may be definitive, pre-operative or post-operative, and is given concurrently with chemotherapy. Pre-operative and definitive radiotherapy will be delivered after cycle 9 of chemotherapy. Radiotherapy for newly diagnosed disease: This trial also contains radiotherapy randomisations for patients with newly diagnosed ES. For patients with non-resectable disease (disease that cannot be removed by surgery) there is the B1 randomisation, in which the patient will be randomised to receive either: - a standard dose 54Gy, this will usually be given in 30 sessions over 6 weeks, with 1.8 Gy of radiotherapy being given each time they go. - A higher dose of radiotherapy 64.8Gy, this will usually be given in 36 sessions over 7.2 weeks, with 1.8 Gy of radiotherapy being given each time they go. Sometimes, the higher dose (64.8 Gy) can be given in 30 sessions over 6 weeks. The treating physician will advise if the higher dose will be given over 30 or 36 sessions. For patients with resectable disease there is the B2 randomisation in which patients will be randomly assigned to either: - a standard dose of 54Gy, this will usually be given in 30 sessions over 6 weeks - A lower dose of radiotherapy 45Gy, this will usually be given in 25 sessions over 5 weeks. All sites and patients participating in the radiotherapy questions will participate in the Radiotherapy Quality Assurance programme, facilitated via the SIOPE QUARTET (Quality and Excellence in Radiotherapy and Imaging for Children and Adolescents with Cancer across Europe in Clinical Trials) initiative. All sites will be required to be approved for radiotherapy delivery via QUARTET, and radiotherapy plans for each individual patient will be uploaded to the online system for approval. There will also be a retrospective Quality Control review of all scans and cross-sectional imaging received as part of the radiotherapy QA review process. Maintenance Chemotherapy (Randomisation C): For the majority of patients the treatment of ES includes intensive chemotherapy and either surgery, radiotherapy or a combination of the two. Currently, once this initial treatment phase finishes, no further treatment is given. However, several other childhood cancers may give patients additional chemotherapy – this is called maintenance chemotherapy. The aim of maintenance chemotherapy is to stop the cancer from returning or to get rid of any traces of cancer that are left over from previous treatment. Eligible patients can be consented and randomised within 8 weeks of commencing the last cycle of consolidation chemotherapy (eligible chemotherapy regimens: VDC/IE/VC/VAI/BuMel). In this part of the INTER-EWING-1 trial, patients will either stop treatment or receive 6 cycles of maintenance chemotherapy. The chemotherapy for this randomisation is vinorelbine and cyclosphosphamide (VnC) and the cycles are each 28 days. Vinorelbine can be given in either an intravenous or oral tablet format. Cyclophosphamide will be given as an oral tablet (oral liquid can be given where licensed formulation is available). Adherence to the intervention treatment will be monitored via the completion of a patient drug diary. Imaging sub-studies: Patients who have a Diffusion Weighted MRI scan at diagnosis may be offered further scans after 3 and then 9 cycles of induction chemotherapy to see whether these additional scans can indicate how well treatment will work in the long term. The study will also investigate whether whole body-MRI scans are better than FDG-PET scans at measuring how widespread disease is before treatment. Where these scans do not form part of standard care, patients will be asked for consent to have a whole body-MRI scan at diagnosis for research purposes. This study will also encourage an FDG PET-CT or FDG PET-MRI scan after 3 and then 9 courses of induction chemotherapy to determine prospectively its prognostic value. Should this not be standard of care, the patient will be asked to consent to these optional sub-studies. QoL sub-study: All Patients that have enrolled in Study Entry, Randomisation B and Randomisation C arms will be asked to complete Quality of Life questionnaires. Follow-up: Following completion of treatment, the frequency of follow-up assessments should be as per local practice.